Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH3:18][C:19]1([CH3:27])[O:23][C@:22]([CH2:25]O)([CH3:24])[CH2:21][O:20]1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:24][C@@:22]1([CH3:25])[CH2:21][O:20][C:19]([CH3:27])([CH3:18])[O:23]1)=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC1(C)OC[C@](C)(CO)O1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@@]3(C)COC(C)(C)O3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 32.2 g, 0.14 mol) and ((4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl)methan-1-ol (15 g, 0.113 mol) in anhydrous dichloromethane (750 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (EDAC) (23 g, 0.12 mol) and N,N-dimethylaminopyridine (DMAP, 7.5 g, 61 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, then quenched with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and solvent was evaporated under reduced pressure. The product was purified by column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give the title compound (37.5 g, 96.5% yield) as a white solid, mp 65–66° C. 1H NMR (CDCl3) δ 7.75 (d, J=8.7 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.46 (dd, J=8.4 and 1.7 Hz, 1H), 7.15 (m, 2H), 4.27 (m, 1H), 4.19 (m, 2H), 4.03–3.92 (m, 2H), 3.96 (s, H), 3.69 (dd, J=8.4 and 6.0 Hz, 1H), 1.64 (d, J=7.1 Hz, 3H), 1.40 (s, 3H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 135.3, 133.7, 129.2, 128.8, 127.1, 126.1, 125.9, 119.0, 109.7, 105.5, 73.4, 66.2, 64.8, 55.2, 45.2, 26.5, 25.3, 18.4; LRMS (APIMS) m/z 362 (M+NH4)+.
Reaction SMILES: [N:1]1C=CC=CC=1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:9]>ClCCl>[C:8](=[O:9])([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[NH2:1]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccncc1
Solvent: ClCCl
Product: NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred, cooled (about 0° C.) solution of methyl-3-amino-4-methoxy benzoate (5.0 g; 27.6 mmol) in dry dichloromethane (175 mL) was added pyridine (2.34 mL; 29 mmol) followed by 4-nitrophenyl chloroformate (5.8 9; 29 mmol) under a nitrogen (N2) atmosphere. After stirring for 8 hours, the, reaction was washed with 2N aqueous hydrochloric acid (2×200 mL), saturated aqueous sodium bicarbonate (2×200 mL), and brine (200 mL), then dried (MgSO4), and filtered. The filtered solution was diluted with ethyl acetate and hexanes (about 800 mL) until a precipitate formed. The solid was collected on a Buchner funnel with suction, and air dried to provide the desired carbamate as a white solid (70% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:50])[CH2:10][C:11]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1>C(Cl)Cl>[F:49][C:47]1[CH:46]=[CH:45][C:12]([CH2:13][CH2:14][C:15]2[C:20]([C:21]([F:23])([F:24])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[N:16]=2)=[C:11]([CH2:10][C:9]([NH2:8])=[O:50])[CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1cc(F)ccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
TFA (0.825 mL, 10.8 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-4-fluorophenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A37) (0.162 g, 0.269 mmol) in DCM (20 mL) under nitrogen and the resulting solution stirred for 24 hours at room temperature. The volatiles were removed in vacuo and the residue was taken up in MeOH and loaded onto an SCX cartridge (10 g). The column was eluted with 5 column volumes of MeOH and then 6 column volumes of 5% v/v aqueous ammonia in MeOH. The volatiles from the ammoniacal eluent were evaporated under reduced pressure to give the title compound 9 as a yellow solid (0.117 g, 87%); 1H NMR (400 MHz, d6-DMSO) δ 10.12 (s, 1H), 8.65 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.48 (s, 1H), 7.23-7.13 (m, 3H), 7.08 (dd, J=10.2, 2.8 Hz, 1H), 7.04-6.95 (m, 2H), 3.50 (s, 2H), 3.14-2.95 (m, 6H), 2.63-2.52 (m, 3H), 1.67 (d, J=10.8 Hz, 2H), 1.49 (qd, J=12.4, 3.9 Hz, 2H). LCMS-A: rt 4.853 min; m/z 502 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]1([NH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCNc1ccccc1
Reactant: Cc1ccc(CC(=O)Cl)cc1
Product: CCOC(=O)CCN(C(=O)Cc1ccc(C)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.115.1, starting from 4-methylphenylacetyl chloride and ethyl N-phenyl-3-aminopropionate, ethyl 3-[2-(4-methylphenyl)-N-phenylacetamido]propanoate was obtained as yellowish oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][N:8]1[C:13]2=[CH:14][NH:15][C:16]([C:17]3[S:18][CH:19]=[C:20]([CH3:22])[N:21]=3)=[C:12]2[C:11](=[O:23])[N:10]([CH3:24])[C:9]1=[O:25].Br[CH2:27][CH:28]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40]>CN(C)C(=O)C.O>[Si:42]([O:41][CH:28]([CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40])[CH2:27][N:15]1[C:16]([C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[C:12]2[C:13]([N:8]([CH3:7])[C:9](=[O:25])[N:10]([CH3:24])[C:11]2=[O:23])=[CH:14]1)([C:45]([CH3:48])([CH3:46])[CH3:47])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)OC(CBr)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1csc(-c2[nH]cc3c2c(=O)n(C)c(=O)n3C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2CC(CN2C(=O)c3ccccc3C2=O)O[Si](C)(C)C(C)(C)C)n1
Temperature: 50 °C

Procedure:
Cesium carbonate (115 mg, 0.351 mmol) was added to a solution of 1,3-dimethyl-5-(4-methylthiazol-2-yl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Intermediate Gc) (53.4 mg, 0.176 mmol) and 2-(3-bromo-2-((tert-butyldimethylsilyl)oxy)propyl)isoindoline-1,3-dione (70 mg, 0.176 mmol) in N,N-dimethylacetamide (1273 μl). The mixture was heated at 50° C. for 18 hours, then cooled to room temperature and diluted with water (30 ml). The mixture was extracted with ethyl acetate (3×30 ml), the combined organic extracts were washed with brine (90 ml), dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][CH2:13][C@@H:14]1[O:32][CH2:31][C@:17]2([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[F:40])[N:18]=[C:19]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:20][CH2:21][C@@H:16]2[CH2:15]1)C1C=CC=CC=1.CO>ClCCl>[F:40][C:34]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[C@:17]12[CH2:31][O:32][C@@H:14]([CH2:13][OH:12])[CH2:15][C@H:16]1[CH2:21][S:20][C:19]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[N:18]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Boron trichloride (1 M solution in heptane, 89.7 mL, 89.7 mmol) was added to a 0° C. solution of C8 (15.20 g, 29.89 mmol) in dichloromethane (150 mL). After 15 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. Methanol (50 mL) was then added, first drop-wise {Caution: violent reaction} and then at a steady rate, while the interior of the flask was flushed with nitrogen gas. The mixture was heated at reflux for 30 minutes, cooled to room temperature and concentrated in vacuo. The residue was again dissolved in methanol, stirred, and concentrated in vacuo. The resulting material was taken up in dichloromethane and washed sequentially with 1 M aqueous sodium hydroxide solution, water, and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Chromatographic purification on silica gel (Gradient: 0% to 3% methanol in ethyl acetate) provided the product as a yellow foam. Yield: 11.97 g, 28.60 mmol, 96%. LCMS m/z 419.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=7.4 Hz, 2H), 7.50-7.56 (m, 1H), 7.41-7.49 (m, 3H), 7.02-7.11 (m, 2H), 4.13 (dd, J=11.9, 1.8 Hz, 1H), 3.90 (d, J=12.1 Hz, 1H), 3.72-3.80 (m, 1H), 3.59 (d, J=5.1 Hz, 2H), 3.14-3.24 (br m, 1H), 2.96 (dd, half of ABX pattern, J=13.1, 4.1 Hz, 1H), 2.75 (dd, half of ABX pattern, J=13.1, 2.7 Hz, 1H), 1.80-1.92 (m, 1H), 1.70 (ddd, J=13.4, 4.2, 2.4 Hz, 1H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:25][CH2:26]1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)n(C)n1
Reactant: NC1CCOCC1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 95 %

Procedure:
As described for example 86, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (60 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (70 mg, 95%) which was obtained as a colorless oil. MS: m/e=377.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1>Br>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])[N:15]=2)[CH:17]=1
Reactant: COc1ccccc1Nc1nccc(-c2cccnc2)n1
Agent: Br
Product: Oc1ccccc1Nc1nccc(-c2cccnc2)n1
Reaction time: 8 h
Yield: 10.5 %

Procedure:
A mixture of 35 g of N-(2-methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine in 200 ml of 47% aqueous hydrobromic acid was refluxed for 7 hours and then evaporated. The residue was mixed with saturated aqueous potassium bicarbonate and allowed to stand overnight, then filtered. The filtrate was concentrated, giving 3.5 g of the desired compound, mp 166°-169° C.
Reaction SMILES: B.CSC.[CH3:5][CH:6]([NH:13][C:14](=O)[CH3:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C1COCC1>[CH2:14]([NH:13][CH:6]([CH3:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:15]
Reactant: CCCCCCC(C)NC(C)=O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCCCCCC(C)NCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A 2M THF solution of borane-dimethylsulfide (31.5 mL, 63 mmol) was added dropwise to an ice water-cooled solution of N-(1-methylhept-1-yl)acetamide (5.13 g, 30 mmol) in THF (60 mL). The resulting solution was stirred at RT for 1 h, then was refluxed overnight. With ice-water cooling, the excess borane-dimethylsulfide was quenched by the dropwise addition of methanol (10 mL), and the mixture was allowed to stand at RT overnight. The amine hydrochloride could not be precipitated with the addition of HCl gas, so the amine hydrochloride was extracted into dilute HCl. The acidic aq solution was extracted with ether, then made basic and extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4) and concentrated to afford 3.70 g of impure N-ethyl-N-(1-methylhept-1-yl)amine as an amber oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH:4]([NH:3][S:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:38])=[O:37])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-(4-fluorophenyl)acetate dihydrochloride (I82) (325 mg, 0.92 mmol) in DCM (10 ml), were added triethylamine (386 μl, 2.78 mmol) and benzenesulfonyl chloride (142 μl, 1.11 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with 1M Na2CO3, water and then brine, dried over Na2SO4 and evaporated to dryness to obtain (R)-quinuclidin-3-yl 2-(4-fluorophenyl)-2-(phenylsulfonamido)acetate (150 mg; 39% yield).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:38]([NH:45][C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCc4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and benzylamine, m.p. m.p. 170-174° C. MS [(+)ESI, m/z]: 542 [M+H]+ Anal. Calcd for C35H31N3O3: C, 77.61; H, 5.77; N, 7.76. Found: C, 77.51; H, 5.74; N, 7.58.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].O>C1(C)C=CC=CC=1>[C:16]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]3[CH:11]([C:12](=[O:15])[NH:13][N:14]=2)[CH2:10]3)=[CH:6][CH:7]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 45 %

Procedure:
Using a method similar to Example 11, 6.0 g (29.8 millimoles) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 8a) are reacted with 4.05 g (44.7 millimoles) of acryloyl chloride in toluene. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from a dimethylformamide/water mixture. 3.5 g (45% of theory) of 2-(p-acryloylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one, hydrated with one mole of water per four moles of compound, are isolated as almost colorless crystals of melting point 240°-241° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1)=[O:9]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1ccsc1C(=O)O
Solvent: O=S(Cl)Cl
Product: Cc1ccsc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 95.1 %

Procedure:
3-Methyl-2-thiophenecarboxylic acid (28 mg, 0.2 mmol) was treated with thionyl chloride in the same manner as that of Example 13, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (42 mg, yield 95%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[OH:8])[CH:2]=1.O1C[CH2:20][CH2:19][CH2:18]1.[H-].[Na+].C(Br)C=C>O>[CH2:20]([O:8][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])[CH:19]=[CH2:18]
Reactant: C1CCOC1
Reactant: OC(c1cccnc1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: C=CCOC(c1cccnc1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet was added 3.56 gm of the 3-pyridyl-2,4-dichlorophenylcarbinol and 60 ml of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.37 gm sodium hydride added. The system was stirred for 75 additional minutes and 1.45 ml of allyl bromide was then added. The system was allowed to come to room temperature over 1/2-hour and stirred there for an additional 1 hour. Afterwards the system was heated at reflux for 18 hours. At this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride was then washed with water and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 1.73 gm of the 3-pyridyl-2,4-dichlorophenylcarbinol allylether and listed as compound number 3 in Table I.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=[O:15])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C([O-])=O.[Na+]>O>[CH:14]1[C:8]2[C:7](=[O:15])[NH:6][C:5]3[CH:16]=[CH:17][CH:2]=[CH:3][C:4]=3[NH:10][C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1Nc2ccc(Cl)cc2Nc2ccccc21
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ccccc2Nc2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A suspension of title compound 85 (1.75 g, 7.15 mmol) in a solution of sodium formate (2.43 g, 35.8 mmol) in water (32 mL) was stirred at 50° C. for 8 hours and then at room temperature. The reaction mixture was filtered and the resulting solid was dissolved in THF (20 mL), diluted with ethyl acetate (200 mL) then filtered through Celite® and concentrated. The crude residue was triturated in 30% ethyl acetate in hexanes to afford title compound 86 (1.17 g, 78%) as a yellow solid. LRMS (ESI): (calc) 210.08 (found) 211.2 (MH)+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.84 (s, 1H), 7.84 (s, 1H), 7.67 (dd, J=7.9, 1.7 Hz, 1H), 7.33 (ddd, J=8.1, 7.2, 1.8 Hz, 1H), 7.00-6.86 (m, 6H).
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[NH2:14][C:15](=O)[CH2:16][C@H:17]([C:47](=[O:65])[NH:48][C@H:49]1[CH2:55][CH2:54][S:53][C@H:52]2[CH2:56][CH2:57][CH2:58][C@@H:59]([C:60]([O:62][CH3:63])=[O:61])[N:51]2[C:50]1=[O:64])[CH2:18][CH2:19][C@H:20]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C@H:24]1[CH2:30][CH2:29][S:28][C@H:27]2[CH2:31][CH2:32][CH2:33][C@@H:34]([C:35]([O:37][CH3:38])=[O:36])[N:26]2[C:25]1=[O:39])=[O:22]>C(Cl)Cl>[CH2:40]([C@@H:20]([CH2:19][CH2:18][C@H:17]([CH2:16][C:15]#[N:14])[C:47]([NH:48][C@H:49]1[CH2:55][CH2:54][S:53][C@H:52]2[CH2:56][CH2:57][CH2:58][C@@H:59]([C:60]([O:62][CH3:63])=[O:61])[N:51]2[C:50]1=[O:64])=[O:65])[C:21]([NH:23][C@H:24]1[CH2:30][CH2:29][S:28][C@H:27]2[CH2:31][CH2:32][CH2:33][C@@H:34]([C:35]([O:37][CH3:38])=[O:36])[N:26]2[C:25]1=[O:39])=[O:22])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)CC(N)=O)C(=O)N21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](CC#N)C(=O)N[C@H]3CCS[C@H]4CCC[C@@H](C(=O)OC)N4C3=O)Cc3ccccc3)C(=O)N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
TFAA (15 mg, 0.069 mmol) was slowly added to a 0° C. solution of Example 29 (27 mg, 0.034 mmol) and TEA (12.2 mg, 0.121 mmol) in DCM (0.25 mL). The reaction mixture was then stirred at rt for 1.5 hr. The reaction mixture was concentrated and the residue was partitioned between EtOAc and 10% aqueous Na2CO3. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified by RP prep-HPLC (Method A) to give dimethyl (4S,7S,10aS,4′S,7′S,10a′S)-4,4′-(((2R,5R)-2-benzyl-5-(cyanomethyl)-1,6-dioxo-1,6-hexanediyl)diimino)bis(5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate) (13 mg, 0.018 mmol, 51% yield). Anal. Calcd. for C37H49N5O8S2 m/z 755.7. found: 756.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (1H, d, J=6.6 Hz), 7.30-7.21 (3H, m), 7.20-7.11 (3H, m), 5.44-5.35 (2H, m), 5.18-5.00 (4H, m), 3.72 (3H, s), 3.69 (3H, s), 3.20 (1H, ddd, J=14.0, 10.7, 2.7 Hz), 3.15-3.01 (3H, m), 2.96 (1H, ddd, J=14.4, 7.0, 2.7 Hz), 2.91-2.82 (2H, m), 2.71 (1H, dd, J=13.2, 6.6 Hz), 2.65-2.55 (2H, m), 2.53-2.35 (4H, m), 2.25 (1H, ddd, J=10.7, 6.9, 3.3 Hz), 2.09-1.96 (4H, m), 1.82 (1H, td, J=7.1, 3.8 Hz), 1.78-1.51 (10H, m).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:6]([NH:7][C:8](=[O:35])/[C:9](=[N:23]\[O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:10]2[N:11]=[C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][CH:14]=2)[C:5](=[O:36])[NH:4]1.[CH2:37]([O:44][CH2:45][C@H:46]1[CH2:48][O:47]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:37]([O:44][CH2:45][C@H:46]([OH:47])[CH2:48][NH:1][CH2:2][C@@H:3]1[C@H:6]([NH:7][C:8](=[O:35])/[C:9](=[N:23]\[O:24][C:25]([CH3:34])([CH3:33])[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:10]2[N:11]=[C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][CH:14]=2)[C:5](=[O:36])[NH:4]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN)cs1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNC[C@@H](O)COCc2ccccc2)cs1
Yield: 48 %

Procedure:
Prepared in analogous manner to example 63 step 1, using tert-butyl 2-(((Z)-(2-(((2R,3S)-2-(aminomethyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (200 mg, 0.38 mmol), (R)-2-((benzyloxy)methyl)oxirane (623 mg, 3.8 mmol), DCM (2 mL). The crude residue was purified via silica gel chromatography (MeOH-DCM, 4-10%) to afford the title compound (126 mg, 48%). LCMS: m/z=691.3 (M+1).