Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:6].C([O:27][C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29])C.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:3][C:2]=1[C:33]1[CH:34]=[CH:35][C:30]([C:28]([OH:29])=[O:27])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1Br
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(=O)Nc2ccc(N3CCOCC3)cc2)cc1-c1ccc(C(=O)O)cc1

Procedure:
A mixture of 3-Bromo-4-methoxy-N-(4-morpholin-4-yl-phenyl)-benzamide (788 mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (564 mg) in 2:1 DME:water (15 ml) containing cesium carbonate (1.31 g) and tetrakis(triphenylphosphine)palladium0 (232 mg) was heated to reflux for 18 h.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([CH3:37])[N:31]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:30]2=[O:46]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:25][CH2:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[N:33]=[C:32]([CH3:37])[N:31]([CH:38]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[C:30]3=[O:46])=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(CNC(=O)Cc3ccc(Cl)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a stirred solution of (4-chloro-phenyl)-acetic acid (0.30 g, 1.8 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′ carbonyldiimidazole (0.31 g, 1.9 mmol), and the mixture was stirred for one hour. Then 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.59 g, 1.7 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-acetamide as a white solid (550 mg, 70% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.00 min (98.7%); mp, 229.5-231.5° C.; 1HNMR (DMSO-d6) 2.15-2.21 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 3.50 (s, 2H, ArCH2), 4.37 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.27-7.90 (m, 7H, Ar), 8.67 (t, J=5 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.92, 23.40, 30.63, 41.39, 41.87, 56.53, 120.02, 123.99, 126.57, 128.13, 130.87, 131.09, 134.03, 135.21, 137.97, 145.81, 154.61, 160.38, 169.47, 169.85, 172.61. LCMS MH=453, 455; Anal Calcd For C23H21N4O4Cl: C, 61.00; H, 4.67; N, 12.37; Cl, 7.83. Found: C, 60.88; H, 4.60; N, 12.27; Cl, 7.89.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+].C(O)=O>O.O1CCOCC1>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=CO
Solvent: O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCc1occc1-2
Temperature: 130 °C
Yield: 44.6 %

Procedure:
Methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 4, 0.129 g) was added to a solution of lithium hydroxide monohydrate (0.42 g) in water (2 mL) and dioxane (8 mL), and the mixture was sealed in a microwave vial and heated at 130° C. for 1 hour in the microwave. After cooling, the mixture was acidified with formic acid, and evaporated to dryness. The residue was triturated with 10% methanol in DCM, filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-10%. The product was triturated with ethyl acetate, filtered and dried in vacuo to give 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4H-furo[2,3-c]chromene-6-carboxylic acid (0.056 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([O:11]/[N:12]=[C:13](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)\[C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24][I:25])[CH2:22][S:23][C@H:18]12)=[O:15])([CH3:10])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:69]1([P:75]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>C1C=CC=CC=1.C(OC(C)C)(C)C>[I-:25].[C:1]([O:5][C:6]([C:8]([O:11]/[N:12]=[C:13](/[C:44]1[N:45]=[C:46]([NH:49][C:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[S:47][CH:48]=1)\[C:14]([NH:16][CH:17]1[C:42](=[O:43])[N:19]2[C:20]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:21]([CH2:24][P+:75]([C:76]3[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=3)([C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=3)[C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[CH2:22][S:23][C@H:18]12)=[O:15])([CH3:10])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)OC(C)C
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: [I-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-t-butoxycarbonyl-2-propoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (VII-4', 5.3 g, 5 mmoles) and triphenylphosphine (2.6 g, 10 mmoles) in benzene (100 ml) was stirred at room temperature for 1 hour and diluted with diisopropyl ether. The resulting precipitate was collected by filtration to yield 6.0 g (91%) of the title compound VIII-4'.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O.[CH3:23][N:24]([CH:35]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]1)[C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH2:34])[CH:31]=[CH:30][C:28]=2[N:29]=1>>[ClH:20].[CH3:23][N:24]([CH:35]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]1)[C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH:34][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)=[O:16])[CH:31]=[CH:30][C:28]=2[N:29]=1.[CH3:23][N:24]([CH:35]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36]1)[C:25]1[S:26][C:27]2[CH:33]=[C:32]([NH:34][C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:13][CH:12]=3)=[O:15])[CH:31]=[CH:30][C:28]=2[N:29]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CN1CCC(N(C)c2nc3ccc(N)cc3s2)C1
Reactant: O=C(Cl)C(=O)Cl
Product: CN1CCC(N(C)c2nc3ccc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)cc3s2)C1
Product: Cl

Procedure:
The title compound is prepared by following Method C, using 4′-fluoro-biphenyl-4-carboxylic acid (3.46 g, 16.01 mmol), oxalyl chloride (4.65 mL, 53.36 mmol) and isomer-2 of N*2*-methyl-N*2*-(1-methyl-pyrrolidin-3-yl)-benzothiazole-2,6-diamine (2.80 g, 10.76 mmol) to give 4′-fluoro-biphenyl-4-carboxylic acid {2-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-benzothiazol-6-yl}-amide (2.41 g, 49%). The material is dissolved in THF (100 mL), and 1.0 M HCl in EtOH is added to adjusted the pH to 1. The resulting solid is collected and recrystallized from EtOH/Heptane to give 2.03 g (78%). LC/MS: Retention time=5.06 min; (m/z): calcd for, C26H25FN4OS (M+H)+: 461.6; found: 461.0.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.[O:26]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:36]1[CH:37]=[CH:38][C:33]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:34][CH:35]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)[nH]c3c(N)ncnc32)c1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)c1
Temperature: 37 °C
Yield: 44 %

Procedure:
To a stirred mixture of tert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (5) (600 mg, 1.8 mmol) and 400 mg 4 Å MS in 16 mL dry DMF were added 4-phenoxyphenylboronic acid (1.05 g, 4.9 mmol), Cu(OAc)2 (320 mg, 1.8 mmol) and pyridine (1 mL, 12.7 mmol). The reaction mixture was heated at 37° C. for 5 hrs under an O2 atmosphere. After cooling down to rt, the reaction mixture was filtered through a Celite pad. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with water (100 mL×2) and brine (100 mL×1), dried over Na2SO4, then concentrated to dryness. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in DCM) to give tert-butyl 3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenylcarbamate (6) (404 mg, 45%) as a brown solid. LC-MS (ESI): m/z (M+1) 511.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:16]([NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23].[OH-:25].[K+]>C(Cl)CCl>[CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:24][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([O:25][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:8][CH:9]=2)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NCCCCCCCN
Reactant: [OH-]
Reactant: CCCCCOc1ccc(C(=O)Cl)cc1
Agent: [K+]
Solvent: ClCCCl
Product: CCCCCOc1ccc(C(=O)NCCCCCCCNC(=O)c2ccc(OCCCCC)cc2)cc1

Procedure:
m.p. 155°-156° C., 29.9 g., was prepared as in Example 1 using 50 g. of 4-pentyloxybenzoyl chloride in 200 ml. of ethylene dichloride, 13.0 g. of 1,7-heptanediamine, 250 ml. of 10% aqueous potassium hydroxide solution, 500 ml. of ethylene dichloride and recrystallization from ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[CH3:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[CH:36][N:35]=1>>[F:22][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:19][S:18][C:17]([NH2:20])=[N:16]4)[C:14]=2[CH:13]=[C:12]([C:38]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:33])[CH:39]=2)[N:11]=1)=[CH:3][C:2]([C:29]1[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:7][CH:6]=3
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: OB(O)c1cccnc1F
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Product: Cc1cc(-c2cc3c(c(F)n2)Oc2ccc(-c4cccnc4F)cc2[C@@]32CSC(N)=N2)ccn1

Procedure:
The titled compound was synthesized by steps analogous to those described in method BB12 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (prepared as described in Method BB26 but using 7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-one), 2-fluoropyridin-3-ylboronic acid and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[OH:20]OS([O-])=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:5]2[N:11]=[C:10]([C:12]([OH:20])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2nc(Cl)nc(N3CCOCC3)c2n1

Procedure:
2-Chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carbaldehyde (0.56 g) was reacted with Oxone (1.1 eq) in DMF (10 mL) overnight. The DMF was removed under vacuum and the reaction mixture was brought up into water. The pH was adjusted to 2-3 and product crashed out of solution. The solid was collected by filtration and dried to afford 0.45 g of 2-chloro-4-morpholinopyrido[3,2-d]pyrimidine-6-carboxylic acid as a light yellow solid.
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][C:10]=1[S:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)CC(C)C>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH2:9][CH2:1][CH:2]([CH3:7])[CH3:3])=[O:18])[C:12]2=[CH:11][C:10]=1[S:20][CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1cc2n(c1C(=O)c1ccccc1)CCC2C(=O)O
Agent: Cl
Solvent: CC(C)CCO
Product: CSc1cc2n(c1C(=O)c1ccccc1)CCC2C(=O)OCCC(C)C
Reaction time: 24 h

Procedure:
A solution of 300 mg of 5-benzoyl-6-methylthio-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml of isoamyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the residue purified by chromatography on alumina, to yield isoamyl 5-benzoyl-6-methylthio-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CN.C[CH2:15][N:16](C(C)C)C(C)C>CS(C)=O.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:16][CH3:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Agent: CN
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-1-fluoro-2-nitrobenzene (832 mg, 4.7 mmol) in DMSO (10 mL) is added a 2M solution of methylamine (3.56 mL, 7.1 mmol) in tetrahydrofuran, followed by Hunig's base (1.2 mL, 7.1 mmol). The reaction flask is sealed and heated to 80° C. for 16 h. The reaction is cooled to room temperature and poured over ice water. The resulting solid is isolated by filtration to afford the title compound (713 mg, 81%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.[I:41][CH2:42][CH2:43][CH2:44][CH2:45]I>O1CCCC1>[CH2:9]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH:24]([CH2:45][CH2:44][CH2:43][CH2:42][I:41])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCCN1CCN(Cc2ccccc2)CC1
Reactant: ICCCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CCCCI)CCN1CCN(Cc2ccccc2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of lithium diisopropylamide (2 M, 32.0 ml, 6.36 mmol) in tetrahydrofuran (420 ml) was added ethyl 4-(4-benzyl-1-piperazinyl)-butanoate (6.47 g, 21.2 mmol) (Preparation 1) at −78° C. and the mixture was stirred for 1 h at the same temperature. To this mixture was added HMPA (19.4 ml) and the resultant mixture was added to a solution of 1,4-diiodobutane (13.2 g, 4.25 mmol) in tetrahydrofuran (22 ml) at −78° C. After 1 h, the temperature was raised to −50° C. and the mixture was stirred for 1 hour. The reaction was quenched by adding AcOH (0.230 ml). After the mixture was basified with aq. saturated NaHCO3, then the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 200-350 mesh/500 g/hexane:ethyl acetate=2:1) to provide a yellow oil (6.3 g/63%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1

Procedure:
Methyl 4-hydroxyphenylacetate (49.8 g, 0.3 mol) was dissolved in glacial acetic acid (500 ml) and the resultant solution was cooled to below 15° C. Concentrated nitric acid (40 ml) was added slowly and the reaction mixture was sired until completion and then poured onto a mixture of ice and water. The precipitated solid was filtered, washed with ice cold water and dried to give methyl 4-hydroxy-3-nitrophenylacetate (51.2 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11](/[C:13](=[N:17]/[O:18][CH3:19])/[C:14]([OH:16])=O)[N:12]=1)=[O:6])[CH:2]=[CH2:3].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[C:39]([C:43]1[CH2:50][N:49]2[N:45]([C:46](=[O:52])[CH:47]([NH2:51])[CH2:48]2)[C:44]=1[C:53]([O:55][CH2:56][CH:57]=[CH2:58])=[O:54])(=[O:42])[CH2:40][CH3:41]>C(Cl)Cl.C(OCC)(=O)C>[C:39]([C:43]1[CH2:50][N:49]2[N:45]([C:46](=[O:52])[CH:47]([NH:51][C:14](=[O:16])/[C:13](/[C:11]3[N:12]=[C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[S:9][CH:10]=3)=[N:17]\[O:18][CH3:19])[CH2:48]2)[C:44]=1[C:53]([O:55][CH2:56][CH:57]=[CH2:58])=[O:54])(=[O:42])[CH2:40][CH3:41]
Reactant: C=CCOC(=O)C1=C(C(=O)CC)CN2CC(N)C(=O)N12
Reactant: C=CCOC(=O)Nc1nc(/C(=N/OC)C(=O)O)cs1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C=CCOC(=O)Nc1nc(/C(=N/OC)C(=O)NC2CN3CC(C(=O)CC)=C(C(=O)OCC=C)N3C2=O)cs1
Temperature: 0 °C
Yield: 56.8 %

Procedure:
Under a nitrogen atmosphere, 2-[2-(allyloxycarbonylamino)thiazol-4-yl]-2-(Z)-methoxyiminoacetic acid (248 mg, 0.87 mmol) was suspended in methylene chloride (5 ml) and the suspension was cooled to 0° C. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (153 mg, 0.87 mmol) then N-methylmorpholine (0.095 ml, 0.87 mmol) were added and the resultant solution was stirred at 0° C. for 30 minutes. A methylene chloride solution (10 ml) of allyl 3-(propionyl)-7-(R,S)-amino-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate hydrochloride (0.87 mmol) was added followed by the addition of N-methylmorpholine (0.095 ml, 0.87 mmol). The solution was allowed to warm gradually to room temperature over 1.5 hours and then the methylene chloride was removed in vacuo. The resultant residue was flash chromatographed on silica gel eluted with 10% hexane:ethyl acetate to give 270 mg, 57% yield of allyl 3-(propionyl)-7-(R,S)-[2-(2-(allyloxycarbonylamino)thiazol-4 -yl)-2-(Z)-methoxyiminoacetamido]-8-oxo-1,5-diazabicyclo[3.3.0]octa-2-ene-2-carboxylate: n.m.r. (90 MHz, CDCl3): δ 1.11 (t, 3, J=7.2), 2.39-2.79 (m, 2), 3.09 (dd, 1, J=9 and 11.7), 3.95 (s, 3), 3.80-4.24 (m, 3), 4.42 (1/2ABq, 1, J=12.5), 4.60-4.96 (m, 4), 5.16-5.68 (m, 4), 5.72-6.22 (m, 2), 7.09 (s, 1), 8.28 (br.d, 1, J=7.2), 9.55 (br.s, 1); i.r. (CHCl3): 3230, 1733, 1679, 1554, 1423, 1377, 1353, 1044 cm-1 ; u.v. (EtOH): λhd max=208 (ε=21522), 228 (ε=22084), 261 (ε=13612), 365 (ε=8122); f.d.m.s. (m/e): M+ +1=547; m.p. 183°-186° C.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1.C=O.[CH:16]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[C:25](=O)([O-])[O-].[K+].[K+]>C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][N:11]([CH2:25][NH:24][C:22]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:23])[CH2:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)C1CCCCC1
Reactant: C1=C(c2ccccn2)CCNC1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(NCN1CC=C(c2ccccn2)CC1)C1CCCCC1
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A mixture of 1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl hydrochloride (20 mg, 0.10 mmol, Saari, W. S.; et al. J. Med. Chem. 1984, 27, 1182), paraformaldehyde (30 mg, 1 mmol), cyclohexanecarboxylic acid amide (64 mg, 0.5 mmol, Aldrich), and 42 mg of potassium carbonate (0.3 mmol) in 2.5 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 19 mg (64%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ 1.19 (m, 4H), 1.26 (m, 2H), 1.61 (m, 1H), 1.68 (m, 3H), 2.18 (m, 1H), 2.55 (m, 2H), 2.68 (m, 2H), 3.18 (m, 2H), 4.02 (d, J=5 Hz, 2H), 6.68 (m, 1H), 7.22 (m, 1H), 7.52 (d, J=6 Hz, 1H), 7.73 (t, J=6 Hz, 1H), 8.02 (t, J=5 Hz, 1H), 8.52 (m, 1H); MS (ESI/APCI−) m/e 298 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7](Cl)=[O:8].[Cl:23][C:24]1[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:28]=[CH:27][C:25]=1[NH2:26].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[C:16]([Cl:22])[CH:15]=2)[CH:12]=1)[O:5][CH2:6][C:7]([NH:26][C:25]1[CH:27]=[CH:28][C:29]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:30][C:24]=1[Cl:23])=[O:8]
Reactant: CS(=O)(=O)c1ccc(N)c(Cl)c1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)Cl)c2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(NC(=O)COc2cc(Cl)cc(Oc3cc(Cl)cc(C#N)c3)c2)c(Cl)c1

Procedure:
A DMF solution (0.5 mL) of 29 mg (0.081 mmol) of [3-chloro-5-(3-chloro-5-cyanophenoxy)phenoxy]acetyl chloride (5-4), 33 mg (0.163 mmol) of 2-chloro-4-methylsulfonylaniline (5-5) and 21 mg (0.163 mmol) of DIEA were stirred at 25° C. until the reaction would not proceed any further. This solution was loaded directly onto a CombiFlash silica gel column eluted with EtOAc:hexanes (3:97 to 100:0). Clean fractions were combined and concentrated in vacuo to give the desired product 5-6 as a white solid. Rf=0.8 (DCM:MeOH:NH4OH 98:2:0.2). HRMS (M+Na): measured 542.0066; theoretical 542.0105. 1H NMR(CDCl3): 3.07 (s, 3H), 4.69 (s, 2H), 6.61 (m, 1H), 6.74 (m, 1H), 6.89 (m, 1H), 7.15 (m, 1H), 7.25 (m, 1H), 7.42 (m, 1H), 6.94 (dd, 1H), 8.02 (m, 1H), 8.74 (d, 1H), 9.11 (s, 1H).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OC1C=CC(F)=CC=1)=O.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:29]>>[C:1]1([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH:13][C:28](=[O:29])[O:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: NCc1ccc(Oc2ccccc2)cc1
Agent: O=C(Cl)Oc1ccc(F)cc1
Product: COc1ccc(OC(=O)NCc2ccc(Oc3ccccc3)cc2)cc1

Procedure:
The procedure is carried out in a manner similar to Example 4, replacing the 4-phenylbenzylamine with 4-phenyloxybenzylamine and the 4-fluorophenyl chloroformate with 4-methoxyphenyl chloroformate.