Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Cl[C:7]1[S:8][C:9]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[C:10]([Cl:12])[N:11]=1>O1CCCC1>[Cl:12][C:10]1[N:11]=[CH:7][S:8][C:9]=1[CH:13]1[O:17][CH2:16][CH2:15][O:14]1
Reactant: Clc1nc(Cl)c(C2OCCO2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ncsc1C1OCCO1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
Slowly add n-butyllithium (2.5 M in hexanes, 44.0 mL, 110 mmol) to a stirred solution of 2,4-dichloro-5-[1,3]dioxolan-2-yl-thiazole (19.33 g, 85.5 mmol) and anhydrous tetrahydrofuran (400 mL) at −78° C. under nitrogen. Stir for 1.5 h at −78° C. and then quench with water and pour the reaction into brine (300 mL). Extract with ethyl acetate (3×200 mL), dry over sodium sulfate, and filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 25% ethyl acetate/hexanes to yield 15.27 g (93%) of 4-chloro-5-[1,3]dioxolan-2-yl-thiazole: mass spectrum (ion spray): m/z=192.0 (M+1); 1H NMR (CDCl3): δ=8.75 (s, 1H), 6.18 (s, 1H), 4.22-4.04 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Br:17])[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:19][NH3+:20].C(=O)(O)[O-].[Na+].C(O)C>[Cl-].[Na+].O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[N:20]/[OH:19])[CH:14]=[C:15]([Br:17])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)cc(OCc2ccccc2)c1
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O/N=C/c1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A mixture of 3-(benzyloxy)-5-bromobenzaldehyde (5.05 g), hydroxyl ammonium chloride (1.326 g), sodium bicarbonate (1.603 g), and ethanol (50 mL) was stirred overnight at room temperature. To the reaction mixture, water and brine were added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (1.48 g).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([CH:10]=[O:11])=[C:6]([CH:9]=1)C#N.C(=O)([O-])[O-].[K+].[K+].[CH3:18][S-:19].[Na+].C[N:22]([CH:24]=O)C>C(OCC)(=O)C>[CH:10]([C:5]1[CH:4]=[CH:3][C:2]([S:19][CH3:18])=[C:9]([CH:6]=1)[C:24]#[N:22])=[O:11]
Reactant: N#Cc1cc(F)ccc1C=O
Reactant: C[S-]
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CSc1ccc(C=O)cc1C#N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A flask is charged with 5-fluoro-2-formyl-benzonitrile (0.200 g, 1.34 mmol), potassium carbonate (0.371 g, 0.268 mmol), sodium thiomethoxide (0.142 g, 2.01 mmol) and DMF (20 mL). The mixture is stirred at room temperature for 10 min, then diluted with ethyl acetate and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo to afford 5-formyl-2-methylsulfanyl-benzonitrile as a yellow color solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.64 (s, 3H), 7.41 (d, J=8.3 Hz, 1H), 8.01 (dd, J=8.5, 1.9 Hz, 1H), 8.07 (d, J=1.8 Hz, 1H), 9.95 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)\[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCC/C(=C\C=C\C(=O)O)c1cccc(OC)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
As in Example 115, (E,E)-5-(3-methoxyphenyl)-2,4-nonadienoic acid (4.48 g) and 4-nitrophenol (2.97 g) in 25 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide 3.59 g). The mixture was stirred at room temperature for 3 days and after the normal work up, the crude product was crystallized from 2-propanol yield 5.6 g of (E,E)-5-(3-methoxyphenyl)-2,4-nonadienoic acid 4-nitrophenyl ester, mp 81.5°-83° C.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].CN(C)C=O.[NH2:10][C:11](=[N:17][OH:18])[C:12](=[N:15][OH:16])[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:10][C:11](=[N:17][OH:18])[C:12](=[N:15][O:16][CH:2]([CH3:4])[CH3:3])[C:13]#[N:14]
Reactant: N#CC(=NO)C(N)=NO
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)ON=C(C#N)C(N)=NO
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
2.52 g (14.8 mM) of 2-iodopropane was added to an N,N-dimethylformamide solution (30 ml) of 2.00 g (15.6 mM) of 3-amino-2,3-bis(hydroxyimino)propionitrile. The mixture was cooled to 0° C. 2.05 g (14.8 mM) of potassium carbonate was added, followed by stirring at room temperature for 16 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer obtained was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered to remove inorganic matter. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetete:hexane=1:2) to obtain 1.36 g (yield: 51%) of 3-amino-3-hydroxyimino-2-isopropoxyiminopropionitrile (compound No. 1-004).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:5]=2[C:6]([CH3:9])([CH3:8])[CH:7]=1.CC1C2C=C(Br)C=CC=2SC(C)=C1C.[H][H]>C(OCC)(=O)C.[Pd]=S>[CH3:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]2[C:4](=[CH:13][CH:12]=[C:11]([Br:14])[CH:10]=2)[S:3]1
Reactant: CC1=CC(C)(C)c2cc(Br)ccc2S1
Reactant: [H][H]
Agent: S=[Pd]
Agent: CC1=C(C)C(C)c2cc(Br)ccc2S1
Solvent: CCOC(C)=O
Product: CC1CC(C)(C)c2cc(Br)ccc2S1

Procedure:
A solution of 500 mg (1.9 mmol) of 2,4,4-trimethyl-6-bromo-(4H)-1-benzothiopyran (Compound 50) in 5 ml of ethyl acetate was treated with 500 mg of 10% palladium sulfide on carbon and then shaken under an atmosphere (30 psi) of hydrogen in a Parr apparatus for 24 hours. The mixture was filtered through celite and the solvent was removed in-vacuo. The residue was purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl3): & 1.21 (3H, s), 1.33 (3H, d, J=6.6Hz), 1.36 (3H, s), 1.64-1.89 (2H, m), 3.37-3.50 (1H, m), 7.10 (1H, dd, J=8.4 Hz, 2.1Hz), 7.19 (1H, d, 8.4 Hz), 7.20 (1H, d, 2.1 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH2:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[CH:24](=O)[CH3:25].[Na].[C:28](O)(=O)[CH3:29]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:16]([CH2:24][CH3:25])[CH2:28][CH3:29])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CC(=O)O
Reactant: CC=O
Reactant: NCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: [Na]
Solvent: CC#N
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 23, a solution of 8-chloro-1-(aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated with acetaldehyde, sodium cyanoborohidride and acetic acid to give 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8]O.P(Br)(Br)[Br:12]>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=1[Cl:10]
Reactant: OCc1c(Cl)cncc1Cl
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Product: Clc1cncc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
To a solution of (3,5-dichloropyridin-4-yl)methanol (470 mg, 2.6 mmol) in anhydrous chloroform (10 mL) was added dropwise a solution of phosphorus tribromide (250 μL, 2.6 mmol) in anhydrous chloroform (2 mL) at 0° C. The mixture was stirred for 1.5 hours at room temperature. The solid was filtered and washed with dichloromethane to afford 4-(bromomethyl)-3,5-dichloropyridine (471 mg, 75% yield), which was used for next step without further purification; 1H NMR (400 MHz, MeOD4): δ 4.76 (s, 2H), 8.63 (s, 2H).
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.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[C:23]=1[CH3:31].Cl>C(#N)C>[Cl:21][C:22]1[C:23]([CH3:31])=[C:24]([NH:28][C:29]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:6]3)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(Cl)cccc1N=C=O
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Product: Cc1c(Cl)cccc1NC(=O)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
TEA (0.28 ml, 2 mmol) was added 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 1-chloro-3-isocyanato-2-methyl-benzene (0.13 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding 1-(3-chloro-2-methyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (400 mg, 91%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN 0.1% H3PO4 in H2O: tR=3.23 min (97%); mp. 252-254° C. 1H NMR (DMSO-d6) δ 1.93-2.08 (m, 5H, CHH), 2.25 (s, 3H, CH3), 2.33-2.47 (m, 1H, CHH), 2.61-2.64 (m., 1H, CHH), 2.82-3.01 (m, 1H, CHH), 4.25-4.55 (m, 4H, CH2+CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 6.98-7.20 (m, 3H, Ar), 7.46 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, NH), 7.67-7.83 (m, 2H, Ar), 8.02 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.62, 22.49, 31.20, 42.90, 47.12, 51.58, 120.32, 121.96, 123.01, 125.74, 126.78, 126.95, 130.35, 133.39, 139.61, 142.42, 144.61, 155.31, 167.93, 170.99, 172.86. LCMS MH=441. Anal Calcd for: C22H21ClN4O3+0.05 HCl: C, 59.69; H, 4.79; N, 12.66; Cl, 8.41. found: C, 59.44; H, 4.57; N, 12.51; Cl, 8.43.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:27]=[C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:1]([C:3]2[CH:8]=[C:7]([CH2:9][CH2:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: CCOP(=O)(CCc1ccnc(C#N)c1)OCC
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(CCc1ccnc(-c2nc(=O)c3ccccc3s2)c1)OCC
Yield: 44 %

Procedure:
Diethyl 2-(2-cyano-4-pyridyl)ethylphosphonate (1.4 g, 5.4 mmol) and methyl thiosalicylate (1.8 g, 10.9 mmol) were dissolved in toluene (8 ml), and triethylamine (4.0 ml, 28.6 mmol) was added thereto. The mixture was refluxed for 6 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (10:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.96 g, 43%) as white crystals.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH3:15]>O>[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH4+:15]
Reactant: N
Reactant: CCCCCCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCCCCCC(=O)[O-]
Product: [NH4+]
Temperature: 45 °C

Procedure:
While stirring 60 parts of lauric acid melted by heating at 45° C., a mixture comprising 115.5 parts of 10% aqueous ammonia and 150 parts of water, was dropwise added to obtain an aqueous dispersion of ammonium laurate having a solid content of 22%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[C:3]=1[F:12].Br[C:14]1[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[N:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=2)=[C:4]([F:11])[C:3]=1[F:12]
Reactant: OB(O)c1ccc(Br)c(F)c1F
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1cnc(-c2ccc(Br)c(F)c2F)cn1
Temperature: 80 °C
Yield: 33 %

Procedure:
A mixture of (4-bromo-2,3-difluorophenyl)boronic acid (400 mg, 1.69 mmol) and 5-bromopyrazin-2-amine (588 mg, 3.38 mmol was suspended in EtOH (5.6 ml) and toluene (5.7 mL) The resulting mixture was treated with aqueous Na2CO3 (2.0 N, 4.2 mL, 8.45 mmol). The resulting mixture was then sparged with nitrogen through the mixture for 10 min, and then Pd(PPh3)4 (98 mg, 0.085 mmol) was added. The reaction vessel was sealed and heated at 80° Celsius for 17 hours. The reaction mixture was cooled to rt and then partitioned between saturated aqueous NH4Cl and EtOAc. The organic layer was dried over MgSO4 and concentrated to dryness. The residue was suspended in DCM and the solid isolated by filtration to afford the title compound (160 mg, 33%), which was used without further purification. MS (ESI): mass calcd. for C10H6BrF2N3, 284.97; m/z found, 286.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.01 (d, J=1.2, 1H), 7.68-7.56 (m, 2H), 6.87 (s, 2H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH2:22][CH3:23])(=[O:7])[CH3:6].[F:24][C:25]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:26]=1[C:27]([NH:29][CH:30](OC)[CH2:31][Cl:32])=[O:28]>ClCCl>[F:24][C:25]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:26]=1[C:27]([NH:29][CH:30]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5](=[O:7])[CH3:6])=[C:10]([CH2:21][CH2:22][CH3:23])[CH:11]=2)=[CH:16][CH:17]=1)[CH2:31][Cl:32])=[O:28]
Reactant: COC(CCl)NC(=O)c1c(F)cccc1F
Reactant: CCCc1cc(-c2ccccc2)ccc1OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCc1cc(-c2ccc(C(CCl)NC(=O)c3c(F)cccc3F)cc2)ccc1OC(C)=O
Reaction time: 0.5 h
Yield: 97 %

Procedure:
At 0° C., 28.5 g (0.215 mol) of aluminium chloride are added a little at a time with stirring to a solution of 14.9 g (59 mmol) of 4-acetoxy-3-n-propylbiphenyl and 16.2 g (65 mmol) of 2,6-difluoro-N-[2-chloro-1-methoxyethyl]-benzamide in 100 ml of dichloromethane. The mixture is stirred for 30 minutes, a further 4 g (30 mmol) of aluminium chloride are added and the mixture is stirred for a further 2 hours at 0° C. The reaction mixture is poured onto ice, the product is extracted with dichloromethane and the organic phase is concentrated under reduced pressure. 27 g of a resinous crude product (log p=3.92, pH 2.3) are obtained and used for further reactions without any further purification (˜100% crude yield).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[OH:22][CH2:23][CH2:24][NH:25][C:26]1[CH:27]=[CH:28][C:29]([O:33][CH3:34])=[C:30](O)[CH:31]=1.[NH3:35].OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:27]1/[C:26]([NH:25][CH2:24][CH2:23][OH:22])=[CH:31][C:30](=[NH:35])[C:29]([O:33][CH3:34])=[CH:28]/1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: COc1ccc(NCCO)cc1O
Reactant: N
Agent: CS(=O)(=O)O
Agent: OO
Solvent: O
Solvent: CCO
Product: COC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(NCCO)=CC1=N

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 5-[(2-hydroxyethyl)amino]-2-methoxyphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[S:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=1)=[O:10])([O-:5])=[O:4].I[CH2:24][C:25]([NH2:27])=[O:26]>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([N:11]=[C:12]1[N:16]([CH2:24][C:25]([NH2:27])=[O:26])[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[S:13]1)=[O:10])([O-:5])=[O:4]
Reactant: NC(=O)CI
Reactant: O=C(Nc1ncc([N+](=O)[O-])s1)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1cc([N+](=O)[O-])sc1=NC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
By following the procedure of Example 5, but using a dispersion of sodium hydride (2.1 g 60% w/w) in mineral oil, 3-nitro-N-(5-nitro-2-thiazolyl)benzamide (11.8 g), N,N-dimethylformamide (100 ml) and 2-iodoacetamide (11.1 g), there was obtained 2-[(3-nitrobenzoyl)imino]-5-nitro-4-thiazoline-3-acetamide, m.pt 251°-252°, after recrystallization from pyridine.
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12](F)=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4].[CH2:15]([Mg]Br)[CH3:16]>O1CCCC1.CCOCC>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC/N=C/c1c(F)cccc1Cl
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC/N=C/c1c(Cl)cccc1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
This compound was prepared using methodology described in Synthesis 1999, 2138-2144. To a solution of 21.2 g (99.2 mmol) butyl-[1-(2-chloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine in 150 ml tetrahydrofuran at 0° C. was added dropwise 38.0 ml (114 mmol) of a 3 M solution of ethylmagnesium bromide in ether at such a rate that the temperature of the reaction mixture was maintained below 20° C. After the addition was complete, the reaction mixture was stirred for a further 1 h at room temperature. The reaction mixture was then quenched by dropwise addition of water and diluted with ethyl acetate. The mixture was washed sequentially with water and with saturated brine, then the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was resuspended in carbon tetrachloride and concentrated in vacuo again to afford 19.7 g (89%) of the title compound as a yellow oil which was used in the next step without further purification. MS (ISP): 226.3 ([{37Cl}M+H]+), 224.3 ([{35Cl}M+H]+). 1H NMR and MS analysis indicated that this material contained ca 13% of the by-product butyl-[1-(2-ethyl-6-fluoro-phenyl)-meth-(E)-ylidene]-amine. MS (ISP): 208.3 ([M+H]+).
Reaction SMILES: [CH:1]1([PH:6][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN([CH2:15][C-:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21]N(C)C)C.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30]>C(O)(=O)C>[CH:7]1([P:6]([CH2:15][C-:16]2[CH:20]=[CH:19][CH:18]=[C:17]2[CH2:21][P:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:8][CH2:9][CH2:10][CH2:11]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:30]
Reactant: CN(C)Cc1ccc[c-]1CN(C)C
Reactant: C1CCC(PC2CCCC2)C1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: c1cc(CP(C2CCCC2)C2CCCC2)[c-](CP(C2CCCC2)C2CCCC2)c1

Procedure:
The title compound was prepared in accordance with the procedure of Example 10 employing dicyclopentylphosphine (Strem 566 mg, 3.33 mmol), 1,2-bis(dimethylaminomethyl)ferrocene (0.5 g, 1.66 mmol) and anhydrous acetic acid (100 ml). Yield 0.432 g.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][N:20]=[C:19]([CH2:24][N:25]2[N:53]=[C:29]3[CH2:30][C:31](=O)[C:32]4[CH2:33][S:34][N:35]=[C:36]([N:37](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:27]([C:28]=43)=[N:26]2)[C:18]=1[CH3:54].[Cl:55]C(Cl)C.[CH3:59][NH2:60].[OH-].[Na+]>O1CCCC1.C(O)(=O)C.CO>[ClH:55].[CH3:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][N:20]=[C:19]([CH2:24][N:25]2[N:53]=[C:29]3[CH2:30][CH:31]([NH:60][CH3:59])[C:32]4[CH2:33][S:34][N:35]=[C:36]([NH2:37])[C:27]([C:28]=43)=[N:26]2)[C:18]=1[CH3:54]
Reactant: CC(Cl)Cl
Reactant: COc1c(C)cnc(CN2N=C3CC(=O)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CNC1CC2=NN(Cc3ncc(C)c(OC)c3C)N=C3C(N)=NSCC1=C23
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
Sodium triacetoxyborohydride (16 mg) was added to a mixture composed of di-tert-butyl {2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-8-oxo-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 40 (28 mg), dichloroethane (0.5 mL), a 2 N solution of methylamine in tetrahydrofuran (0.1 mL) and acetic acid (6 μL), and the mixture was stirred at room temperature for 17 hours. Methanol (three drops) was added dropwise to the reaction mixture, and then a 0.2 N sodium hydroxide solution was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reversed phase liquid chromatography. A 4 N solution of hydrochloric acid in dioxane (20 μL) was added to the resulting solid. Methanol and diethyl ether were added and the precipitated solid was collected by filtration to obtain the title compound (5.7 g, 28%) as a solid.
Reaction SMILES: C1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([SH:22])[CH:19]([SH:21])[CH3:20].[C:23]1([CH2:29][CH:30]=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:29]([CH:30]1[S:21][CH:19]([CH3:20])[CH2:18][S:22]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(S)CS
Reactant: O=CCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CC1CSC(Cc2ccccc2)S1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100 cc reaction flask equipped with reflux condenser, magnetic stirring bar and thermometer and hot plate equipped with magnetic stirring apparatus is placed 5 ml cyclohexane, 0.2 grams of para-toluenesulfonic acid and 5.4 grams (0.05 moles) of 1,2-propanedithiol. With stirring, over a period of 30 minutes, 6 grams (0.05 moles) of phenylacetaldehyde is added to the reaction mass. The reaction mass is then heated to reflux and refluxed for a period of 8 hours. During the refluxing period, water of reaction is removed. At the end of the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The resulting filtrate is distilled on a Microvigreux column yielding the following three fractions: