Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>CC(C)=O>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[O:21][CH2:31][CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: COc1ccc(O)c(C(=O)c2oc3ccc(Cl)cc3c2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(OC)cc1C(=O)c1oc2ccc(Cl)cc2c1N
Temperature: 55 °C
Reaction time: 48 h

Procedure:
A suspension of 3-amino-5-chloro-2-(2-hydroxy-5-methoxybenzoyl)-benzofuran (0.06 g, 0.19 mmol), potassium carbonate (0.08 g, 0.6 mmol) and allyl bromide (0.1 g, 0.8 mmol) in dry acetone (3 ml) is stirred 55° C. for 48 h. The solids are filtered off and the solution is concentrated under reduced pressure. Purification of the residue by silicagel column chromatography yields the title compound of m.p. 115-116° C.
Reaction SMILES: [Na+].[CH3:2][O:3][N:4]=[C:5]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([O-:26])=[O:25])=[C:13]([CH:16]=[CH:17][C:18]3[S:22][CH:21]=[N:20][C:19]=3[CH3:23])[CH2:14][S:15][C@H:10]12)=[O:7].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(OCC)(=O)C>CN(C)C=O>[C:35]([O:41][CH2:42][O:25][C:24]([C:12]1[N:11]2[C:27](=[O:28])[CH:9]([NH:8][C:6](=[O:7])[C:5](=[N:4][O:3][CH3:2])[C:29]3[N:30]=[C:31]([NH2:34])[S:32][CH:33]=3)[C@H:10]2[S:15][CH2:14][C:13]=1[CH:16]=[CH:17][C:18]1[S:22][CH:21]=[N:20][C:19]=1[CH3:23])=[O:26])(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=Cc3scnc3C)CS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(C=Cc3scnc3C)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
7-[2-Methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid sodium salt (syn-isomer, trans-isomer) (0.03 g, 0.06 mmol) was dissolved in dimethylformamide (3 ml). To the resultant solution was added a solution in dimethylformamide (1 ml) of iodomethyl pivalate (as prepared by reacting chloromethyl pivalate (0.090 g, 0.60 mmol) with sodium iodide (0.090 g, 0.06 mmol) in acetone) under ice-cooling, followed by stirring the resultant mixture for 10 minutes. The reaction solution as obtained were admixed with ice-water (20 ml) and ethyl acetate (20 ml), stirred thoroughly and then allowed to stand until the mixture separated into aqueous phase and organic phase. The organic phase was separated from the aqueous phase and washed twice with water (10 ml) and then with aqueous saturated NaCl solution (10 ml). The organic phase as washed was subsequently dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified chromatographically on a column of silica-gel (Wako-gel C-300) (5 g) as developed with ethyl acetate. The titled compound was thus obtained (yield 0.025 g, 67%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[CH3:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[F:19][C:17]([F:20])([O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: CC(F)(F)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(Br)c2)cc1
Reactant: OB(O)c1cncnc1
Product: CC(F)(F)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(-c3cncnc3)c2)cc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (R)-5-bromo-N-(4-(1,1-difluoroethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 215.1) and pyrimidin-5-ylboronic acid to afford an off-white foam. HPLC (Condition 4) tR=4.28 min, UPLC-MS (Condition 3) tR=0.84 min, m/z=442.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74 (m, J=4.30 Hz, 1H) 1.81-1.99 (m, 4H) 2.87 (d, J=11.34 Hz, 1H) 3.21 (m, J=11.30, 4.70 Hz, 2H) 3.37 (m, J=7.00 Hz, 1H) 4.15-4.24 (m, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.16 (d, J=8.99 Hz, 2H) 7.74 (d, J=8.60 Hz, 2H) 8.08 (d, J=1.95 Hz, 1H) 8.77 (d, J=1.00 Hz, 1H) 8.87 (s, 2H) 9.18 (s, 1H) 10.06 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:48]=[CH:49][C:50]=1[C:51]([O:53]C)=[O:52])[CH2:5][NH:6][C:7](=[O:47])[CH:8]([S:19][S:20][CH:21]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34]C)=[O:33])=[C:28]([OH:36])[CH:27]=1)=[O:23])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:22](=[O:23])[CH:21]([S:20][S:19][CH:8]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:7]([NH:6][CH2:5][C:4]2[CH:48]=[CH:49][C:50]([C:51]([OH:53])=[O:52])=[C:2]([OH:1])[CH:3]=2)=[O:47])[CH2:37][C:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)=[CH:27][C:28]=1[OH:36])([OH:34])=[O:33]
Reactant: COC(=O)c1ccc(CNC(=O)C(Cc2c[nH]c3ccccc23)SSC(Cc2c[nH]c3ccccc23)C(=O)NCc2ccc(C(=O)OC)c(O)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CNC(=O)C(Cc2c[nH]c3ccccc23)SSC(Cc2c[nH]c3ccccc23)C(=O)NCc2ccc(C(=O)O)c(O)c2)cc1O

Procedure:
Hydrolysis of 57 (0.28 g) with K2CO3 in MeOH/water at 50° C. for 5 hours, under nitrogen as above, gave an oil. Chromatography on silica gel, eluting with EtOAc:light petroleum (1:1) containing 1% AcOH, gave 2,2'-dithiobis[N-(4-carboxy-3-hydroxybenzyl)-3-(3-indolyl)propanamide] (58) [VI: n=2; R1 =R3 =H, R2 =(CH2)2CONHCH2Ph{3-OH, 4-COOH}] (72 mg, 27% mp (MeOH/dilute HCl) 160°-163.5° C. (dec).
Reaction SMILES: [C:1]([C:4]1([O:17][CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].[CH:27](=[O:30])[CH2:28][CH3:29].[Cl-].[NH4+]>O1CCCC1>[OH:30][CH:27]([CH2:28][CH3:29])[CH2:2][C:1]([C:4]1([O:17][CH3:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1)=[O:3]
Reactant: CCC=O
Reactant: COC1(C(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCC(O)CC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
To a solution of tert-butyl 4-acetyl-4-methoxypiperidine-1-carboxylate (0.589 g, 2.29 mmol) from Step A in tetrahydrofuran (20 mL) at −78° C. was added lithium diisopropylamine (0.650 mL, 0.974 mmol) followed by propionaldehyde (0.266 g, 0.330 mL, 4.58 mmol). After 5 min, the reaction mixture was poured into saturated ammonium chloride, and extracted three times with diethyl ether. The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfite, filtered, and concentrated. The residue was purified by flash chromatography eluting with 40% ethyl acetate/hexanes to afford the title compound (0.404 g). MS/EI (acetonitrile/water): m/z 216.1 (M+1−BOC) retention time=2.69 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:8](=[O:12])[C:7](=O)[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]=2[O:3]1.[NH2:19][C:20]1[CH:48]=[CH:47][C:23]([C:24]([O:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][CH:34]2[C:46]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:40]3[C:35]2=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:8](=[O:12])/[C:7](=[N:19]\[C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][CH:34]4[C:46]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:40]5[C:35]4=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])=[O:25])=[CH:47][CH:48]=3)/[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]=2[O:3]1
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C(=O)C2=O
Reactant: Nc1ccc(C(=O)OCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC2=C(O1)c1ccccc1/C(=N/c1ccc(C(=O)OCCNC(=O)OCC3c4ccccc4-c4ccccc43)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12.8 %

Procedure:
A solution of 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (2.975 g, 12.3 mmoles) in 120 ml of methylene chloride is treated with 6.14 ml of a 1.0 M solution of TiCl4 in methylene chloride. The mixture is stirred at room temperature for 5 minutes, then a solution of 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethyl 4-aminobenzoate (5.436 g, 13.5 mmoles) in 60 ml of methylene chloride is introduced followed by triethylamine (10.3 ml, 73.7 mmoles). The mixture is stirred at room temperature for 10 minutes. A second portion of 6.14 ml of a 1.0 M solution of TiCl4 in methylene chloride is added and the mixture is stirred at room temperature for 10 minutes. A third portion of 6.14 ml of a 1.0 M solution of TiCl4 in methylene chloride is added and the mixture is stirred at room temperature for 15 minutes. After stirring with the third aliquot of TiCl4, the mixture is poured onto 300 ml of ice, to form a mixture having a precipitate. The mixture is filtered to remove the precipitate and the organic and aqueous phases are then separated. The aqueous phase is extracted with two portions of 200 ml of methylene chloride. The combined organic extracts are dried with Na2SO4, filtered and concentrated in vacuo, giving a brown oil. Purification on silica gel using a gradient of 0-10% ethyl acetate in methylene chloride provided a brown reddish foam, which is triturated in diethyl ether, yielding 990 mg (13%) of the title compound as a brown solid. M.p.: 163-164° C. 400 MHz 1H NMR (DMSO-d6) δ: 8.13 (d, J=7.3 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.88 (d, J=7.7 Hz, 2H), 7.82 (d, J=8.1 Hz, 1H), 7.7-7.55 (m, 5H), 7.40 (t, J=7.5 Hz, 2H), 7.30 (t, J=7.5 Hz, 2H), 6.79 (d, J=8.4 Hz, 2H), 4.33 (d, J=7.0 Hz, 2H), 4.3-4.2 (m, 3H), 3.45-3.35 (m, 2H), 2.25 (t, J=6.4 Hz, 2H), 1.79 (t, J=6.4 Hz, 2H), 1.41 (s, 6H). LCMS: 627 [M+H]. Calc. for C39H34N2O6.0.1 water: C, 74.46; H, 5.48; N, 4.46; Found C, 74.48; H, 5.06; N, 4.43.
Reaction SMILES: O1CCCC1.[CH3:6][S:7]([C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]([O:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:18])=[CH:12][N:11]=1)(=O)=O.[C:27]1(S)[CH:32]=[CH:31]C=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:16][C:14]1[C:13]([C:17]([O:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:18])=[CH:12][N:11]=[C:10]([S:7][C:6]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)[N:15]=1
Reactant: Sc1ccccc1
Reactant: CC(CCOC(=O)c1cnc(S(C)(=O)=O)nc1C)=C(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CCOC(=O)c1cnc(Sc2ccccc2)nc1C)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To 5 ml of tetrahydrofuran were dissolved 0.56 g (1.8 mmol) of 4,4-difluoro-3-methyl-3-butenyl 2-methanesulfonyl-4-methylpyrimidine-5-carboxylate and 0.21 g (1.9 mmol) of thiophenol, followed by the addition of 0.30 g (2.8 mmol) of sodium carbonate and stirring at room temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:8) to obtain 0.54 g (yield: 88%) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-(phenylthio)pyrimidine-5-carboxylate.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10](OC1C=CC([N+]([O-])=O)=CC=1)=[O:11])([CH3:8])[C:3](OCC)=[O:4].Cl.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][C:2]1([CH3:8])[O:9][C:10](=[O:11])[N:23]([C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:26][CH2:25]2)[C:3]1=[O:4]
Reactant: N[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC(=O)N([C@H]2CC[C@H](C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of the compound (1.3 g) obtained in step 1, benzyl trans-4-aminocyclohexanecarboxylate monohydrochloride (1.1 g), potassium carbonate (0.88 g) and DMF (30 mL) was stirred at 60° C. for 6 hr. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 0→25% ethyl acetate/hexane) to give benzyl trans-4-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)cyclohexanecarboxylate (1.2 g, 81%) as a white powder.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.OO.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH2:17])[CH2:12]1.C(OO)(=O)C>S(=O)(=O)(O)O.C(Cl)Cl>[N:17]([CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([CH3:10])[CH2:12]1)=[O:3]
Reactant: CC1CCCC(N)C1
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)OO
Agent: O=S(=O)(O)O
Agent: OO
Solvent: ClCCl
Product: CC1CCCC(N=O)C1
Temperature: 0 °C
Reaction time: 10 h
Yield: 19.5 %

Procedure:
1-Nitroso-3-methylcyclohexane dimer was prepared as follows: Acetic anhydride (55 g) was added over a 30-minute period, to a solution of 12.2 ml of 90% hydrogen peroxide and one drop of concentrated sulfuric acid in 50 ml of methylene chloride, while the temperature was maintained at 0° C. This solution was then added slowly to 22.8 g of 3-methylcyclohexylamine in 75 ml of methylene chloride while the temperature was maintained at 15° C. After the addition of the peracetic acid solution was completed, the reaction mixture was allowed to warm to room temperature and stirred an additional 10 hours. The solution was extracted with 200 ml of water, 100 ml of cold 15% ammonium hydroxide, 100 ml of 10% sulfuric acid and 100 ml of water, and dried over anhydrous magnesium sulfate. The methylene chloride was removed by distillation to leave a pale blue solid. This solid was recrystallized from methanol-water to give 5.0 g of 1 -nitroso-3-methylcyclohexane dimer as a white solid, mp 81°-83° C. The structure was confirmed by IR, UV and NMR spectra.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([CH3:13])=[C:3]1[C:14](=[O:18])[CH2:15][C:16]#[N:17].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([CH3:13])=[C:3]1[C:14](=[O:18])[CH:15]([C:26](=[O:27])[NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]#[N:17]
Reactant: CCOC(=O)c1c(C)c(C(=O)CC#N)n(C)c1C
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)c(C(=O)C(C#N)C(=O)Nc2ccccc2)n(C)c1C

Procedure:
To the solution of 1.6 g of 1,3,5-trimethyl-4-ethoxycarbonyl-β-oxo-2-pyrrolpropionitrile in 30 ml of dry toluene and 0.8 g of anhydrous triethylamine, 0.8 g of phenylisocyanate are added while stirring. The mixture is allowed to stand 10 minues at the steam cone and at room temperature overnight. It is evaporated, the residue taken up in methanol and the solution treated with 2 ml of 5 N hydrochloric acid and 200 ml of water. The crystals formed are collected, washed with water, triturated with methanol-ethanol and recrystallized from methanol, to yield the 1,3,5-trimethyl-4-ethoxycarbonyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 164°-166°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([Cl:19])=[O:15])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1cc(C(=O)O)c2ccccc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(C(=O)Cl)c2ccccc2c1
Yield: 100 %

Procedure:
3-Cyano-1-naphthoic acid (see Bioorg. Med. Chem. Lett. 2001, 2769; 1.1 g, 5.6 mmol) was slurried in CH2Cl2 (10 mL) and then oxalyl chloride was added with stirring. A drop of DMF was added and the mixture stirred at room temperature overnight under nitrogen. The solvent was removed by evaporation and there was obtained 1.2 g (100%) of 3-cyano-1-naphthoyl chloride as a pale yellow solid. 1H NMR (300 MHz, CDCl3): 7.7-7.8 (m, 1H), 7.8-7.9 (m, 1H), 8.0-8.1 (m, 1H), 8.5 (s, 1H), 8.7 (s, 1H), 8.8 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].[CH2:23](C1C(NC2C3C(=CC=CC=3)CCC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:23][CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCCc3ccccc32)n1
Product: CCc1nc(NC2CCCc3ccccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.34, 7.21, 5.40, 4.54, 2.55, 2.09, 1.95, 1.28; 13C NMR (100 MHz, CDCl3) δ 152.49, 150.66, 141.49, 138.29, 138.21, 129.63, 129.27, 127.64, 126.65, 124.90, 60.81, 49.31, 29.89, 28.87, 29.39, 21.46, 20.32, 14.61, 11.26. (MS/CI) calcd for C18H22BrN3+H 360.3, found 360.3.
Reaction SMILES: [CH3:1][C:2]([CH3:50])([CH3:49])[C@H:3]([NH:7][C:8](=[O:48])[C@@H:9]([CH2:17][C@@H:18]([O:40][Si](C(C)(C)C)(C)C)[CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:4](C)=[O:5].[F-].[CH2:52]([N+:56](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[CH3:50][C:2]([CH3:1])([CH3:49])[C@H:3]([NH:7][C:8](=[O:48])[C@@H:9]([CH2:17][C@@H:18]([OH:40])[CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:4](=[O:5])[NH:56][CH3:52]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CCCCCCC[C@H](C[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C)C(=O)N[C@H](C(C)=O)C(C)(C)C
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC[C@H](C[C@@H](O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a solution of 5.13 g (7.027 mmol) of the product of Example 29 dissolved in 75 mL of THF was added 17.6 mL (0.01 8 mmol) of a 1.0M solution of tetrabutylammonium fluoride in THF. The reaction mixture was stirred at room temperature for 4 h and then diluted with ether. The resulting solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexanes (gradient: 1:3-1:1) to provide 2.78 g (64%) of the desired product as a colorless oil. Electrospray Mass Spec: 617.5 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([OH:27])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(N(CC)CC)C>>[Si:9]([N:16]1[C@H:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C@@H:18]([C@H:25]([O:27][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])[CH3:26])[C:17]1=[O:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
t-Butyldimethylchlorosilane (940 mg, 6.25 mmol) is added in one portion to a solution of (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-carbomethoxymethylazetidin-2-one (1.88 g, 6.25 mmol) and triethylamine (1.27 g, 6.25 mmol) in 15 ml of anhydrous diemthylformamide at 0° C. After 15 min. at 0° C. the cooling bath is removed and the reaction mixture is stirred at room temperature for 24 hrs. Ether (100 ml) is added and the mixture is filtered, then washed with 2.5N hydrochloric acid (20 ml), water (3×20 ml) and brine. The organic phase is dried over magnesium sulfate, then concentrated in vacuo. The residue is chromatographed on silica gel (7:3 petroleum ether:ether) to yield (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-carbomethoxymethylazetidin-2-one. n.m.r. (CDCl3) δ4.1(m, 2), δ3.68(S, 3), δ3.03(dd, 1, J=4.3, 2.7), δ2.8(ABq, 2), δ1.17(d, 3, J=6.6), δ0.98(s, 9), δ0.89(s, 9), δ0.23(s, 6), δ0.1(s, 6).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](SC)=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].CSC(NCC1C=NC=CC=1)=C[N+]([O-])=O.CN>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:18][NH2:19])=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Agent: CN
Agent: CSC(=C[N+](=O)[O-])NCc1cccnc1
Solvent: O
Product: NNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1

Procedure:
The reaction procedure of Example 3 was repeated except that 1-(6-chloro-3-pyridylmethyl)amino-1-methylthio-2-nitroethylene and hydrazine hydrate were used in lieu of 1-methylthio-1-(3-pyridylmethyl)amino-2-nitroethylene and aqueous methylamine solution, respectively. The procedure gave the title compound as pale yellow crystals.
Reaction SMILES: O=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[CH:6]=1)[CH:3]=O.[NH2:16][C:17]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>CCO>[F:13][C:12]([F:15])([F:14])[O:11][C:7]1[CH:6]=[C:5]([C:2]2[CH:3]=[N:26][C:25]3[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([OH:21])=[O:20])[C:17]=3[N:16]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=CC(=O)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cccc(C(=O)O)c1N
Solvent: CCO
Product: O=C(O)c1cccc2ncc(-c3cccc(OC(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
2-oxo-2-(3-(trifluoromethoxy)phenyl)acetaldehyde (1.0 g, 4.58 mmol) and 2,3-diaminobenzoic acid (634 mg, 4.17 mmol) were dissolved in EtOH (70 mL), and stirred at room temperature overnight. The volume was reduced to 30 mL, the precipitate was collected by filtration, washed with ethanol, and dried under vacuum to give 3-(3-(trifluoromethoxy)phenyl)quinoxaline-5-carboxylic acid as a gray solid (1.0 g, yield: 72% yield).
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:18]=[CH:17][C:5]([O:6][CH2:7][C:8]3[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[O:11][C:12]=3[CH3:13])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1oc(C(=O)O)cc1COc1ccc(I)cc1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)c1

Procedure:
Compound (116) was prepared from compound (26) and (3-methoxy-phenyl)-boronic acid by adapting the procedure of Example 27B. LC/MS System B; Rt=1.79 mins, m/z (ES−)=337 (M−H for C20H18O5).