Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([Cl:28])[CH:25]=1)[O:21][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)cc(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Cl)cc(OC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of N-tert-butoxycarbonyl-4-(3,5-dichlorophenoxy)piperidine (A, 815 mg) in dichloromethane (20 mL) at room temperature. After stirring at room temperature for 30 min, the reaction mixture was evaporated in vacuo. The residue was partitioned between chloroform and saturated sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo to give the title compound, which was washed with hexane and used in the next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:12]3[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=3[C:18](=[N:19][OH:20])[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.COC1C=CC2C3C(N4CCNCC4)=NC4C(C=3C(=O)C=2C=1)=CC=CC=4.C(C1OC1)Cl>>[N:26]1([CH2:25][CH2:24][O:20][N:19]=[C:18]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([OH:1])[C:11]=3[C:12]3[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]2=3)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc2c(c1)C(=NO)c1c-2c(O)nc2ccccc12
Agent: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Agent: Cl
Solvent: ClCC1CO1
Product: COc1ccc2c(c1)C(=NOCCN1CCCC1)c1c-2c(O)nc2ccccc12
Yield: 46 %

Procedure:
6-Hydroxy-9-methoxy-11H-indeno[1,2-c]quinolin-11-one O-2-pyrrolidin-1-yl)ethyl oxime (6bb) was prepared substantially according to the procedures as set forth in the above Synthesis Example 18, except that compound 6c and 1-(2-chloroethyl)pyrrolidine·HCl were used in place of compound 5x and epichlorohydrin, respectively, giving the title compound at a yield of 46%.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CC([O-])(C)C.[K+].I[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][N:4]1[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]1)[CH3:19]
Reactant: CCOC(=O)CI
Reactant: Nc1cc[nH]n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
57.1 To a stirred, cooled (0° C.) solution of the 1.6 g 3-aminopyrazole in DMF under an argon atmosphere was added potassium tert-butylate. After 30 min. stirring at 0° C., ethyl iodoacetate was added in one portion. After 2 h stirring at 0° C., the ice bath was removed and stirring at r.t. was continued for 22 h. The mixture was concentrated in order to remove as much DMF as possible. The residue was taken up in EtOAc and washed with H2O. The aqueous phase was extracted with EtOAc. The combined organics were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on silica using a gradient from cyclohexane to EtOAc in 40 min to give 366 mg (3-amino-pyrazol-1-yl)-acetic acid ethyl ester as viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:27]([CH3:29])[CH3:28])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:82](=[NH:95])([C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)[C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1>O1CCCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:82](=[N:95][C:13]1[CH:12]=[C:11]2[C:16]([C:17](=[O:18])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([CH:27]([CH3:29])[CH3:28])[O:10]2)=[CH:15][CH:14]=1)([C:89]1[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=1)[C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)c1oc2cc(OS(=O)(=O)C(F)(F)F)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1oc2cc(N=C(c3ccccc3)c3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
A mixture of trifluoromethanesulfonic acid 3-(4-chlorophenyl)-2-isopropyl-4-oxo-4H-chromen-7-yl ester (6.96 g, 15.6 mmol), palladium acetate (0.35 g, 1.56 mmol), cesium carbonate (12.7 g, 38.9 mmol) and racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP; 0.97 g, 1.56 mmol) in anhydrous tetrahydrofuran (230 ml) under an atmosphere of nitrogen is treated with benzophenone imine (3.66 g, 20.2 mmol) and allowed to stir at 80° C. for 22 hours. After allowing the resultant mixture to stir at room temperature for an additional 24 hours, it is diluted with water (300 ml) and extracted with ethyl acetate (3×300 ml). The organic extracts are combined, washed with brine, dried (MgSO4), filtered, concentrated in vacuo and purified by flash chromatography over silica gel (10% ethyl acetate/cyclohexane) to afford the desired compound as a dark yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:65]=[CH:64][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:65]=[CH:64][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(Cl)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.2 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 91 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 2 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:9) to give 65 mg white solid (42%). MS (ISP) 479.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[C:25]([O-])(=[O:27])[CH3:26].[Na+].C(Cl)(=O)C>O1CCOCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:25](=[O:27])[CH3:26])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)Cl
Product: COc1ccc2c(c1)c(CN(O)C(C)=O)c(C)n2C(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 47.6 %

Procedure:
To a suspension of 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine (1,2 g, 3.5 mmol) and sodium acetate (730 mg, 8.9 mmol) in 120 ml of 1,4-dioxane and 30 ml of water is added dropwise acetyl chloride (420 μl, 5.9 mmol) at 0° C. After 10 minutes additional acetyl chloride (40 ul, 0.6 mmol) is added. The reaction mixture is stirred for 15 minutes, and then is diluted with ethyl acetate. It is washed once with a dilute solution of sodium bicarbonate, once with water, and a saturated solution of sodium chloride The organic phase is further dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is purified by column chromatography on silica gel, eluting first with 1:4 ethyl acetate:methylene chloride then 1:1 ethyl acetate:methylene chloride. Recrystallization from isopropyl ether gives N-[[1-(4-chlorobenzoyl) -5-methoxy-2-methyl-lH-indol-3-yl]methyl]-N-hydroxy-acetamide (645 mg, 47%); mp 160°-161° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:2]=1.Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1>>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:35]3[CH2:36][CH2:37][CH:32]([C:30](=[O:31])[C:27]4[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=4)[CH2:33][CH2:34]3)=[O:16])=[CH:19][CH:20]=2)[CH:2]=1
Reactant: CCOC(=O)c1ccc(-n2cnc3cccnc32)cc1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Product: COc1ccc(C(=O)C2CCN(C(=O)c3ccc(-n4cnc5cccnc54)cc3)CC2)cc1
Yield: 66.6 %

Procedure:
Using ethyl 4-(imidazo[4,5-b]pyridin-3-yl)benzoate (300 mg) described in Preparation Example 77 and (4-methoxyphenyl)(piperidin-4-yl)methanone hydrochloride (287 mg) and by the reaction and treatment in the same manner as in Example 170, the title compound (329 mg) was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.Cl.C(N(CC)CC)C.[CH3:39][C:40]1[CH:41]=[C:42](O)[CH:43]=[CH:44][CH:45]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([CH3:39])[CH:45]=3)[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Cc1cccc(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Reaction time: 20 h

Procedure:
A stirred mixture of 48 g (0.2 mole) of 1-diphenylmethyl-3-azetidinol and 22 g (0.22 mole) of triethylamine in 800 ml of toluene under nitrogen was cooled in a water bath while 27.5 g (0.22 mole) of methanesulfonyl chloride was added dropwise. After stirring for 20 hr, the reaction mixture was treated with 200 ml of water to dissolve the triethylamine hydrochloride. The aqueous phase was separated and the toluene phase was washed with 2×100 ml water. The toluene solution was added to a mixture of 22.8 g (0.2 mole) of 3-methylphenol (95%), 24 g (0.6 mole) of sodium hydroxide and 100 mg of tetrabutylammonium bromide in 100 ml of water and the mixture was heated at reflux and stirred vigorously for 42 hr.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9]C(=O)[C:7]2=[O:12].[OH-:15].[Na+].[Na+].[Cl-].OO>O.C(Cl)Cl>[NH2:9][C:10]1[C:2]([Cl:1])=[C:3]([O:13][CH3:14])[CH:4]=[CH:5][C:6]=1[C:7]([OH:12])=[O:15]
Reactant: [OH-]
Reactant: COc1ccc2c(c1Cl)NC(=O)C2=O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)O)c(N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A suspension of compound 246d (6.03 g, 28.52 mmol), NaOH (1.25 g, 31.37 mmol), and NaCl (3.49 g, 59.89 mmol) in water (60 mL) was stirred at room temperature for 30 min and was then ice-cooled. H2O2 was added dropwise. The mixture was stirred at 0° C. for 20 min and at room temperature for 3 hrs. The reaction mixture was quenched with glacial AcOH, filtered, and washed with water. The solid obtained was dissolved in DCM, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel (DCM/MeOH) to yield compound 247d as an orange solid in 36% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 3.85 (s, 3H), 6.41 (d, J=9.05 Hz, 1H), 6.77 (brs, 2H), 7.74 (d, J=9.05 Hz, 1H), 12.7 (brs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:16]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][CH:5]=1)[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][C:14]=1[C:20]([F:23])([F:22])[F:21])=[CH:5][NH:6]2
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: Clc1cccc2[nH]ccc12
Product: Fc1ccc(C(c2c[nH]c3cccc(Cl)c23)c2c[nH]c3cccc(Cl)c23)c(C(F)(F)F)c1

Procedure:
The compound Bis(4-chloroindol-3-yl)-(4-fluoro-2-trifluoromethylphenyl)methane was prepared following procedure A, starting from 4-chloro indole and 4-fluoro-2-(trifluromethyl) benzaldehyde. LC: Tr 2.52 min, MS: 477 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]4[O:24][C:23]([C:25]5([NH:33]C(=O)OC(C)(C)C)[CH2:30][O:29]C(C)(C)[O:27][CH2:26]5)=[CH:22][C:21]=4[CH:41]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH3:11].ClC1C=C(C2ON=C(C3C=CC4OC(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)=CC=4C=3)N=2)C=CC=1OCCC>>[NH2:33][C:25]([C:23]1[O:24][C:20]2[CH:19]=[CH:18][C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH3:11])=[C:2]([Br:1])[CH:3]=4)[O:16][N:15]=3)=[CH:41][C:21]=2[CH:22]=1)([CH2:26][OH:27])[CH2:30][OH:29]
Reactant: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Br
Agent: CCCOc1ccc(-c2nc(-c3ccc4oc(C5(NC(=O)OC(C)(C)C)COC(C)(C)OC5)cc4c3)no2)cc1Cl
Product: CCCOc1ccc(-c2nc(-c3ccc4oc(C(N)(CO)CO)cc4c3)no2)cc1Br
Yield: 10 %

Procedure:
When the product of Step C is substituted for tert-butyl 5-(5-(5-(3-chloro-4-propoxyphenyl)-1,2,4-oxadiazol-3-yl)benzofuran-2-yl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 36, Step E, the similar procedure afforded the title compound in 10% yield, as light yellow solid. 1H NMR (CD3OD) 8.32 (b, 2H); 8.1 (d, 1H, J=8.46 Hz); 8.00 (d, 1H, J=8.52 Hz); 7.59 (d, 1H, J=8.61 Hz); 7.18 (d, 1H, J=8.58 Hz); 6.91 (s, 1H); 4.1 (t, 2H, J=6.06 Hz); 3.91 (d, 2H, J=10.98 Hz); 3.03 (d, 2H, J=10.95 Hz); 3.32 (b, 2H); 1.9-1.8 (m, 2H); 1.1 (t, 3H, J=7.35 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([Cl:15])=[O:12])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)CCc1ccc(F)cc1
Reaction time: 24 h
Yield: 86.8 %

Procedure:
3-(para-Fluorophenyl)propionic acid (25.00 g, 150.0 mmol, 1 eq.) was dissolved in methylene chloride (100 mL) at 25° C. under N2 and thionyl chloride (54.2 mL, 740.0 mmol, 5 eq.) added dropwise via an addition funnel. Worked up after 24 hours by stripping off the solvent then rerotovaping 2 times from toluene (25 mL) to obtain 24.3 g of a yellow oil.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](OC)=O)[C:3]=1[C:4]([OH:6])=O.[N+](C1C=CC=[C:20]([C:21](O)=[O:22])[C:19]=1C(O)=O)([O-])=O.C(O)(C(F)(F)F)=O>CO>[OH:6][CH2:4][C:3]1[CH:2]=[CH:10][CH:9]=[C:8]2[C:7]=1[CH:11]=[CH:19][CH:20]=[C:21]2[OH:22]
Reactant: COC(=O)c1cccc(N)c1C(=O)O
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: OCc1cccc2c(O)cccc12

Procedure:
2-Amino-6-(methoxycarbonyl) benzoic acid (1) was made from 3-nitrophthalic acid using the procedure first reported by Rogers and Averill (Rodgers, M. E. and Averill, B. A., J. Org. Chem., 1986, 51, 3308) and then used immediately to make Diels Alder cycloadduct 2 via the 3-(methoxhycarbonyl)dehydrobenzene intermediate that is generated under aprotic diazotization reaction conditions (based on modified conditions first reported by Giles, R. G. F., Sargent, M. V., and Sianipar, H., J. Chem. Soc. Perkin Trans I, 1991, 1571). Treatment of cycloadduct 2 with TFA in refluxing methanol yielded a 1:2 mixture of regioisomeric naphthols 3a and 3b which were separated by column chromatography on silica gel. The 1,5-naphthol regioisomer (3a) was then reduced with LAH to produce 5-hydroxymethyl naphthol 4, which was then coupled to carbapenem intermediate 5 (CPI 5) with catalytic palladium to produce the 1-carbon naphthol coupled CPI 6.
Reaction SMILES: [S:1]([N:17]([S:25]([C:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:33]([N:34]([CH3:36])[CH3:35])[C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:18][CH2:19][S:20][S:21][CH2:22][CH2:23][NH2:24])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].C(C(O)=O)CP(CCC(O)=O)CCC(O)=O.Br[C:58]1[C:63](=[O:64])[NH:62][C:60](=[O:61])[C:59]=1Br.CC([O-])=O.[Na+]>CO>[S:1]([N:17]([S:25]([C:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:33]([N:34]([CH3:36])[CH3:35])[C:32]=2[CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH2:18][CH2:19][S:20][S:21][CH2:22][CH2:23][NH2:24])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:11])[CH3:12])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:60]1(=[O:61])[NH:62][C:63](=[O:64])[CH:58]=[CH:59]1
Reactant: O=C1NC(=O)C(Br)=C1Br
Agent: CC(=O)[O-]
Agent: CN(C)c1cccc2c(S(=O)(=O)N(CCSSCCN)S(=O)(=O)c3cccc4c(N(C)C)cccc34)cccc12
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: CO
Product: O=C1C=CC(=O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A round bottomed flask was charged with di-dansyl cystamine (100 mg, 0.16 mmol), TCEP (46 mg, 1 eq) and MeOH (10 ml). The reaction mixture was stirred at ambient temperature under argon for 3 hrs. Dibromomaleimide (36 mg, 0.9 eq), in MeOH (5 ml) was then added to the reaction mixture. After 30 mins NaOAc (56 mg, 4 eq), was added to the reaction mixture and the solvent evaporated in vacuo. The residue was worked up with DCM and brine. The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-20% EtOAc-DCM) afforded the desired compound as a yellow gum (40 mg, 40%). 1HNMR (CDCl3, 600 MHz), δ8.5 (2H, d J 8.5 Hz aromatic H's), δ8.2 (4H, m aromatic H's), δ7.53 (1H, s CONH), δ7.46 (4H, m, aromatic H's), δ7.1 (2H, d, J=7.4 Hz aromatic H's), δ5.65 (2H, t, J 6.27 SO2NH), δ3.3 (4H, t, J 6.0 SCH2), δ3.17 (4H, q, J 6.0 NHCH2), δ2.8 (12H, s NCH3); 13CNMR (CDCl3, 150 MHz), 6165.9, 152.0, 136.5, 134.7, 130.7, 129.94, 129.85, 129.62, 129.57, 128.63, 123.3, 118.8, 115.4, 45.5, 43.6, 31.8; IR (cm−1) 3288 (br) 1720 (s) MS (Na+) m/z relative intensity: 736 (M, 100); Exact mass calculated for [C32H35N5O6NaS4] requires m/z 736.1368. Found 736.1390 (Na+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:17])[NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:18]=[CH2:19])[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc([C@@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Yield: 82.2 %

Procedure:
A solution of [(R)-1-(3-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (10.26 g, 0.0342 mol.) and tributyl(vinyl)stannane (32.5 g, 30 mL, 0.103 mol.) in toluene (175 mL) was purged with nitrogen for 30 minutes before addition of bis(triphenylphosphine palladium II chloride (2.38 g, 0.0034 mol.). The stirred mixture was heated to 60° C. for 16 hours before cooling to room temperature. The reaction mixture was filtered through hyflo-supercel then evaporated to give a dark coloured oil. The oil was purified by silica gel chromatography using iso-hexanes/ethyl acetate 19:1 to yield the title compound (6.95 g, 82%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ1.39-1.51 (m, 12H), 4.80 (br s, 2H), 5.24-5.32 (m, 1H), 5.77 (d, J=17.6 Hz, 1H), 6.73 (dd, J=17.6, 10.9 Hz, 1H), 7.18-7.36 (m, 4H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>C(Cl)Cl>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH3:13])=[C:7]([CH:11]=1)[C:8]([NH:34][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=1)=[O:10])=[O:2]
Reactant: COc1ccc(C=O)cc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a suspension of 1.00 g of 5-formyl-2-methoxybenzoic acid in 50 ml of methylene chloride were added 1.00 ml of triethylamine and 0.60 ml of ethyl chlorocarbonate, and the mixture was stirred for 15 minutes at room temperature. Then, a solution of 1.17 g of 4-trifluoromethylbenzylamine in 10 ml of methylene chloride was added and the mixture was stirred further for 3 hours at room temperature. After washed with water, the reaction mixture was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue obtained was purified by means of column chromatography (silica gel, hexane:ethyl acetate=1:1) and then recrystallized from a mixed solvent of diethyl ether-ethyl acetate-hexane to obtain 1.46 g of 5-formyl-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:20])[N:16]([CH2:18][CH3:19])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:20])[N:16]([CH2:18][CH3:19])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: CCn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCn1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2C)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-ethyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=439.3 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][NH2:18])=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(=O)CCCCC1>[C:1]([N:9]1[CH2:20][CH2:19][C:12]2[N:13]=[N:14][C:15]([NH:17][N:18]=[C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:16][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1cc2c(nn1)CCN(C(=O)c1ccccc1)C2
Solvent: O=C1CCCCC1
Product: O=C(c1ccccc1)N1CCc2nnc(NN=C3CCCCC3)cc2C1

Procedure:
A suspension of 8.3 g of 6-benzoyl-3-hydrazino-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 20 cc of cyclohexanone is boiled at reflux at a bath temperature of 180° for 2 hours. The title compound has a M.P. of 188°-191° (decomp., from acetonitrile).