Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:31]([F:34])([F:33])[F:32])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:30])[CH2:24][N:23]([C:25](=O)[CH:26]([CH3:28])[CH3:27])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:31]([F:34])([F:33])[F:32])[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:30])[CH2:24][N:23]([C:25](=[S:44])[CH:26]([CH3:28])[CH3:27])[CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)C(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Solvent: Cc1ccccc1
Product: CC(C)C(=S)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)-3-fluoroazetidin-1-yl)-2-methylpropan-1-one (500 mg, 1.9 mmol) was dissolved in toluene (35 mL). Lawesson's reagent (790 mg, 1.9 mmol) was added and the reaction mixture was heated to reflux for 2 hours, then cooled to room temperature and allowed to stir overnight. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The crude residue from the filtrate was chromatographed (40 g Redi-Sep column) eluting from 100% heptane to 25:75 EtOAc:heptane to afford the product (415 mg, 80%) as a solid. 1HNMR (CDCl3): 7.77 (2H), 7.61 (2H), 7.54 (2H), 4.68 (4H), 4.12 (1H), 3.72 (1H), 2.88 (1H), 1.28 (6H); m/z (Cl) 537 ([M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[H-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccnc2)cc1
Temperature: 130 °C

Procedure:
1-Chloro-4-fluorobenzene (16.3 g, 124 mmol) and imidazole (5.0 g, 73.4 mmol) are dissolved in N,N-dimethylformamide (30 ml) and admixed while stirring with sodium hydride (60% strength in mineral oil; 3.82 g, 95.4 mmol) and then heated at 130° C. for 5 hours. After cooling, the reaction mixture is slowly poured into water. The precipitate formed is subsequently filtered off, washed with petroleum ether and subsequently dried under reduced pressure. This gives 10.3 g of 1-(4-chlorophenyl)imidazole.
Reaction SMILES: C(O)C.Cl[C:5]1[CH:10]=[C:9]([CH:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[C:8]([Cl:30])=[CH:7][N:6]=1.O.[NH2:32][NH2:33]>CCCCCC>[Cl:30][C:8]1[C:9]([CH:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])=[CH:10][C:5]([NH:32][NH2:33])=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(Cl)ncc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: CCCCCC
Product: NNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Yield: 18 %

Procedure:
To an ethanol (10 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridine (524 mg, 1.17 mmol) obtained in Example 57 was added hydrazine monohydrate (2 ml). The resulting mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure to afford a pale yellow oil. To the resulting oil was added hexane-ether and the solid thus precipitated was collected by filtration to give the title compound (95 mg, 0.214 mmol, 18%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[NH2:17][CH:18]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:19]1[CH:33]=[CH:32][C:22]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:1][C:2]1[C:7]([C:8]([NH:17][CH:18]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:19]2[CH:20]=[CH:21][C:22]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH:32][CH:33]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(C(N)c2ccc(OC)cc2)cc1)OCC
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(NC(=O)c2cnc(-c3cccnn3)nc2O)c2ccc(OC)cc2)cc1)OCC
Temperature: 50 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (325 mg, 1.5 mmol) and diethyl 4-(amino(4-methoxyphenyl)methyl)benzylphosphonate, 32-f, (540 mg, 1.5 mmol) was dissolved in DMF (5 ml), HATU (570 mg, 1.5 mmol) and DIEA (590 mg, 4.5 mmol) were then added, the reaction mixture was stirred for 2 h at 50° C. under nitrogen. The resulting mixture was cooled to ambient temperature, diluted with water (10 ml), filtered, the residue was washed with water for 3 times, a brown solid was obtained, 32-g, (500 mg, 60% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.14-1.18 (t, J=4.2 Hz 6H), 3.16-3.23 (d, J=21.3 Hz 2H), 3.73 (s, 3H) 3.89-3.98 (m, 4H), 6.20-6.22 (d, J=7.8 Hz, 1H), 6.89-6.92 (m, 2H), 7.20-7.24 (m, 6H), 7.99-8.02 (m, 1H), 8.49-8.58 (m, 2H), 9.48-9.50 (m, 1H), 14.00 (s, 1H). LC-MS 564 [MH]+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12](C=O)[CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl.[NH2:21][OH:22].N1C=CC=CC=1>C(O)C>[CH2:1]([CH:3]([CH2:9][C:10]1[CH2:11][C:12](=[N:21][OH:22])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(CC)Cc1ccc(OC)c(C=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)C(CC)CC1=CC=C(OC)C(=NO)C1
Yield: 93.3 %

Procedure:
A mixture of ethyl 2-ethyl-3-(3-formyl-4-methoxyphenyl)propanoate (1.06 g, 4.01 mmol), hydroxylamine hydrochloride (293 mg, 4.22 mmol), pyridine (1 mL) and ethanol (20 mL) was refluxed for 6 hours. After cooling, the mixture was concentrated and the residue was dissolved in ethyl acetate, which was washed with 1 mol/L hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=6:1 v/v) to afford 1.00 g (89%) of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Br:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH:21]=[CH:22][C:23](O)=O>>[Br:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: COc1ccc(C=CC(=O)O)cc1Br
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(Br)c3)nc2n(CCC)c1=O
Yield: 57.7 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.0 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.75 g (14.6 mmol) of 3-bromo-4-methoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 3.43 g (yield 58%) of Compound 56 as yellow needles.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:19][NH2:20]>C1COCC1>[ClH:1].[ClH:1].[NH:19]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1)[NH2:20]
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(NN)c2ccccc2n1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of 4-chloro-2-methylquinazoline (2 g, 0.111 mol) in dry THF (50 ml) was added potassium carbonate (2.3 g, 0.016 mol) followed by anhydrous hydrazine (0.43 g. 0.013 mol). The reaction mixture was stirred at room temperature for 2 h and filtered. The filtrate was evaporated under reduced pressure and the residue was treated with HCl in dioxane (2M, 50 ml). The solid precipitated was filtered and dried under vacuum to afford 2 g (74%) of the titled compound as a yellow solid.
Reaction SMILES: C1O[CH:4]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)=[CH:7][CH:6]=2)[O:3]C1.Cl>O1CCCC1>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cccc(Cc2ccc(C3OCCO3)cc2)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(Cc2cccc(Cl)c2)cc1
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a solution of 4-(3-chlorophenylmethyl)benzaldehyde ethylene acetal (19.9 g) in tetrahydrofuran (80 ml) was added dropwise 10% hydrochloric acid (25.0 ml). After stirring for 15 minutes under ice-cooling, tetrahydrofuran was removed by using a reduced pressure distillation. and the residue was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled away to give the title compound (16.72 g) at a quantitative yield.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:36][CH2:37][C@H:38]([NH:46][S:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=[O:49])=[O:48])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[C:42]([O:41][C:39](=[O:40])[C@@H:38]([NH:46][S:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=[O:49])=[O:48])[CH2:37][NH:36][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:12]=2)=[CH:24][CH:23]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc(OCCc2cn(Cc3ccccc3)cn2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(OCCc2cn(Cc3ccccc3)cn2)cc1)NS(=O)(=O)c1ccccc1

Procedure:
A stirred mixture of 3-6 (147 mg, 0.46 mmol), HOBT (94 mg, 0.61 mmol), 2-1 (154 mg, 0.46 mmol), NMM (100 μL, 0.91 mmol), and DMF (1.2 mL) at 0° C. was treated with EDC (118 mg, 0.61 mmol) followed by removal of the cooling bath. The reaction pH was adjusted to 8 by addition of more NMM. After 20 h the reaction mixture was concentrated and the residue purified by to a flash chromatography column (silica, 9/0.5/0.5 CH2Cl2 /CH3OH/AcOH) to give 3-7 as a yellow solid after azeotropic removal of residual AcOH with toluene. Rf 0.48 (silica, 9/0.5/0.5 CH2Cl2 /CH3OH/AcOH).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([CH:2]2[CH2:7][CH2:6][CH:5]([N:8]3[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:18])[CH2:4][CH2:3]2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1C1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reaction time: 48 h

Procedure:
To a solution of 2-(4-oxocyclohexyl)-1H-isoindole-1,3(2H)dione (3.78 g, 15.5 mmol), which was prepared according to the literature (J. Med. Chem., 1993, 1918), 1-benzylpiperazine (2.99 g/17.1 mmol) and AcOH (1.00 ml/17.1 mmol) in dichloroethane (50 ml) was added sodium triacetoxyborohydride (6.57 g/31.0 mmol) and the mixture was stirred for 2 days. The reaction mixture was poured into water (50 ml) and the mixture was extracted with dichloromethane (100 ml). The extract was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/dichloromethane) to give a colorless oil (5.00 g/89%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N+:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1cccnc1
Reactant: CCCCc1ccc(CCCCBr)cc1
Solvent: CC#N
Product: CCCCc1ccc(CCCC[n+]2cccc(C)c2)cc1
Product: [Br-]
Yield: 75 %

Procedure:
1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of 3-picoline (3 mmol) in acetonitrile and the solution refluxed for 24 hours. The acetonitrile was removed in vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (75%). 1HNMR (300 MHz, CDCl3, ppm), 9.32 (s, 1H), 9.2 (d, J=5.1, 1H), 8.16 (d, J=5.1, 7.91 (m, 1H), 7.07 (d, J=8.4, 2H), 7.02 (d, J=8.4, 2H), 4.96 (t, J=7.2, 2H), 2.52-2.64 (m, 7H), 2.00-2.06 (m, 2H), 1.60-1.70 (m, 2H), 1.60-1.60 (m, 2H), 1.29-1.36 (m, 2H), 0.90 (t, J=7.2, 3H); 13CNMR, 145.62, 144.71, 142.37, 140.84, 139.73, 138.32, 128.66, 128.48, 127.78, 61.82, 35.54, 34.95, 34.05, 31.71, 27.93, 22.72, 19.07, 14.33.
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)/[C:5](=[O:14])[NH:6]2.CCN(C(C)C)C(C)C.C[Si]([N:34]=[N+:35]=[N-:36])(C)C>C1COCC1.CCO>[N:34]([C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)/[C:5](=[O:14])[NH:6]2)=[N+:35]=[N-:36]
Reactant: O=C1Nc2ccc([N+](=O)[O-])c(F)c2/C1=C/c1ccc[nH]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: [N-]=[N+]=Nc1c([N+](=O)[O-])ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2
Temperature: 25 °C
Yield: 78.6 %

Procedure:
(Z)-1,3-Dihydro-4-fluoro-5-nitro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (400 mg, 1.46 mmol) (from Example 10) was suspended in THF/EtOH (20 mL/10 mL). Hunig's base (diisopropylethyl amine, 3.8 mL, 22 mmol)(Aldrich) and trimethylsilyl azide (1.87 mL, 14.65 mmol)(Aldrich) were successively added at r.t. The mixture was refluxed for 12 h. The homogeneous reaction mixture was cooled to r.t. and quenched with 1N HCl. The precipitate was collected by suction filtration, washed with water and dried in a vacuum oven to yield (Z)-4-azido-1,3-dihydro-5-nitro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red solid (Yield 340 mg, 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:14][OH:15])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C=NO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A solution of 4-methyl-3-nitrobenzaldehyde (3.5 g) in tetrahydrofuran (50 mL) was added dropwise to a solution of hydroxylamine hydrochloride (3.0 g) and sodium acetate (4.0 g) in tetrahydrofuran (50 mL) and water (50 mL) under ice cooling, and, on completion of the dropwise addition, the mixture was stirred for one hour at room temperature. The reaction solution was diluted with water and then extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 4-methyl-3-nitrobenzaldehyde oxime (3.5 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10](O)[CH:9]=[N:8]2)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O.O>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([Cl:18])[CH:9]=[N:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2nc(O)cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc2nc(Cl)cnc2c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.236 mmol) of 6-tert-Butyl-quinoxalin-2-ol in 1.07 mL (11.43 mmol) phosphorus oxychloride under nitrogen was heated at 110° C. for 3 h. The solution was cooled to room temperature and added drop wise to water (10-15° C.). Ethyl acetate was added. The aqueous layer was extracted with ethylacetate. The combined organic phases were washed with water, dried over Na2SO4 and concentrated. The crude compound was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 219 mg (80.3%) of the title compound as a green solid. MS(m/e): 220 (M+H+).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH2:34][C:35]([C@@H:37]1[CH2:41][CH2:40][C@H:39]([C:42]2[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=2)[N:38]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:36].[C:56]1([C@H:62](O)[CH3:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C1COCC1>[NH2:34][C:35]([C@@H:37]1[CH2:41][CH2:40][C@H:39]([C:42]2[CH:47]=[CH:46][C:45]([O:48][C@@H:62]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH3:63])=[CH:44][CH:43]=2)[N:38]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:36]
Reactant: C[C@@H](O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@H]1C(N)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc([C@H]2CC[C@@H](C(N)=O)N2C(=O)OC(C)(C)C)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Polystyrene supported PPh3 (100 mg, 1.5 mmol) and DIAD (30 mg, 1.5 mmol) were added to a solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate (D13, 30 mg, 0.10 mmol) in dry THF (1 ml) at 0° C. After 15 min (1R)-1-phenylethanol (24.4 mg, 0.2 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h. The resin was filtered off and the solvent was evaporated. The crude material was purified by chromatography on silica gel using cyclohexanes/ethyl acetate (8:2) to afford the title compound (20 mg, 48%); Rt (HPLC): 5.70 min, 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.31 (s, 9H); 1.53 (d, 3H); 1.65-1.78 (m, 1H); 1.79-1.92 (m, 1H); 1.93-2.03 (m, 1H); 2.07-2.21 (m, 1H); 4.50 (br. s., 1H); 4.70 (br. s., 1H); 5.41-5.50 (m, 1H); 6.78 (d, 2H); 6.91 (s, 1H); 7.23 (br. s., 1H); 7.31 (br. s., 2H); 7.39 (br. s., 4H); 7.44 (br. s., 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15](=[O:27])[CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15](=[O:27])[CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: NNC(=O)COc1ccc(C(=O)O)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(COc1ccc(C(=O)O)cc1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 7 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 4-(2-hydrazino-2-oxoethoxy)benzoic acid. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 6 mg of the title compound (7%) as a yellow solid in 97.8% purity by HPLC (Rt: 3.63, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9]Br.C(=O)(O)[O-].OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[Br:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: BrBr
Reactant: Nc1ccc(Cl)cn1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Cl)cc1Br
Yield: 88.1 %

Procedure:
A 250 mL round-bottomed flask was charged with 5-chloropyridin-2-amine (80 g, 622.3 mmol) and CHCl3 (100 mL). Added bromine (31.98 mL, 622.3 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was poured into saturated bicarbonate and NaHSO3 and extracted with CH2Cl2. The organic layer was dried with sodium sulfate, filtered and concentrated to afford the title compound (113.8 g, 88.1% yield) as a tan solid. 1H NMR (d6-DMSO) δ 7.97 (d, 1H), 7.90 (d, 1H), 6.44 (bs, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Br.[N+:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2)([O-:23])=[O:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:10]1[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15])[CH2:28]2)([O-:23])=[O:22]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)c21
Yield: 43.1 %

Procedure:
147 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 97 mg of the target compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.B(O)(O)[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=1>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=1)[CH3:16]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccc(C(=O)O)cc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 4-carboxylphenylboronic acid in step 1.F.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[OH2:7].[C:8]1(C)C=[CH:12][C:11](S(O)(=O)=O)=[CH:10][CH:9]=1>O1C=CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:12][CH2:11][CH2:10][C:9]#[CH:8]
Reactant: C#CCCCO
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C1=COCCC1
Product: C#CCCCOC1CCCCO1
Reaction time: 0.08 h
Yield: 63 %

Procedure:
A mixture of 5-hydroxypentyne (5.0 g, 0.06 mol) and freshly distilled dihydropyran (10 mL) was treated with a trace of p-toluenesulfonic acid hydrate. The exothermic reaction was stirred for 5 min, and the excess dihydropyran was removed under reduced pressure. The residue was purified by flash chromatography (alumna, neutral, activity 1, 25% ether/hexane) and gave the title compound (6.4 g, 63%). 1H NMR (400 MHz, CDCl3) δ 4.60 (t, 1 H), 3.86 (m, 2 H), 3.50 (m, 2 H), 2.32 (m, 2 H), 1.96 (t, 1 H), 1.82 (m, 3 H), 1.72 (m, 1 H), 1.48-1.65 (m, 4 H).