Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:26]2[O:25][C:9]3[C:10](=[O:24])[N:11]([C@@H:13]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14](O)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[C:26]2[O:25][C:9]3[C:10](=[O:24])[N:11]([C@@H:13]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:14]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:15])[CH2:12][C:8]=3[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Reactant: Nc1ccccn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccn1)[C@H](CC1CCCCC1)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 29.5 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (100 mg, 0.27 mmol), commercially available 2-aminopyridine (30 mg, 0.31 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (40 mg, 0.29 mmol), and N-hydroxybenzotriazole (HOBt) (56 mg, 0.29 mmol) in methylene chloride (5 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-N-pyridin-2-ylpropionamide (36 mg, 30%), as a white solid. 1H NMR (DMSO-d6) δ: 10.86 (br. s., 1H), 8.34 (d, J=3.4 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.3 Hz, 1H), 7.05-7.16 (m, 2H), 5.10 (d, J=6.8 Hz, 1H), 4.43 (d, J=19.1 Hz, 1H), 4.06 (d, J=19.1 Hz, 1H), 3.83 (br. s., 2H), 1.51-1.87 (m, 7H), 0.75-1.30 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1ccc(Sc2ccc(Br)cc2)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(Cl)cc3)cc2)c1C
Yield: 37.9 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-bromo-4-(4-chlorophenylsulfanyl)-benzene (0.25 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(4-chloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.094 g, 37%) as a solid. MS calcd. for C26H21ClFO2S [(M+H)+] 451, obsd. 451.0.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([CH:28]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=1)[C:29]([O-:31])=[O:30])(C)C.N1CCCCC1.[C:47]1([CH3:57])[CH:52]=CC(S(O)(=O)=O)=C[CH:48]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:48][C:47]([CH3:57])([O:31][C:29]([CH2:28][O:32][C:33]1[CH:34]=[C:35](/[CH:39]=[C:18](/[C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)\[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:36]=[CH:37][CH:38]=1)=[O:30])[CH3:52]
Reactant: CCOC(=O)Cc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CC(C)(C)C(Oc1cccc(C=O)c1)C(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C(=C\c1cccc(OCC(=O)OC(C)(C)C)c1)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 18 h
Yield: 97 %

Procedure:
A mixture of ethyl 4,5-diphenyl-2-oxazoleacetate (25.00 g, 81 mmol), 1,1-dimethylethyl(3-formylphenoxy)acetate (19.22 g, 81 mmol), piperidine (0.69 g, 8 mmol), p-toluenesulfonic acid (catalytic quantity) and toluene (200 mL) was heated at reflux under a Dean-Stark trap. After about 18 hours, the mixture was cooled, diluted with CH2Cl2 and washed with water (2×) and saturated NaCl solution before being dried over Mg2SO4. Evaporation of the solvent left an oil which was subjected to chromatography on a column of silica gel. Elution with a mixture of hexanes and ethyl acetate (4:1) afforded the title compound (41.49 g, 97%) as an oil. IR (film) 1760, 1730 (CO2R) cm-1 ; 1H NMR (CDCl3) δ1.28 to 1.36 (4H, overlapping triplets, OCH2CH3), 1.37 and 1.47 (18H, singlets, C(CH3)3), 4.30 and 4.50 (4H, singlets, OCH2CO2tBu), 4.33 (2H, q, J=7Hz, OCH2CH3 of one isomer), 4.41 (2H, q, J=7Hz, OCH2CH3 of other isomer), 6.70 to 7.70 (29H, m, aromatic H+1 olefinic H), 8.07 (1H, s, olefinic H of (E) isomer); MS m/z 526 (MH+).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15]C(OC(C)(C)C)=O)/[CH:9]=[C:10](/[CH3:14])\[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.S(Cl)([Cl:31])=O>C(O)C>[ClH:31].[NH2:15][C@H:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:6][CH:5]=1)/[CH:9]=[C:10](/[CH3:14])\[C:11]([OH:13])=[O:12]
Reactant: C/C(=C/[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCO
Product: C/C(=C/[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)O
Product: Cl
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
5 g (Z)—(R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid (5a, R1=Boc, R2=H, R3=CO2H) is added to ethanol (50 ml) at room temperature. The mixture was stirred for 15 min and a further quantity of ethanol (10 ml) added. The mixture is then heated to 65° C. Thionyl chloride (1.44 ml) is added and the mixture stirred for 30 min. The volatiles are removed under reduced pressure. Heptane (50 ml) is added to the residue and the volatiles removed under reduced pressure. Ethyl acetate (30 ml) is added to the residue. The solid is collected by filtration. A portion of the solid (1 g) is suspended in ethyl acetate and stirred for 1 h at room temperature. The solid is collected by filtration and dried in vacuo to afford (Z)—(R)-4-amino-5-biphenyl-4-yl-2-methyl-pent-2-enoic acid hydrochloride (5a, R1=H, R2=H, R3=CO2H). 1H-NMR (DMSO): 1.79 (3H), 2.88 (1H), 3.10 (1H), 4.79 (1H), 5.91 (1H), 7.24-7.60 (9H), 8.32 (3H), 12.90 (1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:12])([CH3:11])[C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]>C(OCC)(=O)C>[Br-:13].[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH3:12])([CH3:11])[CH:2]([CH3:1])[NH+:10]=[C:5]12)([OH:21])=[O:20]
Reactant: CC1=Nc2ncccc2C1(C)C
Reactant: O=C(O)CCCCCBr
Solvent: CCOC(C)=O
Product: CC1[NH+]=C2C(=CC=CN2CCCCCC(=O)O)C1(C)C
Product: [Br-]
Temperature: 120 °C

Procedure:
A mixture of 0.54 g of 2,3,3-trimethyl-3H-pyrrolo[2,3-b]pyridine and 1.32 g of 6-bromohexanoic acid is heated at 120° C. for one hour. Ethyl acetate (10 mL) is added, and the reaction mixture is heated at reflux for 15 minutes, then cooled to room temperature. The supernatant liquid is decanted to yield the product.
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=O.C=O.[ClH:13].[CH3:14][NH:15][CH3:16].[CH3:17][C:18]([CH3:20])=[O:19]>C(O)C>[ClH:13].[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:17][C:18](=[O:19])[CH2:20][N:15]([CH3:16])[CH3:14])=[CH:5][CH:6]=1
Reactant: CC(C)=O
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)CC(=O)Cc1ccc(F)cc1
Yield: 51 %

Procedure:
A suspension of 4-fluoroacetophenone (8.8 ml, 72.4 mmol), paraformaldehyde (2.9 g, 94.1 mmol), dimethylamine hydrochloride (7.8 g, 96.78 mmol) conc. HCl (1 ml) in ethanol (10 ml) was heated under reflux for 3 hrs. The solution was added to acetone (50 ml), allowed to cool and placed in the fridge overnight. The resulting white solid was filtered washed with acetone (100 ml) and dried over P2O5 under vacuum to give 1-(4-fluorophenyl)-3-(N,N-dimethylamino)propanone hydrochloride 7.82 g, (51%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6](C)[C:5]2(O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.N[OH:23]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:23])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NO
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1(O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ccc(Br)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 77.6 %

Procedure:
A stirred mixture of 28.28 g (0.085 mole) of 6-bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone and 17.6 g (0.25 mole) of hydroxylamine hydrochloride in 425 ml of ethanol was refluxed for 192 hours and then cooled. The solid portion of the reaction mixture was collected on a filter, washed with ethanol, and dried in air to give 20.92 g (0.066 mole, 78%) of 6-bromo-4-phenyl-2(1H)-quinazolinone 3-oxide as light yellow crystals: mp 275°-276°.
Reaction SMILES: [CH:1]1([N:4]([C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[F:18])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1>>[CH:1]1([NH:4][C@@H:12]2[CH2:17][CH2:16][N:15]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=3)[CH2:14][C@@H:13]2[F:18])[CH2:2][CH2:3]1
Reactant: CCc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@@H]1CCNC[C@@H]1F
Product: CCc1cnc(N2CC[C@@H](NC3CC3)[C@@H](F)C2)nc1

Procedure:
The title compound is prepared from tert-butyl N-cyclopropyl-N-[(3S,4R)-3-fluoropiperidin-4-yl]carbamate and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described for Intermediate 87. LC (method 20): tR=1.80 min; Mass spectrum (APCI): m/z=265 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:29]([NH:32][NH2:33])(=[O:31])[CH3:30]>C(OCC)(=O)C.ClCCl>[C:29]([NH:32][NH:33][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)(=[O:31])[CH3:30]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CC(=O)NN
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NNC(=O)c1ccc(C)c([N+](=O)[O-])c1
Yield: 43.9 %

Procedure:
4-Methyl-3-nitrobenzoic acid (3.00 g, 16.5 mmol) was added to dichloromethane (50 ml), triethylamine (3.0 ml, 21.3 mmol) and isobutyl chloroformate (2.80 ml, 21.5 mmol) were added under ice-cooling with stirring, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was ice-cooled again, acetohydrazide (2.45 g, 33.1 mmol) was added with stirring, and the mixture was stirred at room temperature for about 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 10% aqueous citric acid solution, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was washed with diethyl ether and hexane to give the title compound (1.72 g, yield 44%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][NH2:12].Cl.Cl[C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=C[C:16]=1N.C1C[O:28][CH2:27]C1>>[CH2:20]([C:19]1[NH:22][C:27](=[O:28])[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[Cl:1])[N:12]=1)[CH2:21][CH2:15][CH3:16]
Reactant: NNc1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: C1CCOC1
Agent: Cl
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)[nH]1
Yield: 19 %

Procedure:
By the procedure of Example 4, Step C, 2-chloro-5-nitrophenylhydrazine [generated from the hydrochloride, which was prepared from 2-chloro-5-nitroaniline according to H. Stroh and G. Westphal, Chem. Ber. 96, 184 (1963), by partitioning between ether and 1N sodium carbonate] was reacted with ethyl N-carbethoxyvalerimidate (from Example 4, Step B). Enough THF was added to the reaction mixture to ensure dissolution of all starting material. After work-up, the residue was purified by flash chromatography on silica gel (gradient elution with 0.5-5.0% methanol in CH2Cl2) to give a 19% yield of the title compound as an orange solid, mp 145°-147° C., homogeneous by TLC (19:1 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 297 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[N:7]=1.[Br:11]Br>Br>[BrH:11].[OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=[O:10])[CH2:9][Br:11])[N:7]=1
Reactant: BrBr
Reactant: CC(=O)c1c[nH]c(CO)n1
Agent: Br
Product: O=C(CBr)c1c[nH]c(CO)n1
Yield: 112.8 %

Procedure:
1.826 g (0.013 mol) of 2-hydroxymethyl-4- acetylimidazole was dissolved in 40 ml of 48% hydrobromic acid and 2.1 g (0.013 mol) of bromine was added. The reaction was warmed at 80° for 2 hours and then concentrated in vacuo to a solid. This material was triturated with isopropylether and the resultant solid was collected by filtration and was washed with ether and dried to give 2.2 g (56%) of 2-hydroxymethyl-4-bromoacetylimidazole hydrobromide, mp 183° with decomposition. nmr (DMSO-d6) (δ): 8.8 (s, 1H); 4.8 (s, 2×2H).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:27])[CH2:4][CH:5]([S:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.C(O)C>C(Cl)Cl>[OH:1][NH:2][C:3](=[O:27])[CH2:4][CH:5]([S:16]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:36])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)NO)cc1OC
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(S(=O)C(CCCCc2ccccc2)CC(=O)NO)cc1OC
Reaction time: 0.17 h
Yield: 38.1 %

Procedure:
To a solution of (±)-N-hydroxy-3-(3,4-dimethoxyphenyl)sulfanyl-7-phenylheptanamide (1.26 g, 3.24 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. is added m-CPBA (0.56 g, 3.24 mmol) in one portion. The mixture is stirred for 10 minutes after which TLC analysis indicated complete reaction. Ethanol (2 mL) is added and the mixture is partitioned between water (100 mL) and EtOAc (100 mL). Aqueous layer is extracted with EtOAc (2×50 mL) and combined organic phases are washed successively with 5% aqueous Na2S2O3 (50 mL), water (50 mL), 5% aqueous NaHCO3 (50 mL), water (50 mL) and brine (50 mL) then dried over MgSO4 and concentrated. The resulting yellow oil is chromatographed on silica gel (CH2Cl2 →2% MeOH/CH2Cl2 →5% MeOH/CH2Cl2) to afford 0.5 g of (±)-N-hydroxy-3-(3,4-dimethoxyphenyl)sulfinyl-7-phenylheptanamide (38%) as a mixture (2:1) of diastereomers in the form of a white foam. TLC analysis [CH2Cl2 /MeOH, 19:1, Rf (sulfide)=0.20, Rf (sulfoxide)=0.10]. 1H NMR (300 MHz, d6 -DMSO) δ 1.35-1.72 (m, 6H), 1.88-2.20 (m, 2H), 2.49 (m, 2H), 3.05 (m, 1H), 3.78 (br s, 6H), 7.0-7.18 (m, 6H), 7.22 (m, 2H), 8.80 (m, 1H), 10.49 (m,1H) ppm. Mass spectrum (FAB) m/z 406 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C.O1CCCC1>[CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 4′-(2-benzylbenzofuran-3-yl)biphenyl-4-carbaldehyde (5.0 g, 12.9 mmol) in ethanol (100 mL) and tetrahydrofuran (25 mL) was added sodium borohydride (980 mg, 25.8 mmol) as a solid in 3 portions. The reaction was stirred at room temperature for 1 hour (TLC control) and then poured into water (100 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the title compound as a white solid (5.02 g, 99%).
Reaction SMILES: [CH:1]1([N:4]([CH3:27])[C:5]2[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[NH:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[CH:34][CH:35]=2)[CH:30]=[N:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[CH:1]1([N:4]([CH3:27])[C:5]2[C:6]([C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[NH:28][N:29]=[CH:30]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N(C)C3CC3)nc2c1
Reactant: OB(O)c1ccc2[nH]ncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N(C)C3CC3)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (300 mg, crude) in dioxane (10 mL), 1H-indazol-5-ylboronic acid (430 mg, 1.76 mmol), K3PO4 (370 mg, 1.76 mmol), and Pd(PPh3)4 (51 mg, 0.04 mmol). The resulting solution was stirred for 1 h at 90° C. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%-50% ethyl acetate in petroleum ether to afford methyl 3-(cyclopropyl(methyl)amino)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylate as a yellow solid (40 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[N+](=[C:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][CH:14]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:15]([O:17][CH3:18])=[O:16])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COC(=O)C(CC(C)C)=[N+]=[N-]
Reactant: Nc1ccc2ccncc2c1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(CC(C)C)Nc1ccc2ccncc2c1
Temperature: 80 °C

Procedure:
800 mg of rhodium(II) acetate (dimer) are added to a solution of 5.19 g (36.0 mmol) of 7-aminoisoquinoline and 5.47 g (35.0 mmol) of methyl 2-diazo-4-methylpentanoate in 200 ml of toluene, and the mixture is heated at 80° C. for 12 hours. The cooled reaction mixture is filtered, and the filtrate is evaporated. The residue is chromatographed on a silica-gel column with ethyl acetate as eluent, giving methyl 2-(isoquinolin-7-ylamino)-4-methylpentanoate as a yellowish solid; ESI 273.
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.ClCl.[C:8]([S:11][C:12]([S:34][C:35](=[O:37])[CH3:36])=[C:13]([N:27]1C(SC)[CH2:29][C:28]1=[O:33])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([S:11][C:12]([S:34][C:35](=[O:37])[CH3:36])=[C:13]([N:27]1[CH:1]([Cl:5])[CH2:29][C:28]1=[O:33])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:10])[CH3:9]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CSC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(SC(C)=O)SC(C)=O
Agent: ClCl
Solvent: ClCCl
Product: CC(=O)SC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl

Procedure:
Following the procedure of Example 1(b), a carbon tetrachloride solution containing an equimolar amount of chlorine was added to a solution of p-nitrobenzyl 2-[bis(acetylthio)methylidene]-2-(4-methylthio-2-azetidinon-1-yl)acetate (144 mg, 0.306 mmole) in methylene chloride (2 ml) to give p-nitrobenzyl 2-[bis(acetylthio)methylidene]-2-(4chloro-2-azetidinon-1-yl)acetate. This crude 4-chloroazetidinone derivative was dissolved in methylene chloride (3 ml) and triethylamine (43 μl), and then 135 μl of a 30% methanol solution of methylamine were added thereto, after which the mixture was stirred for 15 minutes. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent:ethyl acetate) to afford 60 mg of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].O>C(#N)C>[C:19]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(=O)NNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
15.3 g of p-nitrophenylhydrazine and 10.1 g of triethylamine were dissolved in 100 ml of acetonitrile, and 7.9 g of acetyl chloride was added dropwise over 15 minutes with cooling with water. After conclusion of the addition, the mixture was stirred at 25° C. for 1 hour and thereafter 100 ml of water as added thereto. The precipitated crystals were filtered off, and washed with acetonitrile to obtain 16.6 g of 1-acetyl-2-(4-nitrophenyl)hydrazine. Yield: 16.6 g. Melting point: 209°-214° C.