Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:8](CC1C=CC=CC=1)([C:20]([N:22]1[CH2:38][C@H:37]([OH:39])[CH2:36][C@H:23]1[C:24]([NH:26][C@H:27]([C:33]([O-:35])=[O:34])[CH2:28][CH2:29][C:30]([O-:32])=[O:31])=[O:25])=[O:21])[NH:9]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1>[Pd].O.CO.CO>[NH2:9][CH2:8][C:20]([N:22]1[CH2:38][C@H:37]([OH:39])[CH2:36][C@H:23]1[C:24]([NH:26][C@H:27]([C:33]([OH:35])=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:25])=[O:21]
Reactant: O=C([O-])CC[C@H](NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)C(Cc1ccccc1)(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NCC(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of protected tripeptide 5 (0.50 g, 0.79 mmol) and 10% palladium on activated carbon (0.08 g, 0.08 mmol) in 20% water/methanol (100 cm3) was stirred under an atmosphere of hydrogen at room temperature for 20 h. The solution was filtered through a Celite™ pad, washed with methanol (60 cm3) and the filtrate evaporated to dryness to form a clear gum. This gum was dissolved in methanol (30 cm3) and refiltered through a Celite™ pad. The solution was evaporated to dryness to form a clear gum. The gum was placed on a vacuum line for 15 min and then triturated with anhydrous diethyl ether to form GHypE (0.20 g, 80%) as a white solid. GHypE was shown to be an 80:20 trans:cis mixture of conformers by 13C NMR analysis (the ratio was estimated from the integration of the signals at 6 70.2 and 68.5, assigned to the Proγ-C of the major and minor conformers respectively): mp 158-160° C.; [α]D −58.1 (c 0.1 in MeOH); δH (300 MHz; D2O) 1.96-2.23 (4H, m, Gluβ-H2, and Proβ-H2), 2.48-2.56 (2H, m, Gluγ-H2), 3.62 (2H, d, J 10.0, Glyα-H2), 3.80 (1H, dd, J 8.8 and 4.9, Gluα-H), 4.08 (1H, dd, J 10.4 and 2.6, Proα-H), 4.30-4.35 (2H, m, Proδ-H2) and 4.63-4.69 (1H, m, Proγ-H); δC (75 MHz, D2O) 29.2 (CH2, Gluβ-C), 31.7 (CH2, Proβ-C), 32.3* (CH2, Proβ-C), 37.6 (CH2, Gluγ-C), 40.0* (CH2, Glyα-C), 41.0 (CH2, Glyα-C), 54.8 (CH2, Proδ-C), 55.3 (CH, Gluα-C), 59.1* (CH, Proα-C), 59.7 (CH, Proα-C), 68.5* (CH, Proγ-C), 70.2 (CH, Proγ-C), 166.4 (quat., Gly-CO), 167.1* (quat., Gly-CO), 173.0* (quat., Pro-CON), 173.4 (quat., Pro-CON), 177.9 (quat., Gluα-CO) and 179.2 (quat., Gluγ-CO); m/z (FAB+) 318.1329 (MH+.C17H20NO5 requires 318.1342).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=1)[CH2:5][CH2:6][Cl:7].O.N>Cl.O>[ClH:1].[Cl:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][Cl:7])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1
Reactant: O=[N+]([O-])c1cccc(N(CCCl)CCCl)c1
Agent: Cl
Agent: N
Solvent: O
Product: Nc1cccc(N(CCCl)CCCl)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 192.1 %

Procedure:
In 35 ml of concentrated hydrochloric acid was dissolved 2.0 g (7.6 mmols) of 3-[N,N-bis(2-chloroethyl)amino]nitrobenzene, and 6.9 g (30.6 mmols, 4.0 eq.) of stannic chloride (II) dihydrate was added, followed by stirring for 1 hour in an oil bath at 100° C. Next, the solution was allowed to stand until its temperature lowered to room temperature, and then diluted with water. The solution was basified with concentrated ammonia water, extracted with ethyl acetate twice, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Afterward, 4N hydrochloric acid and dioxane were added to the resulting residue, and after concentration, the residue was crystallized from a small amount of methanol-ether to obtain 1.97 g (7.3 mmols, 96.1%) of the desired compound in the state of yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][O:28][C:22]=3[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1C
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.NC1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:12]
Reactant: Nc1ccc2[nH]c(=O)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Product: O=c1ccc2ccccc2[nH]1

Procedure:
Scheme I describes a method to prepare quinolinone compounds such as Structure 5, nitro-quinolinone compounds such as Structure 6, and amino-2-quinolinone compounds such as Structure 3 through modified Knorr reactions. Thermal condensation of a 4-aminoacetanilide (Structure 1) with a 3-ketoester, for example, ethyl 4,4,4-trifluoroacetoacetate in nitrobenzene affords a bis-amide such as Structure 2. When a bis-amide compound of Structure 2 is treated with concentrated sulfuric acid at 60-100° C., aminoquinolinone compounds of Structure 3 are produced. An alternate process of preparing 6-aminoquinolinone compounds such as Structure 3 starts with a similar Knorr reaction. The synthesis begins with reaction of an aniline such as Structure 4 and a 3-ketoester in refluxing toluene followed by treatment of a Lewis acid such as p-toluenesulfonic acid to produce a 2-quinolinone such as Structure 5. Classic nitration of the 2-quinolinone (e.g., Structure 5) selectively provides a 6-nitroquinolinone compound (e.g., Structure 6). Reduction of the nitroquinolinone such as Structure 6 under standard reduction conditions (e.g., metal catalyzed hydrogenation or tin chloride reduction) affords aminoquinolinone compounds such as Structure 3.
Reaction SMILES: C([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[O:25][CH2:24][CH:23]=[CH:22][C:17]4=3)[NH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:26]>C(O)C.[Pd]>[ClH:26].[CH2:22]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[C:16]2[O:25][CH2:24][CH2:23]1)[NH:12][C:11]1[CH2:10][CH2:9][NH:8][CH2:21][CH2:20][C:19]3=1
Reactant: C1=Cc2c(ccc3[nH]c4c(c23)CCN(Cc2ccccc2)CC4)OC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1cc2[nH]c3c(c2c2c1OCCC2)CCNCC3
Yield: 95 %

Procedure:
A solution of 10-benzyl-7,8,9, 10,11,12-hexahydro-3H-azepino[4,5-b]pyrano[3,2-e]indole (0.38 g., 1.17 mmol, Example 3) in ethanol (20.0 mL) was hydrogenated in the presence of palladium-on-carbon (0.20 g.) and 2N hydrochloric acid (0.58 mL, 1.17 mmol) at 55 psi for 24 hours. After filtration through a pad of celite, the filtrate was concentrated in vacuo. The residue was recrystalized from EtOAc/MeOH to yield the title compound (0.31 g, 94%) as a light yellow solid. M.p.>283° C. (dec.); IR (KBr) 3235, 3229, 2983, 2957, 2946, 2926, 2877, 2855, 2817, 2752, 2738, 2717, 2681, 2639, 2600, 2540, 1585, 1497, 1454, 1435, 1430, 1225, 1186, 1089, 805 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 10.82, 9.55, 6.95, 6.48, 4.04-4.02, 3.30-3.23, 3.13-3.10, 3.07-3.04, 1.99-1.93; 13C NMR (DMSO-d6) δ 147.7, 135.1, 129.4, 125.9, 111.6, 111.5, 110.2, 109.6, 64.8, 46.3, 44.4, 24.3, 22.7, 22.5, 22.2; MS (ESI+) m/z 243 (M++H); HRMS (FAB) cacld for C15H18N2O+H: 243.1497, found: 243.1500; Anal. Calcd. for C15H18N2O.HCl: C, 64.63; H, 6.87; N, 10.05. Found: C, 64.23; H, 6.95; N, 9.87.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[C:5]([Cl:14])=[CH:4][N:3]=1.COC1C=CC(C[NH2:22])=CC=1.FC(F)(F)C(O)=O>CN(C=O)C>[Cl:14][C:5]1[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])=[N:7][C:2]([NH2:22])=[N:3][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC[C@H](C)Oc1nc(Cl)ncc1Cl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)Oc1nc(N)ncc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-2,5-dichloro-4-((1-methoxypropan-2-yl)oxy)pyrimidine (intermediate 91, 1.26 g, 4.15 mmol) and 4-methoxybenzylamine (0.65 ml, 4.97 mmol) in DMF (7 ml) was heated at 50° C. for 18 h. The reaction mixture was partitioned between aqueous 1M HCl and DCM, extracted with DCM (2×), the combined DCM layers were washed with water, dried over Na2SO4 and evaporated. To the residue was added trifluoroacetic acid (3.93 ml, 51.0 mmol) and the reaction mixture stood at room temperature for 18 h, heated for 5 h at 70° C., stood 3 days at room temperature, heated at 80° C. for 2 days. The reaction mixture was evaporated and purified by a combination of normal and reversed phase chromatography (RP 3) to give the title compound as a colorless oil. (UPLC-MS 7) tR 0.74; ESI-MS 218.1 and 220.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([O:16]C2C=CC=CC=2)=O)=[CH:6][CH:5]=1.[NH2:25][C:26]1[N:27]=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=1>>[C:32]([C:29]1[N:30]=[CH:31][C:26]([NH:25][C:14]([N:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:3]([O:2][CH3:1])[O:23][CH3:24])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])=[N:27][CH:28]=1)#[N:33]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2
Reactant: N#Cc1cnc(N)cn1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cnc(C#N)cn1)CCC2

Procedure:
From intermediate 3 and 5-aminopyrazine-2-carbonitrile, reacted in an analogous manner to the preparation of intermediate 2. (UPLC-MS 1) tR 1.08 min, ESI-MS 355.3 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].C[S](Cl)C.[CH3:24][S:25]([CH3:27])=O>O>[CH3:1][N:2]([CH2:24][S:25][CH3:27])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1)=[O:4]
Reactant: CNC(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: CS(C)=O
Agent: C[S](C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CSCN(C)C(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
11 g of N-methyl-N'-(3,4-dichlorophenyl)-urea, 60 g of potassium carbonate and 50 ml of dimethylsulfur chloride were added at 10° C. to 150 ml of dimethylsulfoxide and the mixture was allowed to stand until exothermic generation of heat ceased. The reaction mixture was added to water and was extracted with ether. The ether solution was washed with water, dried and concentrated to dryness by distillation under reduced pressure. The residue was crystallized from isopropyl ether and then ethyl acetate to obtain 7.7 g of N-methyl-N-(2-thiapropyl)-N'-(3,4-dichlorophenyl)-urea melting at 103° C.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4([C:28]#[N:29])[CH2:27][CH2:26]4)[CH:20]=3)[CH:16]=2)=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[CH:8]=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:26][CH2:27]5)[CH:20]=4)[CH:16]=3)[CH:32]=[CH:33][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
Potassium thiocyanate (7.00 g, 72 mmol) was suspended in acetic acid (120 mL) and the mixture was stirred at room temperature for 10 min. To the obtained solution was added a solution of N-[5-(4-aminophenoxy)-2-methylphenyl]-3-(1-cyanocyclopropyl)benzamide (6.90 g, 18 mmol) in acetic acid (120 mL), and the mixture was further stirred at room temperature for 30 min. To the obtained solution was added dropwise slowly a solution of bromine (3.60 g, 22.5 mmol) in acetic acid (80 mL) and, after the completion of the dropwise addition, the mixture was further stirred at room temperature for 12 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and the washing were combined and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (400 mL), washed with 5% aqueous sodium hydrogencarbonate solution (200 mL×2) and saturated brine (200 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (6.27 g, 79%) as a pale-yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=O.C(O)(=O)C.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]2[CH2:37][O:38][CH2:39][C:40]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[O:41])(=[O:30])=[O:29])=[C:23]([CH3:48])[CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[NH:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][C:6]=1[CH2:7][N:45]1[CH2:46][CH2:47][N:42]([C:40](=[O:41])[CH2:39][O:38][CH2:37][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][N:31]2[S:28]([C:24]2[C:23]([CH3:48])=[CH:22][C:21]([O:20][CH3:19])=[CH:26][C:25]=2[CH3:27])(=[O:29])=[O:30])[CH2:43][CH2:44]1
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCNCC2)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(Cc3nc(-c4ccccc4)[nH]c3Cl)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
4-Chloro-2-phenyl-1H-imidazole-5-carbaldehyde (1.5 eq.) and acetic acid (cat.) were added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)-1-(piperazin-1-yl)ethanone (1 eq.) in dichloromethane (25 ml/mmol). The reaction mixture was stirred for 30 min. at 25° C., then sodium triacetoxyborohydride (4 eq.) was added and stirring was carried out for a further 16 h at 25° C. The mixture was diluted with dichloromethane and washed with saturated bicarbonate solution and saturated sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography using 3% methanol in ethyl acetate. Yield: 50%; MS, m/z 630.2 (MH+)
Reaction SMILES: [N+](=[CH:3][CH3:4])=[N-].[OH:5][CH:6]([CH2:25][O:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:8][N:9]1[C:13](=[O:14])[CH2:12][S:11](=[O:15])[CH:10]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>CCOCC>[OH:5][CH:6]([CH2:25][O:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:8][N:9]1[C:13](=[O:14])[CH2:12][S:11](=[O:15])[CH:10]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:3][CH3:4])=[O:23]
Reactant: CCCOCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O
Reactant: CC=[N+]=[N-]
Solvent: CCOCC
Product: CCCOCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)OCC
Reaction time: 4 h

Procedure:
A solution of diazoethane (approximately 3.4 g., 0.06 mole) in ether (100 ml.) is slowly added to a solution of 7-[3-(3-hydroxy-4-propoxybutyl)-1,4-dioxo-2-thiazolidinyl]heptanoic acid (11.3 g., 0.03 mole) in ether (50 ml.) with stirring and cooling (0° to 5° C.). The resulting solution is allowed to warm to and stand at room temperature for 4 hours. After destroying excess diazoethane with acetic acid, the reaction solution is washed with 5% sodium bicarbonate solution and water, dried over sodium sulfate, and filtered. In vacuo evaporation of the filtrate leaves the title compound as an essentially colorless, viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.[Sn]>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1Sc1ccc(Cl)cc1
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Product: Nc1ccccc1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.2 %

Procedure:
2-(4-Chlorophenylthio)nitrobenzene (1.0 g) was dissolved in a mixture of acetic acid (5 ml) and 6N hydrochloride (5 ml), and tin (1.0 g) was added thereto, followed by stirring for six hours at room temperature. After the solvent was removed under reduced pressure, the residue was dissolved in water (50 ml) and a pH of the resultant solution was adjusted to 9-10 with potassium carbonate. The thus-obtained solution was extracted with ethyl acetate. The extracted solution was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Subsequently, the solvent was removed under reduced pressure and the residue was crystallized from ethyl acetate under stirring, to thereby yield the target compound (880 mg) as pale-yellow crystals.
Reaction SMILES: [I:1]Cl.Cl.[N+:4]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)([O-:6])=[O:5]>O>[I:1][C:12]1[CH:13]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: ClI
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1I
Temperature: 20 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A solution of iodine monochloride (25.8 mL, 514 mmol) in water (220 mL) at 0° C. was treated with concentrated hydrogen chloride (87 mL, 2800 mmol) and stirred until the iodine monochloride dissolved. This cooled ICl solution was then added to a solution of p-nitroaniline (71 g, 510 mmol) in water (590 mL) and concentrated hydrogen chloride (50 mL, 2000 mmol) and stirred at 20° C. for 3 hours. The reaction mixture was filtered, washed with water, and dried to give the desired product (132 g, 94%) as a yellow solid. LCMS for C6H61N2O2 (M+H)+: m/z=264.7.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:8]([OH:10])=[O:9])[N:6]=1.[Cl:32]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([Cl:32])=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)c(Cl)s1
Yield: 70.9 %

Procedure:
To a solution of (Z)-2-(2-aminothiazol-4-yl)-2-(triphenylmethoxyimino)acetic acid (5.81 g, 13.47 mmol) in DMF (30 mL) at room temperature (1 mL) was added N-chlorosuccinimide (1.80 g, 13.47 mmol). After overnight reaction the reaction mixture was poured into water (about 500 mL) and the resulting precipitate was filtered, washed with water and then with ethyl acetate and dried in vacuum to afford 4.43 g (71%) of the title compound. 13C NMR (CDCl3) δ 108.5, 125.6, 126.2, 126.6, 12.3, 134.7, 141.8, 146.5, 162.1, 163.3.
Reaction SMILES: N.[Na].[Si:3]([O:10][C@H:11]([C@H:14]1[C@@H:17]([C:18]#[CH:19])[N:16]([C@@H](C2C=CC=CC=2)C)[C:15]1=[O:28])[CH2:12][CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl-].[NH4+]>CCOCC.C(O)C>[Si:3]([O:10][C@H:11]([C@H:14]1[C@@H:17]([C:18]#[CH:19])[NH:16][C:15]1=[O:28])[CH2:12][CH3:13])([C:6]([CH3:8])([CH3:7])[CH3:9])([CH3:5])[CH3:4]
Reactant: C#C[C@@H]1[C@H]([C@H](CC)O[Si](C)(C)C(C)(C)C)C(=O)N1[C@H](C)c1ccccc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCO
Product: C#C[C@H]1NC(=O)[C@H]1[C@H](CC)O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To 35 ml of ammonia were added sodium (50.4 mg, 2.19 mmol) and iron nitride nonahydrate (a catalytic amount) at -78° C. in an argon atmosphere. The mixture was stirred for 15 minutes, while the temperature was allowed to rise. Then, the temperature was returned to -78° C., followed by dropwise addition of a solution of the compound (509 mg, 1.37 mmol) prepared in Example 4 in ether (4 ml). After stirring at the same temperature for 40 minutes, sodium (189 mg, 8.20 mmol) was again added, and the mixture was stirred for a further 30 minutes at the same temperature. Next, ammonium chloride (3.5 g) and ethanol (3.5 ml) were added, followed by heating of the mixture. Ammonia was removed by evaporation, insoluble matters were removed by filtration, and the mixture was washed with ethyl acetate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate 4/1) to obtain 304 mg (yield 83%) of the title compound as a colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCC.C1COCC1>[CH2:10]([C:14]1[CH:19]=[CH:18][C:17]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1ccc(Cl)cc1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCc1ccc(-c2ccc(F)cc2)cc1
Reaction time: 24 h
Yield: 88 %

Procedure:
Using a THF solution of 4-fluorophenylmagnesium bromide (1.46 mL, 1.03 M, 1.5 mmol), 4-butylchlorobenzene (168.7 mg, 1.0 mmol), FeF3.3H2O (8.34 mg, 0.05 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (63.8 mg, 0.15 mmol) and triphenylphosphine (13.1 mg, 0.05 mmol) as starting materials, the reaction was performed at a scale of 1.0 mmol at 60° C. for 24 hours, then at 80° C. for 12 hours in the same manner as in Example 15. After performing silica gel chromatography (pentane), the above compound was obtained as a white solid (0.201 g, yield=88%, purity=>98% (GC analysis)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:5]2.C([O:21]P(OCC)OCC)C.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([OH:21])[CH2:5]2
Reactant: O=C1c2ccc(Cl)cc2CC1c1ccc(Cl)cc1
Reactant: CCOP(OCC)OCC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Cl)cc2CC1(O)c1ccc(Cl)cc1
Yield: 45.5 %

Procedure:
A solution of 2.4 g (0.009 moles) of the product obtained from Step B and 20 mL of toluene was added with stirring to a mixture of 1.8 g (0.010 moles) of triethylphosphite, 0.1 g (0.0004 moles) of benzyltriethyl ammonium chloride, 100 mL of toluene and 50 mL of 50% aqueous sodium hydroxide solution. A steady stream of air was introduced into the vigorously stirred reaction mixture at room temperature for 1 hour. The resulting mixture was partitioned between 100 mL of Et2O and 200 mL of water and the aqueous layer was extracted with two 100 mL portions of Et2O. The combined organic layers were washed twice with 100 mL of water, twice with saturated aqueous sodium bisulfite solution, dried over MgSO4 and concentrated. The resulting crude product was chromatographed on silica gel using 2:1 hexanes-ethyl acetate to give 1.2 g of an oil that solidified on standing.