Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]3[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH:35]1[CH:39]=[C:38]([CH2:40][C:41](O)=[O:42])[N:37]=[CH:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:35]1[CH:39]=[C:38]([CH2:40][C:41]([N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:17][C@H:16]2[C:14](=[O:15])[NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[O:42])[N:37]=[CH:36]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
Step (c) A flask was charged with (S)-benzyl 3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate (1.08 g, 2.41 mmol), 4-imidazoleacetic acid hydrochloride (392 mg, 2.41 mmol), DIEA (1.0 mL, 5.8 mmol), HATU (1.01 g, 2.65 mmol) and DMF (5 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and then quenched with saturated sodium bicarbonate (aq., 10 mL). The mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 257, (S)-benzyl 4-(2-(1H-imidazol-4-yl)acetyl)-3-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1-carboxylate (0.80 g, 1.43 mmol, 67% yield), as an off-white solid. 1H-NMR (400 MHz, CDCl3): 10.27 (s, 1H), 9.18 (s, 1H), 7.60-7.49 (m, 3H), 7.47-7.21 (m, 5H), 7.06-6.91 (m, 6H), 5.45 (s, 1H), 5.17 (s, 2H), 5.09-5.00 (m, 2H), 4.04 (m, 2H), 4.09-3.97 (m, 2H), 3.81-3.73 (m, 2H), 3.46-3.77 (m, 1H), 3.17 (dd J=13.6, 4.8 Hz, 1H), 3.13-3.00 (m, 1H). MS (EI) for C30H28FN5O5. found 558.2 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:14]=[CH:15][CH:16]=1)[N:12]([C:32](=[O:33])[CH2:31][O:30][CH3:29])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: COCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: COCC(=O)N(C)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 3-benzyloxy-2-nitro-N-methylaniline (400 mg) and N,N-dimethylaniline (1 ml) was added methoxyacetyl chloride (310 μl) under nitrogen atmosphere, and the mixture was stirred for 2.5 hours at 90° C. After cooling, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1, v/v) to give 3-benzyloxy-2-nitro-N-methoxyacetyl-N-methylaniline (474.2 mg).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:29][NH:30][CH3:31]>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14][N:30]([CH3:31])[CH3:29])=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: CNC
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CCCN(C)C)c(=O)n(CC3CC3)n2)cc1F
Yield: 64.7 %

Procedure:
Following the procedure of Example 7, 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 64.7%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[C:19]([O:23][C:24](=[O:42])[C:25]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][C:38]([NH:40][NH2:41])=O)=[CH:31][CH:30]=1)([CH3:27])[CH3:26])([CH3:22])([CH3:21])[CH3:20]>CO>[C:19]([O:23][C:24](=[O:42])[C:25]([CH3:27])([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][C:38]2[NH:40][N:41]=[C:7]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:10][CH:9]=3)[N:8]=2)=[CH:31][CH:30]=1)[CH3:26])([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN)cc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCCc2nc(-c3ccc(C(F)(F)F)cc3)n[nH]2)cc1
Yield: 43.6 %

Procedure:
Add 4-(trifluoromethyl)benzonitrile (0.51 g, 3.0 mol) and potassium tert-butoxide (0.023 g, 0.21 mmol) to a solution of 2-[4-(3-Hydrazinocarbonyl-propyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester (0.5 g, 1.5 mmol) in MeOH (5 mL). Stir the mixture at reflux overnight. Add an additional 0.2 equivalents of potassium tert-butoxide and stir the reaction for 24 h. Quench the crude with water, remove the MeOH in vacuo, and extract the aqueous layer with EtOAc. Separate the organic layer, dry with MgSO4, and concentrate in vacuo. Purify the crude by Biotage (Hexane/EtOAc 4:1) yielding 0.32 g (44%) of the title compound, example 10 as a pale yellow oil. MS Data (ES+) m/z 490.6 [M+H]
Reaction SMILES: [N+:1]([C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][C@H:21]([C:25]([N:27]3[CH2:44][CH2:43][CH2:42][C@H:28]3[C:29]([NH:31][CH:32]([CH:39]([CH3:41])[CH3:40])[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:46]=[CH:45][C:7]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([NH:20][C@H:21]([C:25]([N:27]3[CH2:44][CH2:43][CH2:42][C@H:28]3[C:29]([NH:31][CH:32]([CH:39]([CH3:40])[CH3:41])[C:33](=[O:38])[C:34]([F:37])([F:35])[F:36])=[O:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc1)C(C)C)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCc2ccc(N)cc2)cc1)C(C)C)C(=O)C(F)(F)F
Yield: 96.5 %

Procedure:
A solution of 3(RS)-[[4-[(4-nitrobenzyl)aminocarbonyl]phenylcarbonyl]-L-valyl-L-prolyl]amino -1,1,1-trifluoro-4-methyl-2-oxopentane (50 mg) in methanol (10 ml) was hydrogenated over 10% palladium on carbon (10 mg) at 4 atmosphere pressure of hydrogen for 2 hours. The catalyst was removed by filtration and the liltrate was evaporated under reduced pressure to give 3(RS)-[[4-[(4aminobenzyl)aminocarbonyl]phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (46 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2].[F:23][C:24]([F:41])([F:40])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32]([C:37](O)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:37]([C:32]3[C:31]([C:28]4[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:40])[F:41])=[CH:26][CH:27]=4)=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:38])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CN2CCN(c3ccc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a stirred solution of 4-[4-(3-cyano-benzyl)-piperazin-1-yl]-phenylamine (0.29 g), 4′-trifluoromethyl-biphenyl-2-carboxylic acid (0.26 g), HOBt (0.16 g), and Et3N (0.12 g) in CH2Cl2 (15 mL) was added at room temperature EDCl (0.23 g) and the mixture was stirred at room temperature for 4 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2Cl2/AcOEt (90/10) and the solid obtained was recrystallized from EtOH to give the title compound (0.48 g) as white crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]([NH:12][CH:13]=[C:14]([C:20](=[O:27])[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:15]([O:17]CC)=O)=[CH:10][CH:9]=[N:8]1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCOCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:20]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[O:27])[C:15]([OH:17])=[C:10]2[CH:9]=[N:8]1
Reactant: CCOC(=O)C(=CNc1ccnn1Cc1ccco1)C(=O)c1cccnc1
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(c1cccnc1)c1cnc2c(cnn2Cc2ccco2)c1O
Temperature: 25 °C

Procedure:
7.3 g. of α-[[[1-(2-furanylmethyl)- 1H-pyrazol-5-yl]-amino]methylene]-β-oxo-3-pyridinepropanoic acid, ethyl ester (0.02 mol.) are heated in 20 ml. of diphenylether at 250° for 10 minutes. The mixture is cooled to room temperature and 20 ml. of ether are added. The product, [1-(2-furanylmethyl)-4-hydroxy-1H-pyrazolo]3,4 -b]pyridin-5-yl]-3-pyridylmethanone precipitates and is recrystallized from butyl alcohol, yield 3.8 g. (60%); m.p. 152°-153°.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(O)C.[S:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])(=[O:24])[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:27][CH:28]=3)[CH:6]=2)=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 76.27 %

Procedure:
(compound 33a, 1.45 g, 4.19 mmol) in a mixture of toluene:ethanol (10:40 ml) was added (4-sulfamoylphenyl)boronic acid (0.84 g, 4.19 mmol) and potassium carbonate (1.16 g, 8.39 mmol) at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.20 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 95 to about 100° C. for 16 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite, the celite cake was washed with Ethanol (2×25 ml). The filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (1.35 g, 76.27%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([O:31][CH:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[CH:35][CH:34]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Reactant: Oc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Br)cc3)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-bromophenol:
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCCC2)CC1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OC(=O)C1C=C(OCCOC)C(OCCOC)=CC=1N)C>[CH3:15][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OC)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
5-Methoxy-2-nitro-benzoic acid (2.5 g) was dissolved in N,N-dimethylformamide (compound A′) (40 ml). Potassium carbonate (4.5 g) and methyl iodide (2.5 ml) were added to the solution at room temperature, and the mixture was then stirred at that temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a hexane-acetone system to give 5-methoxy-2-nitrobenzoic acid methyl ester (2.7 g, yield 100%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:31]N1C(=O)CCC1=O>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[C:8]([Cl:31])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 60 °C
Yield: 55 %

Procedure:
To a solution of methyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoate [Example 9 (4.34 g, 0.01 mol) in tetrahydrofuran (20 mL) was added N-chlorosuccinimide (1.35 g, 0.01 mol) in portions over a one hour period. The mixture was heated to 60° C. for one-hour. The tetrahydrofuran was evaporated, the residue was dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate solution and water. The dried, concentrated product was flash chromatographed over silica gel with 1:1 hexane/ethyl acetate to provide 2.7 g (55%) of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH3:33].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:26][N:27]([CH3:34])[CH2:28][CH2:29][CH2:30][CH2:31][N:32]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:33]
Reactant: CNCCCCN(C)C
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(C)CCCCN(C)c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 150 °C
Yield: 23 %

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.1 g), N-(4-dimethylaminobutyl)-N-methylamine (Intermediate 78, 1.07 g) and triethylamine (0.42 g) in NMP (6 mL) was stirred and heated in a sealed tube at 150° C. for 3 days. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%) followed by repurification by HPLC (C18) to give (1aRS,7bSR)-5-{2-[N-(4-dimethylaminobutyl)-N-methylamino]-benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.03 g) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][NH:6][C:5]1=[O:13].Br.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CN1CCCC1=O>[CH3:3][N:4]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:5]1=[O:13]
Reactant: BrCc1ccccn1
Reactant: COC(=O)C1CNC(=O)N1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CN(Cc2ccccn2)C(=O)N1C
Temperature: 0 °C
Reaction time: 20 h
Yield: 25.4 %

Procedure:
A suspension of sodium hydride (240 mg, 6 mmol, 60% dispersion in oil) in N-methyl-2-pyrrolidinone (6 ml) was stirred at 0° C. under argon. A solution of methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (474 mg, 3 mmol) (prepared as described in step (ii) of Example 8) in N-methyl-2-pyrrolidinone (3 ml) was added dropwise over 10 minutes. The reaction was stirred at 0° C. for 15 minutes and 2-(bromomethyl)pyridine hydrobromide (835 mg, 3.3 mmol) was added portionwise over 5 minutes. The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 20 hours. The reaction was treated with ice water and extracted with dichloromethane. The mixture was applied to a SCX ion exchange cartridge and washed with methanol and then 2M ammonia in methanol. The basic fractions were combined and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give methyl 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylate (190 mg), LC/MS [M+H]+=250. (ii) A stirred solution of methyl 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylate (190 mg, 0.76 mmol) in tetrahydrofuran (1.5 ml)/water (1 ml) at 0° C. was treated with lithium hydroxide (55 mg, 2.28 mmol) and the reaction mixture was stirred at 0-5° C. for 3 hours. The reaction was acidified to pH 2 with 2N hydrochloric acid and the solvent was evaporated. The residue was dried to give 3-methyl-2-oxo-1-(2-pyridinylmethyl)-4-imidazolidinecarboxylic acid which was used crude in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10](Cl)=[CH:9][C:8]([CH3:12])=[N:7][C:6]=1[Cl:13])[CH3:2].[CH3:15][CH2:16][O-:17].[Na+]>CCO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([O:17][CH2:16][CH3:15])=[CH:9][C:8]([CH3:12])=[N:7][C:6]=1[Cl:13])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(OCC)cc(C)nc1Cl
Temperature: 60 °C

Procedure:
To a solution of 2,4-dichloro-6-methylnicotinic acid ethyl ester (2.49 mmol) in 6 mL EtOH was added NaOEt (2.61 mmol). The reaction mixture was heated to 60° C. overnight in a closed vessel. At RT, the mixture was diluted with EtOAc and washed with aq. NH4Cl solution. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as beige solid;
Reaction SMILES: [N+:1]([CH:4]([CH3:13])[CH:5]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[OH:6])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][CH:4]([CH3:13])[CH:5]([CH:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)[OH:6]
Reactant: CC(C(O)C1CCOCC1)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(N)C(O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
2-Nitro-1-(tetrahydro-pyran-4-yl)-propan-1-ol (1.3 g, 6.87 mmol) was dissolved in ethanol (55 mL) and treated with palladium on carbon (0.2 g) under 1 atm of hydrogen. After stirring at room temperature overnight, the palladium was filtered off and the solvent reduced under reduced pressure to provide 1.0 g (91%) of 2-amino-1-(tetrahydro-pyran-4-yl)-propan-1-ol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.3 %

Procedure:
A solution of 2,4-dibenzyloxybenzoic acid (3.34 g) and methyl glycinate hydrochloride (1.25 g) in DMF (40 mL) is treated with triethylamine (2.23 g) and 1-hydroxybenzotriazole (1.53 g) at 0° C. The mixture is stirred for 10 minutes, treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (2.05 g) and allowed to warm to 25° C. The solution is evaporated. The residue is partitioned between ethyl acetate and water. The organic layer is washed with 1 M HCl, 1 M NaOH, water, dried and evaporated. The residue is recrystallized from methanol to yield methyl N-(2,4-dibenzyloxybenzoyl)glycinate as a solid (900 mg). H NMR (CDCl3) 3.7(3H,s), 4.2(2H,d), 5.1 (2H,s), 5.2(2H,s), 6.6(1H,s), 6.7(1H,d), 7.3-7.5(10H,m), 8.2(1H,d), 8.4(1H,t).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[CH:27]([C:29]1[N:30]2[CH:36]=[N:35][CH:34]=[C:31]2[S:32][CH:33]=1)=[O:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:35]3[CH:34]=[C:31]4[S:32][CH:33]=[C:29]([CH:27]=[O:28])[N+:30]4=[CH:36]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: O=Cc1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(C=O)[n+]4c3)[C@H](C)[C@H]12
Yield: 3.3 %

Procedure:
The same procedure as in Example 1 was repeated except that 93 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 58 mg of 3-formylimidazo[5,1-b]thiazole were used, thereby obtaining 3.2 mg of the title compound.