Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:8].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[CH3:19][N:20]([CH3:22])/[CH:21]=[C:6](\[C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)/[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)=[O:8]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1ccc(C(=O)Cc2ncc[nH]2)cc1
Product: CN(C)/C=C(/C(=O)c1ccc(C#N)cc1)c1ncc[nH]1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
A mixture of 4-(2-imidazolylacetyl)benzenecarbonitrile (0.30 M) and N,N-dimethylformamide dimethyl acetal (DMFDMA) (80 ml) was stirred for 12 h at 75° C. The DMFDMA was then removed under reduced pressure and dried under high vacuum for several hours giving an orange-yellow solid 4-[(2E)-3-(dimethylamino)-2-imidazolylprop-2-enoyl]benzenecarbonitrile in quantitative yield. The enaminone product was typically used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Br:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[BrH:9].[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Cl)cn1
Product: Br
Product: CCOC(=O)Cn1cc(Cl)ccc1=N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-amino-5-chloropyridine, compound 9 (Aldrich, 10 g, 0.078 mol) was added ethyl bromoacetate (30 mL, 0.269 mol) and the reaction mixture stirred at room temperature for 8 hours. The heavy white precipitate was removed by filtration and recrystallized from EtOH to yield 21.9 g (95%) yield of compound 11 as white crystals.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>CN(C)C=O.C([O-])([O-])=O.[K+].[K+]>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][S:4][C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]([OH:10])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CSc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Thiosalicylic acid 15.419 g(0.1M) was dissolved in 150 mL of dimethylformamide (DMF) and 41.463 g(0.3M) of K2CO3, was added to the mixture with stirring. To the above solution, 4-methoxybenzyl chloride 15.661 g(0.1M) was added and the mixture was refluxed for 10 hours. The solution then was cooled to room temperature and 150 mL of water was added and the mixture was acidified with 3M HCL. The precipitated material was collected by gravity filtration and washed with acetone to give 27.364 g(99.7%) of white powder with a melting point of 225-227° C. and the following specifications:
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Br:75][C:76]1[CH:81]=[C:80](/[CH:82]=[CH:83]/[C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)[CH:79]=[CH:78][N:77]=1>C(O)CC.O>[Br:75][C:76]1[CH:81]=[C:80]([C@@H:82]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@H:83]([OH:12])[C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)[CH:79]=[CH:78][N:77]=1
Reactant: CC(C)(C)OCl
Reactant: Brc1cc(/C=C/c2ccccc2)ccn1
Reactant: CC(C)(C)OC(N)=O
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CC(C)(C)OC(=O)N[C@H](c1ccnc(Br)c1)[C@H](O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl carbamate (2.96 g, 25.3 mmol) in propanol (30 mL) was added sodium hydroxide (0.994 g, 24.86 mmol) in water (54 mL) followed by tert-butyl hypochlorite (2.81 mL, 24.86 mmol). After 5 min, the solution was cooled to 0° C. and treated with a solution of (DHQD)2PHAL (0.317 g, 0.407 mmol) in propanol (30 mL). To this was added a solution of (E)-2-bromo-4-styrylpyridine (2.12 g, 8.15 mmol) in propanol (51 mL). To this was added potassium osmate dihydrate (0.120 g, 0.326 mmol) as a solid in one portion. The reaction was allowed to gradually warm in the glass dewar overnight. In the morning, the bath was still cool (5° C.). The reaction was quenched by addition of sodiumthiosulfate (2.7 g) in water (30 mL). The cooling bath was removed and the reaction stirred for 30 min. The reaction was poured into water (ca. 400 mL) and extracted with diethyl ether (2×). The combined organics were washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. The resulting residue was concentrated from toluene (3×) to help remove an unknown impurity. The resulting residue was purified by column chromatography (25%-->40% EtOAc/Hex) to give 1.85 g (58%) as a mixture of regioisomers which was used without further purification. Mass spec.: 393.15 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[N:15]=[C:16]([C:17]3[N:18](C(OC(C)(C)C)=O)[C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:3]=12.C([O-])(O)=O.[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[N:15]=[C:16]([C:17]3[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:3]=12
Reactant: CN1CCN(CCn2nc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(CCn2nc(-c3cc4ccccc4[nH]3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
A solution of tert-butyl 2-(4-chloro-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-1H-indole-1-carboxylate (29 mg, 0.051 mmol) in CH2Cl2 (3 mL) and trifluoroacetic acid (0.8 mL) was stirred at room temperature for 1 d. Solid NaHCO3 was added until no gas was evolved and sat. aq. NaHCO3 solution and CH2Cl2 was added. The layers were separated and the aqueous was extracted with CH2Cl2, the combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was freeze dried from acetonitrile and water to provide Compound Im as a solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[C:4](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:5].C1C[O:28]CC1.OO.[Li+].[OH-]>O>[OH:1][CH2:2][C@@H:3]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[C:4]([OH:5])=[O:28]
Reactant: C1CCOC1
Reactant: C=CCCCC[C@H](CO)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C=CCCCC[C@H](CO)C(=O)O
Temperature: 25 °C

Procedure:
A 0.05 M solution of (4S)-3-[(2R)-2-(hydroxymethyl)-7-octenoyl]-4-benzyl-1,3-oxazolidin-2-one (2.55 g, 7.70 mmol) in a 4:1 mixture of THF and H2O was treated with 30% H2O2 (4.0 mL, 30.82 mmol), followed by LiOH (0.70 g, 15.41 mmol) at 0° C. The resulting mixture was stirred and allowed to warm to room temperature overnight. THF was then removed under vacuum. The residue was washed with dichloromethane (50 mL×2) to remove (S)-4-benzyl-oxazolidin-2-one. The desired product was isolated by EtOAc extraction of the acidified (pH 1˜2) aqueous phase. No further purification was required. Standing under high vacuum yielded the title compound. MH+173.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:16](=[O:32])[NH:17][C:18]1([CH:22]([OH:31])[C:23](=[O:30])[NH:24][C:25]2[CH:29]=[CH:28][NH:27][N:26]=2)[CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]1([F:15])[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:39](Cl)([O:41][CH2:42][CH:43]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]2[C:44]1=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40]>O1CCOCC1.O.C(Cl)Cl>[CH:54]1[C:55]2[CH:43]([CH2:42][O:41][C:39]([N:27]3[CH:28]=[CH:29][C:25]([NH:24][C:23](=[O:30])[CH:22]([C:18]4([NH:17][C:16](=[O:32])[CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:33])[CH2:9][C:10]5([F:15])[CH2:14][CH2:13][CH2:12][CH2:11]5)[CH2:21][CH2:20][CH2:19]4)[OH:31])=[N:26]3)=[O:40])[C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:50]=2[CH:51]=[CH:52][CH:53]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)Nc2cc[nH]n2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)Nc2ccn(C(=O)OCC3c4ccccc4-c4ccccc43)n2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
Compound 57-c (22.5 mg, 0.0482 mmol) was dissolved in a mixture of dioxane:water 1:1 (4 mL). NaHCO3 (14.2 mg, 0.168 mmol) was added to the solution followed by addition of Fmoc-Cl (48 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with DCM and extracted. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated. Purification by flash column chromatography (EtOAc/iso-Hexane, 0:100-40:60) gave the title compound (28 mg, 84%). MS m/z 690.3 (M+H)+.
Reaction SMILES: [OH].[H][H].ClC1C=CC=C(C(OO)=[O:12])C=1.[CH:15]([N:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:30])([CH2:26][CH:27]([CH3:29])[CH3:28])[C:19]1=[O:31])([CH3:17])[CH3:16]>>[CH2:26]([C:20]1([CH3:30])[N:21]([OH:12])[C:22]([CH3:24])([CH3:25])[CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[C:19]1=[O:31])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CC1(C)NC(C)(C)CN(C(C)C)C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [H][H]
Agent: [OH]
Product: CC(C)CC1(C)C(=O)N(C(C)C)CC(C)(C)N1O

Procedure:
A hydroxyl radical may be substituted for hydrogen on the N4 atom of the diaza ring in a manner similar to that described immediately hereinabove, except that only one equivalent of m-chloroperbenzoic acid is used. Thus starting with 1 equiv of N1 -isopropyl-3,5,5,-trimethyl-3-isobutyl-2-piperazinone and 2 equivs of m-chloroperbenzoic acid, we obtain 3-isobutyl-N4 -hydroxy-N1 -isopropyl-3,5,5-trimethyl-2-piperazinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@H:13]([OH:24])[C@@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.C([OH:27])C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[C:9]([C@H:13]([OH:24])[C@@H:14]3[N:19]4[CH2:20][C@:21]([OH:27])([CH:22]=[CH2:23])[C@H:16]([CH2:17][CH2:18]4)[CH2:15]3)[CH:10]=[CH:11][N:12]=2)[CH:8]=1
Reactant: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Reactant: CCO
Product: C=C[C@@]1(O)CN2CC[C@@H]1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Reaction time: 72 h

Procedure:
A few drops of a suspension of M. plumbeus MMP 430 spores are added to 100 ml of medium A, described below, adjusted to pH7, in a 250 ml Erlenmeyer flask. Incubation is continued for 72 hours at 27° C. in a rotating agitator (327 RPM). A solution of 50 mg of quinidine in 1 ml of ethanol is then added under sterile conditions to the culture, and agitation is continued for 14 days under the same conditions. The culture is filtered on celite, the filtrate saturated with NaCl, brought to pH 10-12 by 2N NaOH, the extracted 6 times by methylene chloride. The dried and subsequently evaporated organic fractions are chromatographed on a preparative layer of silica gel, using as solvent CHCl2 -MeOH-NH4OH (85:14:1). The (3S)-3-hydroxy-quinidine band, identified by its fluorescence at 254 nm and its migration, which is smaller than that of quinidine, is scraped off and eluted by methanol. One obtains 1 mg of (3S)-3-hydroxy quinidine, identical with an authentic sample. Non-reacted quinidine is recovered in the same manner, and almost quantitatively (42 mg).
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]([C:15]12[CH2:22][CH2:21][C:18]([CH2:23][OH:24])([CH2:19][CH2:20]1)[CH2:17][CH2:16]2)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(C(CC)(CC)CN)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:12][C:13]([C:15]12[CH2:20][CH2:19][C:18]([CH:23]=[O:24])([CH2:21][CH2:22]1)[CH2:17][CH2:16]2)=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(OCc1ccccc1)C12CCC(CO)(CC1)CC2
Agent: CCC(CC)(CC)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC12CCC(C(=O)OCc3ccccc3)(CC1)CC2
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (COCl)2 (16.5 ml, 188 mmol) in methylene chloride (150 ml) is cooled to −63°. DMSO (18 ml, 362 mmol) is then added dropwise. The resulting mixture is stirred for 30 minutes and then a mixture of 4-hydroxymethylbicyclo[2.2.2]octane-1-carboxylic acid benzyl ester (XVIII, Example 93, 34.5 g, 125 mmol) in methylene chloride (100 ml) is added over 15 minutes. After another 30 minutes, triethylethylamine (70 ml, 502 mmol) in methylene chloride (30 ml) is added over 25 minutes. (Extra Caution: extremely exothermic reaction when the first equivalent of the triethylamine is added.) The reaction mixture then stirred for another 45 minutes and the cooling bath is removed and allowed to warm up to 20-25°. Water (50 ml) is added and the organic layer is separated, dried over anhydrous sodium sulfate and concentrated to give the title compound, NMR (400 MHz, CDCl3) δ 9.51, 7.32, 5.11, 1.88 and 1.64.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
4-(4-Nitro-benzenesulfonyl)-piperazine-1-carboxylic acid benzyl ester (1.82 g, 4.5 mmol) was suspended in a 5:1 mixture of ethanol and water (30 ml). To this solution was added iron powder (0.65 g, 11.7 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (1.5 g, 89% yield) as a white solid. Tr=1.29 min, m/z (ES+) (M+H)+ 376
Reaction SMILES: C([O:8][C:9]1[C:10]([C:16]#[N:17])=[N:11][C:12]([F:15])=[CH:13][N:14]=1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[F:15][C:12]1[N:11]=[C:10]([C:16]#[N:17])[C:9](=[O:8])[NH:14][CH:13]=1
Reactant: N#Cc1nc(F)cnc1OCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1nc(F)c[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
In 10 mL of toluene was dissolved 1.0 g of 3-(benzyloxy)-6-fluoro-2-pyrazinecarbonitrile. Then, 0.64 g of aluminum chloride was added to the solution at an ice-cooled temperature, and the mixture thus formed was stirred at room temperature for 2 hours. Then, 10 mL of water was added to the reaction mixture, the aqueous layer was separated, and the organic layer was extracted with two 2 mL portions of water. The aqueous layers were united and extracted with two 5 mL portions of ethyl acetate. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.51 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow-colored solid product.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].C(O)(=O)C.CO>O>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCNCC
Reactant: Nc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)c(Br)cc1CC2
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)S(=O)(=O)c1cc2c(cc1Br)CCc1nc(N)[nH]c(=O)c1-2
Yield: 59 %

Procedure:
3-Amino-8-bromo-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonyl- chloride (1.10 g, 2.8 mmole) and diethylamine(5 ml) were dissolved in water(15 ml) and heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature and neutralized with dilute acetic acid. The collected precipitate was suspended in boiling methanol, the suspension allowed to cool, and the solid filtered off and dried under high vacuum to give 3-amino-8-bromo-N,N-diethyl-5,6- dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonamide (0.708 g, 59%). 1H NMR (DMSO-d6, 200 MHz) δ: 1.07 (t, J=7Hz, 6H, ethyl CH3), 2.54-2.62 (m, 2H, Ar CH2), 2.81-2.88 (m, 2H, Ar CH2), 3.26 (q, J=7Hz, 4H, ethyl CH2), 6.83 (br s, 2H, NH2) 7.60(s, 1H, Ar), 9.13 (s, IH, Ar), 10.95 (br s, 1H, NH). Anal Calculated for C16H19BrN4 03S: C,44.97; H,4.48; Br,18.70; N,13.11; S,7.50. Found: C,44.90; H,4.49; Br,18.65; N,13.03; S,7.57.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]([N:17]([C:19]1[N:24]=[C:23]([O:25][CH:26]([F:28])[F:27])[CH:22]=[C:21]([O:29][CH:30]([F:32])[F:31])[N:20]=1)C)=[O:16])(=[O:13])=[O:12])=[O:4]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:14]=[C:15]=[O:16])(=[O:12])=[O:13])=[O:4].[CH3:15][NH:17][C:19]1[N:20]=[C:21]([O:29][CH:30]([F:32])[F:31])[CH:22]=[C:23]([O:25][CH:26]([F:28])[F:27])[N:24]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)N(C)c1nc(OC(F)F)cc(OC(F)F)n1
Solvent: ClCCl
Product: CNc1nc(OC(F)F)cc(OC(F)F)n1
Product: COC(=O)c1ccccc1S(=O)(=O)N=C=O

Procedure:
In the same manner as described in Example 1, 4.6 g (95.8% of theory) of N-(2-methoxycarbonylphenylsulfonyl)-N'-[4,6-bis-(difluoromethoxy)pyrimidin-2-yl]-N'-methylurea are obtained from 2.6 g (0.011 mole) of 2-methoxycarbonylphenylsulfonylisocyanate and 2.4 g (0.01 mole) of 2-methylamino-4,6-bis-(difluoromethoxy)pyrimidine in 30 ml of methylene chloride. The product melts at 114°-115° C. after recrystallisation from a mixture of acetone/ether.
Reaction SMILES: [OH:1]C(C(=O)C=CC)C.[CH3:9][C:10]([CH2:15][CH2:16][CH3:17])([CH2:13][OH:14])[CH2:11][OH:12].[CH2:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[OH:1][CH2:18][CH2:19][C:20]1([CH:21]=[CH:22][CH3:23])[O:14][CH2:13][C:10]([CH3:9])([CH2:15][CH2:16][CH3:17])[CH2:11][O:12]1
Reactant: C1CCCCC1
Reactant: CCCC(C)(CO)CO
Reactant: CC=CC(=O)C(C)O
Product: CC=CC1(CCO)OCC(C)(CCC)CO1

Procedure:
2.9 g of 2-hydroxyhex-4-en-3-one 63 (25 mmoles) and 3.3 g of 2-methyl-2-propylpropane-1.3-diol 24 (25 mmoles) are acetalized in 50 ml of cyclohexane by AAV 1. After distillation through a spinning band column, a clear light yellow oil is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[S:17][C:11]=3[C:10]2=[O:26])[CH:6]=[CH:5][C:4]=1[O:27]S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+].CCO.Cl>O>[OH:27][C:4]1[CH:5]=[CH:6][C:7]([N:9]2[CH2:14][CH2:13][C:12]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[S:17][C:11]=3[C:10]2=[O:26])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(OS(=O)(=O)c4ccc(C)cc4)c(OC)c2)CC3)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(O)c(OC)c2)CC3)cc1
Yield: 88.2 %

Procedure:
Combine toluene-4-sulfonic acid 2-methoxy-4-[2-(4-methoxy-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-phenyl ester (1.029 g, 1.92 mmol) and KOH (2.15 g, 38.48 mmol) with EtOH (30 mL) and water (20 mL). Reflux the reaction for 10 h and dilute with water (50 mL). Acidify with 5.0 M HCl (8 mL). Remove the organic solvent in vacuo and dilute the residue with water (10 mL). Collect the solid material by filtration and wash with water (3×10 mL) and Et2O (2×15 mL) then dry in a vacuum oven to give 0.646 g (88%) of the title compound. MS/ES m/z 382.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1OCc1ccccn1
Reactant: OCc1ccccn1
Solvent: O
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1OCc1ccccn1
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a stirred suspension of 130 mg (0.50 mmol) 2-amino-4-chloro-6-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile in 10 ml DME were added 0.17 ml (1.74 mmol) 2-(hydroxymethyl)pyridine and 0.11 ml (0.75 mmol) DBU and stirring continued for 1 hour at room temperature. 50 ml water was then added and the resulting crystals collected by filtration and washed with ether to afford 80 mg (48%) 2-amino-4,6-bis-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 357 (M+Na+, 40), 335 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][N:18]=3)[CH:5]=[CH:4][C:3]1=2.CCCCCCC>C1COCC1.[OH-].[Na+]>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC1(C)CCC(C)(C)c2cc([Se]C#Cc3ccc(C(=O)O)cn3)ccc21
Yield: 35.7 %

Procedure:
In a manner similar to that of Example 7, by reaction of 600 mg (1.36 mmol) of ethyl 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanylethynyl)nicotinate in 30 ml of THF and 1 g of sodium hydroxide, and after trituration from heptane, 200 mg (36%) of the expected compound are obtained in the form of a yellow solid. m.p.=128° C.
Reaction SMILES: [F:1][C:2]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)([F:17])[C:3]([NH:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:4].[NH2:27][C:28]1[C:32]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:31][N:30]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:29]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](C(C)C)(C(C)C)C(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:1][C:2]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:27][C:28]2[C:32]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[CH:31][N:30]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:29]=2)=[O:23])=[CH:20][CH:19]=1)([F:17])[C:3]([NH:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:4]
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1N
Reactant: COc1ccccc1C(=O)NNC(=O)C(F)(F)c1ccc(C(=O)O)cc1
Agent: CC(C)[P+](On1nnc2ccccc21)(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1C(=O)NNC(=O)C(F)(F)c1ccc(C(=O)Nc2nn(-c3ccccc3)cc2NC(=O)OC(C)(C)C)cc1
Temperature: 60 °C

Procedure:
To a solution of 4-{1,1-difluoro-2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoic acid (65 mg, 0.18 mmol), tert-butyl (3-amino-1-phenyl-1H-pyrazol-4-yl)carbamate (74 mg, 0.27 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) in methylene chloride (1.5 mL) was added (1H-1,2,3-benzotriazol-1-yloxy)(triisopropyl)phosphonium hexafluorophosphate (0.16 g, 0.36 mmol) and the reaction was sealed and heated to 60° C. for 16 hours. The reaction was purified by flash chromatography (0-4% methanol/methylene chloride) to give crude tert-butyl {3-[(4-{1,1-difluoro-2-[2-(2-methoxybenzoyl)hydrazino]-2-oxoethyl}benzoyl)amino]-1-phenyl-1H-pyrazol-4-yl}carbamate. ESIMS calcd 621.2 (M++U), found 621.2 (M++H).