Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]([OH:17])=O)=[N:11][N:10]([CH:18]([CH3:20])[CH3:19])[C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][C:38]=1[F:44].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][CH:28]=[C:27]2[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:15]([C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:21])[N:10]([CH:18]([CH3:20])[CH3:19])[N:11]=2)=[O:17])=[CH:39][C:38]=1[F:44]
Reactant: CC(C)n1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
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
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4nn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (500 mg, 2 mmol), 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (535 mg, 1.70 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (639 mg, 1.68 mmol) and N,N-diisopropylethylamine (279 uL, 1.60 mmol) in N,N-dimethylformamide (8 mL) was stirred at rt for 3 h. The solvent was removed and the residue dissolved in EtOAc and washed with saturated NaHCO3 solution water and brine. After drying over magnesium sulfate, solvent was evaporated and the product was purified by ISCO silica gel chromatography (hexane: EtOAc 1:4) to give 835 mg (83%), which triturated with ether and dried. mp=225-226° C.; LCMS m/z=590 (M+1); 1H NMR DMSO) δ: 10.87 (s, 1H), 8.49 (d, 1H, J=5.2 Hz), 7.97 (dd, 1H, J=12.6, 2.2 Hz), 7.59-7.36 (m, 8H), 6.50 (d, 1H, J=4.9 Hz), 4.90 (m, 1H), 3.95 (s, 6H), 3.32 (s, 3H), 1.38 (d, 6H, J=6.6 Hz).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[F:34][C:35]([F:47])([F:46])[C:36]1[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=O)[CH:39]=[CH:40][CH:41]=1.C(N(CC)C(C)C)(C)C.[Cl:57][C:58]1[S:62][C:61]([C:63]2[N:67]([CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[F:75])[C:66](=[O:76])[N:65]([CH2:77]/[C:78](=[N:80]/O)/[NH2:79])[N:64]=2)=[CH:60][CH:59]=1>CN(C=O)C.O>[Cl:57][C:58]1[S:62][C:61]([C:63]2[N:67]([CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[F:75])[C:66](=[O:76])[N:65]([CH2:77][C:78]3[N:80]=[C:43]([CH2:42][C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:34])([F:47])[F:46])[CH:37]=4)[O:45][N:79]=3)[N:64]=2)=[CH:60][CH:59]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: N/C(Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)=N\O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2noc(Cc3cccc(C(F)(F)F)c3)n2)nc(-c2ccc(Cl)s2)n1Cc1ccccc1F
Reaction time: 0.5 h

Procedure:
Under argon, 81 mg (0.16 mmol) of benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate were added to a solution of 29 mg (0.14 mmol) of 3-(trifluoromethyl)phenylacetic acid and 27 μl (0.16 mmol) of N,N-diisopropylethylamine in 1.3 ml of dry DMF. After 30 min of stirring, 50 mg (0.13 mmol) of the compound from Example 25A were added and the mixture was stirred at RT for 18 h. 2 ml of water were then added, and the mixture was extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases were washed with in each case 5 ml of water and sodium chloride solution, filtered though Extrelut and concentrated under reduced pressure. The residue was dissolved in 2 ml of DMF and stirred in a microwave oven at 250° C. for 15 min. After cooling, the solvent was removed under reduced pressure on a rotary evaporator and the crude product was purified by chromatography [Method 15]. This gave 25 mg (34% of theory) of the target compound as a dark-yellow resin.
Reaction SMILES: O=C1CCCC1C(OCC)=O.F[N+:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[S:23]([O-:26])(=[O:25])=[O:24]>ClCCCl>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:16]=[CH:15][C:14]([S:23]([OH:26])(=[O:25])=[O:24])=[N:13][CH:18]=1
Reactant: O=S(=O)([O-])c1ccc(C(F)(F)F)c[n+]1F
Agent: CCOC(=O)C1CCCC1=O
Solvent: ClCCCl
Product: O=S(=O)(O)c1ccc(C(F)(F)F)cn1
Yield: 95.5 %

Procedure:
A mixture of ethyl 2-oxocyclopentanecarboxylate (148 μl, 1 mmol), N-fluoro-5-(trifluoromethyl)pyridinium-2-sulfonate (245 mg, 1 mmol) and 1,2-dichloroethane (2 ml) was heated under reflux in an argon atmosphere for 6 hours. Thereafter, the precipitate was recovered by filtration and washed with methylene chloride to obtain 5-trifluoromethylpyridine-2-sulfonic acid (217 mg). Yield, 96%. Analysis of the filtrate by 19F-NMR revealed that ethyl 1-fluoro-2-oxocyclopentanecarboxylate was produced at a yield of 57%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[CH:3]=1.[Br:15][CH2:16][C:17](Br)=[O:18].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:15][CH2:16][C:17]([NH:14][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
6-chloro-2-phenylpyrimidin-4-amine (4) (830 mg) was dissolved in anhydrous DCM (50 ml). To this was added dropwise a solution of bromoacetylbromide (1.05 ml in 10 ml DCM), forming a precipitate after 10 min. To this was then added dropwise a solution of N,N-diisopropylethylamine (1.06 ml in 10 ml DCM) and the solution left for 1 hr. The solvent was removed in vacuo, then the crude solid purified by flash chromatography on silica gel eluting with a mixture of ethyl acetate and petroleum ether (1:9 then 1:1 v/v), furnishing the title compound as a solid (1.09 g).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([C:10]1[CH:35]=[CH:34][C:13]([O:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=2)[C:19]([NH:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=O)=[C:12]([CH2:36][CH2:37][CH3:38])[C:11]=1[OH:39])(=[O:9])[CH3:8].[NH:40]=[N+:41]=[N-:42].N=[N+]=[N-].C(Cl)(Cl)[Cl:47]>C(Cl)(Cl)Cl>[Cl:47][C:34]1[C:13]([O:14][CH2:15][C:16]2[CH:33]=[CH:32][CH:31]=[C:18]([C:19]3[N:21]([CH2:22][CH2:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[N:42]=[N:41][N:40]=3)[CH:17]=2)=[C:12]([CH2:36][CH2:37][CH3:38])[C:11]([OH:39])=[C:10]([C:7](=[O:9])[CH3:8])[CH:35]=1
Reactant: ClC(Cl)Cl
Reactant: [N-]=[N+]=N
Reactant: CCCc1c(OCc2cccc(C(=O)NCCCc3cccnc3)c2)ccc(C(C)=O)c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCc1cccc(-c2nnnn2CCCc2cccnc2)c1
Reaction time: 1.75 h

Procedure:
Phosphorus pentachloride (2.80 g) was added in portions to a stirred solution of 5.0 g 3-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-N-[3-(3-pyridinyl)propyl]benzamide in 100 mL of anhydrous chloroform at 3°. The reaction mixture was stirred at 3° for an additional 0.25 hr and 25° for 1.75 hr. To this yellow solution stirred at 25° was added dropwise 22 mL of 1.1M hydrazoic acid in chloroform. The reaction was stirred at 25° for 24 hr and then an additional 22.2 mL of 1.1M hydrazoic acid/chloroform solution was added. After stirring for 24 hr at 25° and refluxing for 10 hr, the reaction mixture was washed with saturated sodium bicarbonate solution, dried (magnesium sulfate) and concentrated in vacuo to an oil which was purified by high pressure liquid chromatography. Elution with triethylamine (1.5):ethyl acetate (98.5) gave 1-[5-chloro-2-hydroxy-3-propyl-4-[[3-[1-[3-(3-pyridinyl)propyl]-1H-tetrazol-5-yl]phenyl]methoxy]phenyl]ethanone.
Reaction SMILES: [OH-].[NH4+:2].Br[CH2:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9][CH:8]=1)=[O:6]>CO>[NH2:2][CH:8]=[C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][CH2:4][C:5]1=[O:6]
Reactant: O=C(CBr)c1coc2ccccc2c1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC=C1C(=O)COc2ccccc2C1=O
Reaction time: 1 h

Procedure:
Concentrated ammonium hydroxide (1300ml) was added to a stirred mixture of 108g (0.041 mole) of 3(bromoacetyl)chromone and 500ml of methanol. All solid went into solution. There was a mild exotherm. After several minutes the product began to separate. After one hour, the reddish-tan solid was filtered, washed well with water and dried; wt. 70g (86%); m.p. 149°-151°. Recrystallization from ethyl acetate gave pure, orange crystals; m.p. 151°-153°.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.N1(/[C:32](/[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[N:33]\[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])C=CC=N1>C1COCC1>[C:44]([O:43][C:42](=[O:48])[NH:41]/[C:32](/[NH:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10]2)=[CH:7][CH:8]=1)=[N:33]/[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(=O)N[C@@H]1CCN(c2ccc(N)cc2)C1
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1CCN(c2ccc(N/C(=N\C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)C1
Yield: 69.8 %

Procedure:
N-[(3R)-1-(4-aminophenyl)pyrrolidin-3-yl]acetamide mono hydrochloride (Method 43; 2.47 g, 9.67 mmol) and Hunigs base (2.02 ml, 1.16 mmol) were reacted with di-tert-butyl [(Z)-1H-pyrazol-1-ylmethylylidene]biscarbamate (2.95 g, 9.5 mmol) in THF (50 ml) at room temperature for 72 hours. After evaporation under reduced pressure, chromatography on silica gel with EtOAc/isohexane (50:50 to 100) gave the title compound as a yellow oil (3.06 g, 69%). NMR: 1.39 (s, 9H), 1.52 (s, 9H), 1.81 (s, 3H), 1.82-1.93 (m, 1H), 2.11-2.24 (m, 1H), 3.00-3.08 (m, 1H), 3.21-3.51 (m, 3H), 4.29-4.40 (m, 1H), 6.50 (d, 2H), 7.29 (d, 2H), 8.12 (d, 1H), 9.74 (s, 1H), 11.49 (s, 1H); m/z 462.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:26]I>CN(C=O)C.CCOC(C)=O.O>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[N:11]([CH3:26])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of compound 15d (300 mg, 0.78 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 68.9 mg, 1.72 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, then CH3I (0.053 mL, 0.86 mmol) was added and stirring continued at 0° C. for another 1 h. The resulting mixture was diluted with EtOAc and water. The organic layer was washed with brine and concentrated. The residue was recrystallized from heptane, filtered and the solid dried to give compound 15f (265 mg) as a light yellow solid. MS m/z (M+H+) 284.1.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4].[Si]([O:46][CH:47]1[CH2:52][CH2:51][CH:50](O)[CH2:49][CH2:48]1)(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C@H:50]3[CH2:51][CH2:52][C@H:47]([OH:46])[CH2:48][CH2:49]3)=[CH:14][CH:13]=2)[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(-c2ccc(O[C@H]3CC[C@H](O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h

Procedure:
To a solution of 6-butyl-3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (1.2 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) and triphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwise diisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). After stirring for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and a mixture of the residue, hydroxylammonium chloride (0.87 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (9 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 30 min. Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.5 mL) was added, and the mixture was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.45 g, 33%) as an amorphous solid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][CH:13]([OH:19])[CH2:14][NH:15][CH:16]([CH3:18])[CH3:17])=[CH:9][CH:8]=1)[CH:2]=[CH2:3].[CH2:22]([Zn]CC)C.ICI.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:18][CH:16]([NH:15][CH2:14][CH:13]([OH:19])[CH2:12][O:11][C:10]1[CH:20]=[CH:21][C:7]([CH2:6][CH2:5][O:4][CH2:1][CH:2]2[CH2:22][CH2:3]2)=[CH:8][CH:9]=1)[CH3:17]
Reactant: C=CCOCCc1ccc(OCC(O)CNC(C)C)cc1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: Cc1ccccc1
Product: CC(C)NCC(O)COc1ccc(CCOCC2CC2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound of formula (1) (1 g, 0.003 mol) in dry toluene (5 ml), diethylzinc (1.1 M solution in toluene, 14 ml, 0.017 mol) was added at 0° C. under nitrogen atmosphere followed by diiodomethane (1.38 ml, 0.017 mol). The reaction was stirred for 16 h at 0° C. and poured over cold aqueous solution of ammonium chloride. The organic layer was separated and the aqueous layer extracted repeatedly with toluene. The combined organic layer was washed with a solution of sodium thiosulphate, dried over anhydrous sodium sulphate, filtered and concentrated to yield racemic betaxolol of formula (2) 1.6 g (84%) mp 70 –72° C. as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1.O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:21])[CH2:9][N:8]=[C:7]([C:13]3[NH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccc[nH]2)c2cc(Cl)ccc2N1
Solvent: C1CCOC1
Solvent: O
Product: S=C1CN=C(c2ccc[nH]2)c2cc(Cl)ccc2N1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 159.6 %

Procedure:
10 g (38.5 mmol) of 7-chloro-1,3-dihydro-5-(1H-pyrrol-2-yl)-1,4-benzodiazepin-2-one were dissolved in anhydrous THF (400 ml) in a 1 litre round-bottom 3-neck flask equipped with a mechanical stirrer. The flask was then placed in the water bath of an ultrasonic apparatus. To the stirred reaction solution was added P4S10 (10 g; 22.5 mmol) and the reaction mixture was irradiated with ultrasound. The temperature was maintained at about 40° C. throughout the reaction. After 2.5 hours, an additional portion of P4S10 (10 g; 22.5 mmol) was added to the mixture and the reaction was continued for an additional 2 hours. The heterogeneous mixture was cooled to ambient temperature and filtered. After washing the solid by-product with several portions of CH2CL2, the filtrates were combined and approximately 80% of the solvent was removed in vacuo. The residual solution was basified with saturated sodium bicarbonate solution until a pH of about 8 was reached. The product which precipitated out was filtered. The filtrate was then extracted with CH2Cl2, followed by concentration in vacuo. The solids were combined and recrystallized in THF/Petroleum ether to give 9.9 g (94% yield) of 7-chloro-1,3-dihydro-5-(1H-pyrrol-2yl)-1,4-benzodiazepin-2-thione as a pale yellow powder having the following characteristics: m.p. 258°-260° C. dec.; IR (KBr) 3450, 3165 cm-1. Anal. Calcd. for C13H10C1N3S: C 56.62; H 3.66; N 15.24. Found: C 56.50; H 3.59; N 15.12.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][CH:14]([CH3:17])[C:15]#[N:16]>>[ClH:13].[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:17][CH2:14][CH2:15][NH2:16])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(Cl)C#N
Product: Cl
Product: NCCCN1CCC(c2ccccc2)CC1

Procedure:
The above compound is prepared as described in Example 1A and B except that 4-phenylpiperidine is employed in place of 4-phenyl-1,2,3,6-tetrahydropyridine and chloropropionitrile is used in place of 4-bromobutyronitrile.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14])([O-:10])=[O:9].[CH3:20][C:21]1([CH3:29])[CH2:26][C:25](=[O:27])[C:24](=O)[CH2:23][CH2:22]1.CC(C)([OH:34])C#N>C(Cl)Cl>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([CH:24]1[C:23](=[O:34])[CH2:22][C:21]([CH3:20])([CH3:29])[CH2:26][C:25]1=[O:27])=[O:14])([O-:10])=[O:9]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC1(C)CCC(=O)C(=O)C1
Reactant: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(=O)C(C(=O)c2ccccc2[N+](=O)[O-])C(=O)C1
Reaction time: 2.5 h

Procedure:
Triethylamine (3.4 ml, 25 mmol) was added dropwise to a methylene chloride solution of 2-nitrobenzoyl chloride (3.5 g, 19 mmol) and 5,5-dimethylcyclohexanedione (2.4 g, 19 mmol). After stirring for one hour at room temperature an additional 3 equivalents of triethylamine and 0.4 ml acetone cyanohydrin were added. The solution was stirred for 2.5 hours, then washed with 2N HCl and extracted with 5% potassium carbonate solution. The basic extracts were acidified with 2N HCl and extracted with ether. The ether portion was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was recrytallized from ethyl acetate yielding 2.0 g of the desired compound (m.p. 130°-133° C.) which was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH3:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][N:2]1[C:34]([C:30]2[N:29]([CH3:28])[CH:33]=[CH:32][N:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: Cn1ccnc1C=O
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Br)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-bromo-1H-indole-3-carbaldehyde, followed by 1-methyl-1H-imidazole-2-carbaldehyde.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25])=[N:15][C:16]#[N:17])C=C.[BH4-].[Na+].CO.C(Cl)(Cl)Cl>C1COCC1>[OH:4][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Br:25])=[N:15][C:16]#[N:17]
Reactant: C=CCOc1cc(C#N)ccc1NC(=NC#N)Nc1ccccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: N#CN=C(Nc1ccc(C#N)cc1O)Nc1ccccc1Br
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a mixture of N-(2-Allyloxy-4-cyanophenyl)-N′-(2-bromophenyl)-N″-cyanoguanidine (100 mg, 0.25 mmol) and sodium borohydride (20 mg, 0.52 mmol) in THF (3 ml) was added at rt tetrakistriphenylphosphine palladium[0] (21 mg, 7 mol %). The reaction was stirred at rt until tlc showed no starting material present. The mixture was partitioned between ethyl acetate and 0.5 M sodium dihydrogen phosphate. After drying over MgSO4 filtration and evaporation under reduced pressure afforded a crude tan solid (100 mg). Column chromatography on silica gel eluting with 5% methanol/chloroform gave the title compound as a pale yellow solid (64 mg) which was recrystallized from chloroform (42 mg, 47%). 1H NMR(400 MHz,DMSO) δ 10.93 (s, 1H), 9.57 (s, 1H), 8.74(s, 1H), 7.84 (d, J=8.3 Hz, 1H),7.71 (d, J=7.8 Hz, 2H), 7-50-7.42 (m, 2H), 7-30-7.26 (m, 2H 7.17 (s, 1H), 7.08 (t, 1H); IR(KBr) 2224,2193 cm−1; MS(ES−) m/e 354,356 [M−H]−; MS(ES+) m/e 356,358 [M+H]+; mp. 175-176°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:19])[C:13]=2[C:12](C=O)=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1[CH2:34][CH2:33][CH2:32][CH2:31]1.[C:35]1([Mg]Br)[CH:40]=CC=C[CH:36]=1.[Cl-].[NH4+].[O:45]1CCCC1>>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:18](=[O:19])[C:13]=2[C:12]([OH:45])=[C:11]1[CH2:31][C:32]1[CH:40]=[CH:35][CH:36]=[CH:34][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Br[Mg]c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=O)cn2COCc2ccccc2)c1=O
Agent: [Cl-]
Agent: [NH4+]
Product: C[Si](C)(C)CCOCn1ncc2c(c(O)c(Cc3ccccc3)n2COCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To 87 ml of dehydrated tetrahydrofuran solution containing 3.60 g (8.71 mmol) of 1-benzyloxymethyl-3-formyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Reference example 33-(d) were added 12.2 ml of 1M phenyl magnesium bromide tetrahydrofuran solution under ice-cooling and under argon atmosphere, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, to the reaction mixture were added a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, and the mixture was extracted with ethyl acetate. The organic layer after separation was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1→1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 3.12 g of the title compound as a yellowish oil. (Yield: 73%)