Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[Br-].[NH4+].O1C[CH2:13][CH2:12][CH2:11]1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[OH:7][CH:1]([C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH:12]=[CH2:11]
Reactant: O=Cc1ccco1
Reactant: C1CCOC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=CCC(O)c1ccco1

Procedure:
Reaction and after-treatment were carried out in the same manner as in Example 3 except that an equimolar amount of furfural was used in place of 5-methylfurfural, and that ammonium bromide and tetrahydrofuran were used in place of ammonium chloride and toluene, respectively, in the same weights as those of the latter, to obtain 50.6 g of the fraction of 2-(1-hydroxy-3-butenyl)-furan (content, 99.3%) (yield, 91.0%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][NH2:10])[CH:6]=[CH:5][C:4]=1[OH:11].[CH3:12][CH:13]([C:17](=O)[CH3:18])[C:14](=O)[CH3:15]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]([N:9]2[C:17]([CH3:18])=[C:13]([CH3:12])[C:14]([CH3:15])=[N:10]2)[CH:6]=[CH:5][C:4]=1[OH:11]
Reactant: NNc1ccc(O)c(Cl)c1
Reactant: CC(=O)C(C)C(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1nn(-c2ccc(O)c(Cl)c2)c(C)c1C

Procedure:
A mixture of 2-chloro-4-hydrazinophenol hydrochloride salt 3.0 g, 3-methyl-2,4-pentanedione, ethanol 100 ml was stirred with heating under reflux for twelve hours. The solvent was distilled off and thereto was added ethyl acetate 200 ml, and the resulting mixture was stirred for one hour. The precipitates was filtered and was washed with hexane, and was then dried under reduced pressure to give 2-chloro-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenol 3.3 g.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:21]=[C:22]([S:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:23]=[N:24][CH:25]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[N:24][CH:23]=[C:22]([S:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)(=[O:28])=[O:27])[CH:21]=2)[CH:11]=1
Reactant: O=S(=O)(c1cncc(Br)c1)N1CCOCC1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1cncc(S(=O)(=O)N2CCOCC2)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-chloro-2-ethynyl phenoxy)acetate (Intermediate 3) and 4-[(5-bromopyridin-3-yl)sulfonyl]morpholine (Apollo), the title compound was obtained as an off-white solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:23]([NH:30][CH2:31][CH2:32][NH2:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C=O)C>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:33][CH2:32][CH2:31][NH:30][C:23](=[O:24])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Triethylamine (30.98 g, 306.1 mmol) was added to a solution of 2,4-dichloro-3-nitroquinoline (50.0 g, 204 mmol) in DMF (200 mL). A solution of N-Boc-ethylenediamine (32.7 g, 204 mmol) in DMF (100 mL) was then added in small portions. The reaction was stirred at room temperature, and then most of the DMF was removed under reduced pressure. Water (600 mL) was added to the residue, and the mixture was stirred for three hours. A solid formed and was isolated by filtration, washed with water, and dried under house vacuum to provide 71 g of tert-butyl 2-[(2-chloro-3-nitroquinolin-4-yl)amino]ethylcarbamate as a yellow solid. A portion of the material (15 g) was dissolved in dichloromethane (200 mL), and the resulting solution was washed with brine (2×100 mL) and deionized water (2×100 mL), dried over magnesium sulfate, filtered, concentrated under reduced pressure, and further dried on a vacuum pump for three days to provide 13.99 g of product.
Reaction SMILES: [OH:1][CH:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=O)[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH2:4][N:3]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccc(N2C(=O)C3CCCCC3C2O)cc1
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(N2CC3=C(CCCC3)C2=O)cc1
Yield: 92.1 %

Procedure:
To 20 ml of acetic acid were added 2.87 g (0.01 mole) of the 4-(3-hydroxy-1-oxo-hexahydro-2-isoindolinyl)phenylacetic acid prepared in step (b) above. The mixture was refluxed, with heating, for 2 hours and the solvent was then evaporated off under reduced pressure, leaving a crystalline residue. These crystals were washed with water, dried and recrystallized from a mixture of ethanol and petroleum ether, giving 2.5 g (89%) of 4-(1-oxo-4,5,6,7-tetrahydro-2-isoindolinyl)phenylacetic acid, melting point 189°-191° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]([OH:15])=O)=[CH:9][CH:10]=[C:5]2[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:41][C@H:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([O:11][CH2:12][C:13]([NH:49][C@H:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH3:41])=[O:15])=[CH:9][CH:10]=[C:5]2[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1
Reactant: C[C@H](N)c1ccccc1
Reactant: Cn1nc(-c2ccccc2)c2ccc(OCC(=O)O)nc21
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)COc1ccc2c(-c3ccccc3)nn(C)c2n1)c1ccccc1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of 2-(1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetic acid (0.14 g, 0.494 mmol), DIC (0.094 g, 0.744 mmol) and HOBt (0.087 g mg, 0.644 mmol) in DMF (4.0 ml) was stirred at rt for 15 min. (S)-(−)-α methyl benzyl amine (0.072 g, 0.594 mmol) was added to the reaction mixture at rt and stirring was continued overnight. The reaction mixture was concentrated. Diethyl ether was added and the mixture was washed with water, followed by brine and dried over Na2SO4. Concentration of the organic layer furnished the crude product as an off-white solid. The product was purified by preparative HPLC using acetonitrile/water as mobile phase to yield the title compound as a white solid (0.133 g, 68%). [1H-NMR (CDCl3, 300 MHz) δ 8.22 (d, 1H), 7.96-7.89 (m, 2H), 7.55-7.38 (m, 3H), 7.37-7.21 (m, 5H), 6.73 (d, 1H), 6.61 (d, 1H), 5.35-5.21 (m, 1H), 4.99 (s, 2H), 4.03 (s, 3H), 1.53 (d, 3H); HPLC RtA=5.273 min (98%) LCMS RtE=1.921 min; [M+H]+=387.1; Mp=55-56° C.]
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2[O:42]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[CH:19]([OH:42])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a stirred solution of methyl 2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (7.8 g, 22.27 mmol) in THF (40 mL) at −78° C. was added KHMDS (44.5 mL, 22.27 mmol) dropwise over 30 min. The mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (8.73 g, 33.4 mmol) in THF (50 mL) was added over 30 min and the reaction mixture was stirred for additional 2 h at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (40 mL). The reaction mixture was allowed to warm to room temperature and then diluted with ethyl acetate (200 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (4.2 g, 51.5%). 1H NMR (500 MHz, CHLOROFORM-d) δ 8.05-7.97 (m, 1H), 7.88 (dt, J=6.7, 1.8 Hz, 1H), 7.44-7.38 (m, 2H), 6.93 (s, 1H), 5.76 (s, 1H), 3.84 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH:1]([NH:4][C:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=[C:7]([S:16][CH3:17])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1NC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc(C(=O)O)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 5.0 g (19.6 mmol) of ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate in 20 mL of ethanol is added a solution of 0.8 g (20.6 mmol) of sodium hydroxide in 30 mL of water. The reaction suspension is stirred at room temperature overnight. The reaction solution is diluted with 100 mL of water and washed twice with diethyl ether. The aqueous phase is neutralized with 20.6 mL of 1N HCl. The precipitate is filtered and washed twice with water, dried under vacuum at 70° C. to give 4.0 g (90%) of the title compound: mp 202-203° C. (dec).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:14][C:15]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:16]=1[CH2:17][N:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21](=[O:29])(=[O:28])[N:20](CC2C=CC=CN=2)[C:19]1=[O:37]>>[Cl:14][C:15]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:16]=1[CH2:17][N:18]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21](=[O:29])(=[O:28])[N:20]([CH2:2][C:3]2([CH3:7])[CH2:6][O:5][CH2:4]2)[C:19]1=[O:37]
Reactant: CC1(CBr)COC1
Reactant: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC1(CN2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)COC1

Procedure:
The title compound (123 mg, 0.29 mmol) was prepared from (IntE1) (0.3 g, 0.88 mmol), 3-(bromomethyl)-3-methyloxetane (0.21 g, 1.32 mmol) and Cs2CO3 (0.86 g, 2.64 mmol) using the methods of (128).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][CH:10]=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:11]=[CH:10][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccnc1-c1ccccc1
Product: Clc1nccnc1-c1ccccc1

Procedure:
A 0.01 mol. sample of 3-phenylpyrazin-2(1H)one is mixed with 9.0 ml. of phosphorous oxychloride (POCl3) and refluxed for 5-6 hr. The excess phosphorous oxychloride is removed by distillation at reduced pressure and 25 ml. of methylene chloride added to the residue. The resultant solution is stirred with a few milliliters of ice water, dried, evaporated and the residue recrystallized to yield the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]4[C:19]=3[C:14](=[CH:15][CH:16]=[CH:17]4)[N:13]=2)[CH:2]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>N1C=CC=CC=1>[N:13]1[C:14]2[C:19]3[C:18](=[CH:23][CH:22]=[CH:21][C:20]=3[C:12]=1[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: c1cncc(CCCCNC2=Nc3cccc4cccc2c34)c1
Solvent: c1ccncc1
Product: O=C(c1cccc(C(F)(F)F)c1)N(CCCCc1cccnc1)C1=Nc2cccc3cccc1c23
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5.0 grams of N-(4-(3-pyridinyl)butyl)benz(cd)indol-2-amine in 50 ml of pyridine was stirred as 2.5 ml of 3-trifluoromethylbenzoyl chloride was slowly added. The reaction mixture was stirred at room temperature for 18 hours, and drowned onto 500 ml of ice. The precipitate was collected, washed with water and dried. Recrystallization from chloroform-hexane gave 3.95 grams of the title product, mp 122° C.-123° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=2.[OH-].[Na+]>CO.O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCCC3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2-methylpiperidin-1-yl)-2-phenylquinoxaline-6-carboxylate (107.9 mg, 0.30 mmol, 1.00 equiv) in methanol (20 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (60 mg, 1.50 mmol, 5.00 equiv) in water (3 mL) with stiffing. The resulting solution was stirred overnight at 50° C. in an oil bath and concentrated under vacuum and diluted by 10 ml of water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solid was collected by filtration and washed with methanol. This resulted in 54 mg (50%) of 3-(2-methylpiperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].CCN(C(C)C)C(C)C.[CH3:24][C:25]([SH:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([S:28][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14])([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)S
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1c(C#N)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
To the solution of 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c, 1.0 g, 3.18 mmol) in anhydrous DMF (1 mL) and DIEA (1.67 mL, 9.54 mmol) was added 2-methyl-2-propanethiol (0.72 ul, 6.4 mmol). The mixture was stirred at room temperature for 4 h. The reaction was extracted with methylene chloride (2×100 mL). The combined organic layers were successively washed with water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-50% ethyl acetate in hexanes in 30 min) afforded 4-tert-butylsulfanyl-6-iodo-quinoline-3-carbonitrile (0.57 g, 48%) as a white solid. LC-MS m/e 369 (MH+).
Reaction SMILES: Br[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][C@@H:13]2[CH3:24])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([O:27][CH3:28])=[O:26])[CH:8]=2)[N:3]=1.[CH3:29][C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][C:35](B1OC(C)(C)C(C)(C)O1)=[CH:34][CH:33]=2.[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>[CH3:29][C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][C:35]([C:2]1[C:11]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:14][C@@H:13]3[CH3:24])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:25]([O:27][CH3:28])=[O:26])[CH:8]=3)[N:3]=1)=[CH:34][CH:33]=2
Reactant: COC(=O)c1ccc2nc(Br)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
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]c(C)cc4c3)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of (S)-methyl 2-bromo-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (200 mg, 0.45 mmol) in dioxane (7 ml) was added 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (140 mg, 0.54 mmol), K3PO4 (190 mg, 0.90 mmol), and Pd(PPh3)4 (26 mg, 0.02 mmol). The resulting solution was stirred for 2 h at 90° C. Then the mixture was concentrated under vacuum, and the residue was purified via silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2-methyl-1H-indol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid (202 mg, 91%).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[O:3].Cl.[NH2:15][C@H:16]([C:21]([O:23]C)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19].[OH-].[Na+].Cl>CCN(CC)CC>[O:3]=[C:2]1[N:15]([C@@H:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:21]([OH:23])=[O:22])[C:6](=[O:8])[C:5]2[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1]1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: COC(=O)c1ccccc1N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)O)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 80 °C

Procedure:
Refer to Scheme 1, a mixture of methyl 2-isocyanatobenzoate (0.5 g, 2.82 mmol) and (S)-methyl leucinate HCl (0.52 g, 2.82 mmol) salt and 1 mL of Et3N was heated to 80° C. for 2 hours. 2 mL of 2M NaOH aqueous solution was added to above mixture and then heated to 100° C. overnight. The mixture was neutralized with concentrated HCl. Extracted by EtOAc and dried over MgSO4. Removing solvent gave the crude product, which used for next step without further purification. [M+H] calc'd for C14H16N2O4, 277; found, 277.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[NH:10]1[CH:14]=[CH:13][NH:12][C:11]1=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:20]([C:14]1[NH:10][C:11](=[O:15])[NH:12][CH:13]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1[nH]cc[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccccc1)c1c[nH]c(=O)[nH]1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 51 ml of nitrobenzene is added 1.68 g of 1,3-dihydro-2H-imidazol-2-one, 5.3 g of aluminum chloride and 3.1 g of benzoyl chloride. The mixture is stirred for 3 hours at 60° C. and poured into ice water. The solids are filtered, washed with ether and recrystallized twice from methyl alcohol-water to afford the title compound. M.P. 329°-30° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9](=[N:35][OH:36])[C:10]([NH:12][CH:13]1[C:33](=[O:34])[N:15]2[C:16]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11])=O>C(O)C.O1CCCC1.O>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9](=[N:35][OH:36])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:4]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
Thiourea (0.18 g.) was added to a suspension of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 1.05 g.) in ethanol (25 ml.), tetrahydrofuran (25 ml.) and water (5 ml.), and stirred at room temperature for 4 hours. The resultant solution was concentrated under reduced pressure and cooled. The residue was crystallized by treating with a mixture of tetrahydrofuran and ethyl acetate, and collected by filtration to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.95 g.), colorless crystals, mp 172° to 175° C. (dec.)
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13]1([C:16](Cl)=O)[CH2:15][CH2:14]1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH:13]1([C:16]2[O:12][C:11]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:2]=2)[CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cccc2oc(C3CC3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.4 %

Procedure:
To a mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (0.25 g, 1.07 mmol) and cyclopropanecarbonyl chloride (0.10 mL, 1.07 mmol) in dichloromethane (8 mL) was added triethylamine (0.60 mL, 4.28 mmol) dropwise, then the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane, and then washed with 2 N HCl. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in toluene (8 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (204 mg, 1.07 mmol). The reaction mixture was then heated to reflux for 5 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated then washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, 9:1 to 3:1 ethyl acetate/methanol) to afford 2-cyclopropylbenzoxazole-4-carboxylic acid (0.14 g, 65%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 12.92 (br s, 1H), 7.85 (dd, J=8.0, 0.6 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 2.37-2.31 (m, 1H), 1.26-1.16 (m, 4H); MS (ESI+) m/z 204 (M+H).
Reaction SMILES: Br[N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].C(O)C#CCO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:34][C:35]1[N:43]=[C:42]2[C:38]([NH:39][CH:40]=N2)=[C:37]([Cl:44])[N:36]=1.C([O-])([O-])=O.[K+].[K+]>ClCCl.CN(C)C=O>[NH2:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[CH:40][N:2]2[CH2:6][C:5]#[C:4][CH2:3][OH:8])=[C:37]([Cl:44])[N:36]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: OCC#CCO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc(Cl)c2ncn(CC#CCO)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
N-Bromosuccinimide (1.78 g, 10 mmol) was added in portions to a stirred suspension of 2-butyne-1,4-diol (2.50 g, 30 mmol) and triphenylphosphine (2.62 g, 10 mmol) in 20 ml of dichloromethane at room temperature. After 1 h, the unreacted butynediol was removed by filtration. The solution was evaporated in vacuum to small volume, dissolved in 20 ml of dry dimethylformamide (DMF) and added to a suspension of 2-amino-6-chloropurine (1.70 g, 10 mmol) and finely ground anhydrous K2CO3 (2.07 g, 15 mmol) in 75 ml of dry DMF, stirred at 0° C. The stirring was continued at room temperature for 3 days. Then the mixture was evaporated in vacuum to dryness. Chromatography (silica gel, CHCl3 +MeOH 7+1) afforded 467 mg (20%; after recrystallization from water to remove 2-butyne-1,4-diol) of 4-(2-amino-6-chloropurin-9-yl)-2-butyn-1-ol (TLC on silica gel, CHCl3 +MeOH 5+1; Rf 0.57).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=O)=O)=CC=1.[I-:21].[Na+].O>CC(C)=O>[I:21][CH2:11][CH:12]1[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)OCC2=Cc3ccccc32)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: ICC1Cc2ccccc21
Yield: 88 %

Procedure:
6 g of benzocyclobuten-1-ylmethyl para-toluenesulfonate (prepared according to the process described in J.A.C.S., (1975), 154, p. 347) are mixed with 6.2 g of sodium iodide in 85 ml of acetone. The reaction medium is brought to reflux for 8 hours, then introduced into 150 ml of water and extracted several times with ethyl ether. The organic phase is then washed with normal sodium thiosulfate solution, dried over anhydrous magnesium sulfate and concentrated to obtain the expected compound in the form of an oil.