Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:17][CH2:16]1)[C:10]([F:15])([F:14])[C:11]([NH2:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:17])([CH2:16][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C:10]([F:15])([F:14])[C:11]([NH2:13])=[O:12]
Reactant: NC(=O)C(F)(F)C1(c2ccc(Cl)cc2Cl)CO1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 40.2 %

Procedure:
In 8 ml of N,N-dimethylformamide was dissolved 0.8 g of 3-(2,4-dichlorophenyl)-3,4-epoxy-2,2-difluorobutanamide. To the resulting solution were added 0.59 g of anhydrous potassium carbonate and 0.29 g of 1,2,4-triazole. The mixture was subjected to reaction at 80°-90° C. for 1 hour. The solvent was removed by distillation under reduced pressure. To the residue obtained were added 10 ml of ethyl acetate and 10 ml of water. The mixture was adjusted to pH 1.0 with 2N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=100/1) to obtain 0.40 g of 3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:58][C:59]1[C:67]([NH2:68])=[CH:66][CH:65]=[CH:64][C:60]=1[C:61]([NH2:63])=[O:62]>CN(C=O)C>[NH2:58][C:59]1[C:60]([C:61](=[O:62])[NH2:63])=[CH:64][CH:65]=[CH:66][C:67]=1[NH:68][C:18]([CH:17]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:19]
Reactant: NC(=O)c1cccc(N)c1N
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C(C(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C(C(=O)Nc1cccc(C(N)=O)c1N)C2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Step-2: To a solution of 2-(tert-butoxycarbonyl)-7-((tert-butoxycarbonyl)amino)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (200 mg, 0.51 mmol) in anhydrous DMF (3 mL) was added EDC.HCl (293 mg, 1.53 mmol), HOAt (105 mg, 0.77 mmol) and triethylamine (0.107 ml, 0.77 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (77 mg, 0.51 mmol) was added and heated to 80° C. over night. The reaction mixture was concentrated and purified by preparative TLC to afford tert-butyl 3-((2-amino-3-carbamoylphenyl)carbamoyl)-7-((tert-butoxycarbonyl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 526.30 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].C(O[C:13](S)=[S:14])C.[OH-].[K+].Cl>C(O)C.O>[SH:14][C:13]1[O:9][C:3]2[CH:4]=[C:5]([OH:6])[CH:7]=[CH:8][C:2]=2[N:1]=1
Reactant: CCOC(=S)S
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1ccc2nc(S)oc2c1
Yield: 90 %

Procedure:
To a solution of 4-aminoresorcinol (1 eq) and ethylxanthic acid (3 eq) in ethanol was added potassium hydroxide (2.1 eq). The mixture was refluxed for two hours then diluted with water and acidified using 1N HCl to a pH of 4. The product was extracted into ethyl acetate then concentrated. The resulting solid was triturated with dichloromethane to give pure product with a 90% yield. MH+=168.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12][CH2:13][CH3:14])=[N:7][C:6]=1Cl)[CH3:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12][CH2:13][CH3:14])=[N:7][C:6]=1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(SCC)nc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(F)c(SCC)nc1NCc1ccc(OC)cc1
Yield: 64.2 %

Procedure:
A solution of 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester (66) (53 g, 201 mmol) in anhydrous ethanol was purged with argon and added p-methoxybenzylamine (52.5 mL, 402 mmol) at room temperature. The solution was refluxed overnight under argon. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was taken in dichloromethane, sonicated briefly and undissolved solids were filtered off. The filtrate washed by water, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography eluting with hexane:CH2Cl2 (1:1) to yield 47 g (64%) of 6-ethylsulfanyl-5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester (67) as a viscous oil which solidified to a white solids after keeping several days under vacuum at room temperature. Mp 59° C. 1H-NMR (DMSO-d6): δ 1.18 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H), 3.08 (q, J=7.2 Hz, 2H), 3.71 (s, 3H), 4.26 (q, J=7.2 Hz, 2H), 4.62 (d, J=5.6 Hz, 2H), 6.87 (m, 2H), 7.24 (m, 2H), 7.71 (d, J=10 Hz, 1H), 8.32 (m, 1H); EIMS m/z 365 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.C(N(CC)CC)C.[N:28]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[O:20]=[C:14]1[CH:13]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][NH:1][C:34]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:35])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2Cc3cc(CNC(=O)N4CCOCC4)ccc3C2=O)C(=O)N1
Reaction time: 4 h
Yield: 20.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and triethylamine (0.30 mL, 2.2 mmol) in acetonitrile (10 mL) was added morpholine-4-carbonyl chloride (012 mL, 1.05 mmol) at room temperature under nitrogen. After 4 h, the reaction mixture was filtered and rinsed with acetonitrile (30 mL) and the filtrate was concentrate on the rota-yap. The residue was stirred with 20 mL of acetonitrile and water mixture (1:1). The resulted suspension was filtered to give morpholine-4-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.08 g, 20% yield): HPLC: Waters Nova-Pak C18 column, 3.9×150 mm, 4 μm; gradient CH3CN/0.1% aq H3PO4, 10 min, 1.0 mL/min, 4.8 min (96%); mp: 208-210° C.; 1H NMR (DMSO-d6) δ 1.92-2.07 (m, 1H, CHH), 2.39 (qd, J=4.4, 13.3 Hz, 1H, CHH), 2.55-2.66 (m, 1H, CHH), 2.84-2.99 (m, 1H, CHH), 3.27-3.32 (m, 4H, CH2+CH2), 3.52-3.59 (m, 4H, CH2+CH2), 4.25-4.49 (m, 4H, CH2+CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, CHN), 7.22 (t, J=5.8 Hz, 1H, Ar), 7.40 (d, J=7.9 Hz, 1H, Ar), 7.47 (s, 1H, NH), 7.67 (d, J=7.9 Hz, 1H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.51, 31.20, 43.54, 43.86, 47.10, 51.56, 65.92, 121.88, 122.77, 126.89, 130.11, 142.23, 145.28, 157.57, 168.02, 171.01, 172.86; LCMS: MH=387; Anal Calcd for C19H22N4O5+0.6H2O: C, 57.45; H, 5.89; N, 14.10. Found: C, 57.10; H, 6.07; N, 13.97.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([F:18])([F:17])([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[C:19](=[O:21])=[O:20].Cl>CCCCCC.CCOCC>[F:14][S:13]([F:18])([F:17])([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:19]([OH:21])=[O:20])=[CH:8][CH:9]=1
Reactant: O=C=O
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A solution of n-butyllithium (9.4 ml of a 1.6M solution in hexane) was added to a stirred solution of 4-bromophenylsulphur pentafluoride (3.87 g) in ether at -78° C. under an inert atmosphere. After maintaining at -78° C. for 1 hour, solid carbon dioxide (20 g) was added and the mixture allowed to warm to 5° C. during 1.5 hours. Hydrochloric acid (2M) was added, the mixture stirred for 0.5 hour and the organic phase separated and itself extracted with sodium carbonate solution. The basic extract was washed (ether) and acidified (hydrochloric acid). The precipitated solid was extracted (ether), dried (magnesium sulphate) and evaporated. The residue was triturated (hexane) to give 4-pentafluorosulphanylbenzoic acid as a fawn solid (1.2 g), m.p.188-190° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=N[C:21]2[CH:22]=[CH:23][CH:24]=[N:25][C:20]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCCCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:25]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:10])=[N:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Br)cn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C(c1ccc(Br)cn1)N1CCCCC1
Reaction time: 18 h
Yield: 364.1 %

Procedure:
5-bromo-2-pyridinecarboxylic acid (501 mg, 2.480 mmol, available from Apollo) was mixed with HATU (2358 mg, 6.20 mmol), DIPEA (1.625 mL, 9.30 mmol) and piperidine (0.307 mL, 3.10 mmol), dissolved in N,N-dimethylformamide (DMF) (22.5 mL) and stirred under nitrogen for 18 hours. The reaction was partitioned between distilled water (30 mL) and DCM (100 mL). The aqueous layer was extracted with DCM (2×70 mL) and the organic fractions were combined, washed (brine (2×50 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a dark brown solid (2.43 g). The crude product was purified on a 40+M Biotage silica column, eluting with cyclohexane:EtOAc (1:0 to 3:2, 19 CV). Product-containing fractions were evaporated to dryness to give a dark yellow solid (573 mg). LCMS (Method C): Rt=0.83, MH+=271
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:3].[NH:37]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:39]([OH:41])=O>>[NH:37]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][C:39]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:3])=[O:41]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Yield: 77.8 %

Procedure:
By using 3.50 g of Boc-Ala-Ser(Bzl)-Leu-OEt and 1.30 g of Boc-Gly-OH, and the same procedure as in Reference Example 15 was repeated to obtain 3.03 g (yield: 77.8%) of the above-mentioned objective product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][O:7][CH2:8][CH2:9]Cl>>[CH3:6][O:7][CH2:8][CH2:9][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCCl
Reactant: C1CCNC1
Product: COCCN1CCCC1
Yield: 70 %

Procedure:
Pyrrolidine (Wako Pure Chemical Industries, Ltd.), 1.51 parts by weight, and 2-methoxyethyl chloride (Kanto Chemical Co., Inc.), 1.00 part by weight, were mixed together and reacted for 1 hour under refluxing. Following the reaction, the reaction mixture was separated into two phases, then left to cool for a while, whereupon the bottom phase solidified. The top phase alone was collected by decantation, and purification was carried out by vacuum distillation. This distillation gave 0.96 part by weight of the target substance N-2-methoxyethylpyrrolidine (boiling point, 76° C.; vapor pressure, 45 mmHg) in a yield of 70%.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([OH:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH3:4].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1F)[C:19]#[N:20]>C(#N)C.CCCCC>[CH2:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([O:12][C:23]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[F:15])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH3:4]
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: CCc1cc(OC)c(O)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCCCC
Product: CCc1cc(OC)c(Oc2ccc(C#N)cc2F)cc1F
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Potassium hydroxide (2.4 g, 43.13 mmol) was added to a solution of 4-ethyl-5-fluoro-2-methoxyphenol (6.1 g, 35.94 mmol) and 3,4-difluorobenzonitrile (5.0 g, 35.94 mmol) in anhydrous acetonitrile (80 mL). The reaction mixture was stirred at 85° C. overnight then concentrated under vacuum. The residue was solubilized in ethyl acetate (300 mL) and diluted by addition of a saturated solution of ammonium chloride (200 mL). The aqueous layer was separated and extracted with ethyl acetate (2×200 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness to give a brown solid. After trituration in pentane, the title product was obtained as a brown solid (8.10 g, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]O)=[CH:26][CH:25]=1)[CH2:20][CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH2:19]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:30][CH:31]=1)[CH2:20][CH3:21]
Reactant: CCCOCc1ccc(CO)cc1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCOCc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 68 h
Yield: 179.2 %

Procedure:
Into a solution of methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 4-(propoxymethyl)benzyl alcohol (502 mg) and triphenylphosphine (782 mg) in THF (10 ml) was added at 0° C. diethyl azodicarboxylate (a 40% solution in toluene) (1.30 g), and the resulting mixture was stirred at room temperature for 68 hours. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:1) to obtain methyl 7-[[4-(propoxymethyl)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.15 g) as colorless crystals.
Reaction SMILES: O.O.[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:14]1(NC2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.C1([NH2+]C2C=CC=CC=2)C=CC=CC=1.S(OC)(OC)(=O)=O>C(Cl)Cl.C1CCCCC1>[C:3]1([CH3:13])[CH:4]=[CH:5][C:6]([S:9]([O:12][CH3:14])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1ccc([NH2+]c2ccccc2)cc1
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: C1CCCCC1
Product: COS(=O)(=O)c1ccc(C)cc1

Procedure:
To a suspension of p-toluenesulfonic acid dihydrate (10 g, 0.05 mol) in methylene chloride (50 mL), diphenylamine (10.8 g, 0.06 mol) was added dropwise, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated to dryness under the reduced pressure to obtain a crude product containing diphenylammonium p-toluenesulfonate salt. To a suspension of this crude product (5 g, 0.011 mol) in cyclohexane (50 mL), dimethyl sulfate (3.0 g, 0.023 mol) was added, and the mixture was reacted at 80° C. for 2 hours. The reaction liquid was condensed under the reduced pressure to obtain the desired product of methyl p-toluenesulfonate. Quantitative analysis by 1H-NMR showed a conversion rate of 63%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:14])[CH2:11][C:12]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C(OCC)=[O:17].[Cl-].[NH4+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([O:8][CH2:9][CH:10]([CH3:14])[CH2:11][CH:12]=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CC#N)COCc1ccccc1
Reactant: CCOC=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(CC=O)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 5.8 g. (0.0307 mole) of rac. 4-benzyloxy-3-methylbutyronitrile in 290 ml. of hexane was stirred at -65° C. to -70° C. while 22.4 ml. (4.78 g.; 0.0337 mole) of 25% diisobutylaluninum hydride solution in toluene was added dropwise. The resulting solution was stirred at -65° C. to -70° C. for 0.5 hours then at room temperature for 5 hours whereupon 2.8 ml. of ethyl formate was added dropwise. The reaction mixture was then treated with 250 ml. of saturated aqueous ammonium chloride solution. Stirring was continued for 20 minutes at which point 125 ml. of 5% by weight aqueous sulfuric acid was added and stirring was continued for an additional 10 minutes. The organic layer was separated and the aqueous layer was extracted with ether. The organic solutions were combined and processed as in Example 1 giving 4.79 g. (81.3%) of rac. 4-benzyloxy-3-methylbutanal as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[N+]([O-])([O-])=O.N1C=CN=C1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(C=O)[nH]1
Reaction time: 3 h
Yield: 77.1 %

Procedure:
2-n-Butyl-4-chloro-5-hydroxymethylimidazole (50.0 g, 265 mmol, 1 eq.) was dissolved in glacial acetic acid (150 mL). A 1 N cerricammonium nitrate (CAN) solution (575.0 mL, 595 mmol, 2.25 eq.) was then added dropwise to the stirred imidazole solution maintaining the temperature at 20°-30° C. After the addition was complete, an additional 10 mL of 1 N CAN solution was added so that the mixture remained orange. After 3 hours, the reaction was cooled on ice and 50% NaOH (210 mL) was added to neutralize the acetic acid. The product precipitated. The pH was adjusted to 6 and the solids were filtered, washed with water (3×500 mL) and dried under high vacuum to yield 38.13 g of a white powder; M.P. 92.5-93.5° C. NMR (200 MHz, CDCl3): δ 11.83 (m, 1H); 9.64 (s, 1H); 2.85 (t, 2 H, J=7Hz); 1.78 (t of t, 2H, J=7,7Hz); 1.38 (t of q, 2H, J=7,7Hz); 0.93 (t, 3H, J=7Hz). Anal. calcd. for C8H11ClN2O: C, 51.48; H, 5.94; Cl, 19.00; N, 15.01. Found: C, 51.75; H, 5.82; Cl, 18.73; N, 14.87.
Reaction SMILES: [I-].[Na+].Cl[Si](Cl)(C)C.[Cl:8][C:9]1[C:10]2[N:11]([C:15]([CH:21](O)[C:22]3[CH:41]=[CH:40][C:25]4/[C:26](=[C:36](/[CH3:39])\[C:37]#[N:38])/[C:27]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:28]=5[O:29][CH2:30][C:24]=4[CH:23]=3)=[C:16]([CH:18]3[CH2:20][CH2:19]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.CC(C)=O>[Cl:8][C:9]1[C:10]2[N:11]([C:15]([CH2:21][C:22]3[CH:41]=[CH:40][C:25]4/[C:26](=[C:36](/[CH3:39])\[C:37]#[N:38])/[C:27]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:28]=5[O:29][CH2:30][C:24]=4[CH:23]=3)=[C:16]([CH:18]3[CH2:20][CH2:19]3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: C/C(C#N)=C1/c2ccc(C(O)c3c(C4CC4)nc4c(Cl)cccn34)cc2COc2cc(F)ccc21
Agent: C[Si](C)(Cl)Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CC(C)=O
Product: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(Cl)cccn34)cc2COc2cc(F)ccc21
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
[step 4] Sodium iodide (4.63 g, 30.9 mmol) was suspended in a mixed solution of dichloromethane (15 mL)-acetone (15 mL), dichlorodimethylsilane (1.84 mL, 15.4 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Under ice-cooling, a solution (15 mL) of (E)-2-{8-[(8-chloro-2-cyclopropylimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (1.5 g, 3.09 mmol) obtained in step 3 in dichloromethane was added, and the mixture was stirred at room temperature for 30 min. To the mixture were added 10% aqueous sodium thiosulfate solution (50 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue was added isopropylalcohol (15 mL)-diisopropyl ether (15 mL), and the precipitated crystals were collected by suction filtration to give the title compound (1.4 g, 97%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.CCN(C(C)C)C(C)C.CC(N(C)C)=O>CCOC(C)=O>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:22][CH2:21][CH2:20][NH:19][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=2)=[N:24][CH:25]=1)([O-:31])=[O:30]
Reactant: CCOC(=O)c1cnc(Cl)cc1-c1ccccc1
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(NCCNc2ccc([N+](=O)[O-])cn2)cc1-c1ccccc1
Yield: 70 %

Procedure:
The crude material above, ethyl 6-chloro-4-phenylpyridine-3-carboxylate (140 mg, 0.56 mmol) was mixed with (2-aminoethyl)(5-nitro(2-pyridyl))amine (408 mg, 2.24 mmol), Hünig's base (390 ul), and DMA (2 ml) for 48 hours at 70-75° C. with stirring under argon. The reaction was followed by TLC and HPLC. When judged complete, the reaction was diluted with EtOAc (100 ml) and washed with sat. aq. NaHCO3 (5×30 ml), brine (30 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The yellow solid was purified by column chromatography using 5% MeOH in CH2Cl2 as the eluent. The product was dried overnight in vacuo giving ethyl 6-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)-4-phenylpyridine-3-carboxylate in 70% yield.