Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-]#N.[Na+].[C:4](O)(=[O:6])C.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]=[O:19])=[CH:12][C:11]=1[CH:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([OH:24])=[O:23].Cl>CO.[O-2].[O-2].[Mn+4].C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([C:18]([O:6][CH3:4])=[O:19])=[CH:12][C:11]=1[CH:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CC(=O)O
Reactant: CCCCCC(CC(=O)O)c1cc(C=O)c(OC)cc1OC
Agent: [Mn+4]
Agent: Cl
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CCCCCC(CC(=O)O)c1cc(C(=O)OC)c(OC)cc1OC
Reaction time: 4 h
Yield: 88.1 %

Procedure:
2.66 g (54.3 mmol) of sodium cyanide, 37.78 g (434.4 mmol) of manganese dioxide and 979 mg (16.3 mmol) of acetic acid were added to a solution of 3.35 g (10.9 mmol) of 3-(2,4-dimethoxy-5-formylphenyl)octanoic acid (prepared as described in Preparation 32) in 70 ml of methanol, and the resulting mixture was stirred for 4 hours. At the end of this time, the reaction mixture was acidified with 1N aqueous hydrochloric acid and filtered using a Celite (trade mark) filter aid. The filtrate was then concentrated by evaporation under reduced pressure, and the concentrate was mixed with a small amount of water, after which it was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 100 g of silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol ranging from 50:0 to 50:3 by volume as the eluent, to give 3.25 g (yield 88%) of the title compound, melting at 106°-107° C. (from ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.C[O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([OH:22])=[O:13])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(I)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Yield: 54.5 %

Procedure:
A solution of 2,4-dichlorophenyl boronic acid (3.96 g, 15.11 mmol) and 4-Iodo-benzoic acid methyl ester (2.88 g, 15.11 mmol), K2CO3 (7.31 g, 52.89 mmol) in 1,4-dioxane (85 mL), and water (20 mL) is purged with nitrogen for 10 min. Pd(PPh3)4 (0.87 g, 0.756 mmol) is added and the resulting reaction mixture is refluxed overnight. The reaction is diluted with water and extracted with Et2O. The combined organic layers are washed with water, dried with MgSO4, and concentrated. The crude material is purified by chromatography to give the title compound (2.20 g, 50%). LC/MS (m/z): calcd for C13H18Cl2O2: 267.1; found: 266.9.
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[C:7](=O)([O-:9])[O-:8].[K+].[K+].C(=O)=O.Cl>O>[OH:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: On1cccn1
Agent: Cl
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cnn(O)c1
Reaction time: 20 h
Yield: 45 %

Procedure:
1 part of 1-hydroxypyrazole is mixed thoroughly with 4 parts of potassium carbonate, and the mixture is introduced into an autoclave. Carbon dioxide is forced in at room temperature until the pressure reaches 50 bar, after which heating is carried out for 20 hours at 150° C. The reactor content is then dissolved in water, the solution is acidified with hydrochloric acid, which precipitates the 1-hydroxypyrazole-4-carboxylic acid, and the latter is filtered off and recrystallized from water. 0.68 part (45% of theory) of 1-hydroxypyrazole-4-carboxylic acid of melting point 230° C. is obtained.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[O:6][C:5]1=[O:24])[CH:2]=[CH2:3].[NH2:26][C@@H:27]([CH:30]1[CH2:32][CH2:31]1)[CH2:28][OH:29].Cl>C(OC(C)C)(=O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C@H:8]([CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[OH:6])[CH2:9][C@:4]([CH3:25])([CH2:1][CH:2]=[CH2:3])[C:5]([NH:26][C@@H:27]([CH:30]2[CH2:32][CH2:31]2)[CH2:28][OH:29])=[O:24])[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@H](c2ccc(Cl)cc2)OC1=O
Reactant: N[C@H](CO)C1CC1
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)C(O)c1ccc(Cl)cc1)C(=O)N[C@H](CO)C1CC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 100.2 %

Procedure:
(3S,5R,6R)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (125.0 g, 333 mmol, Example 1, Step D) was added to (S)-2-amino-2-cyclopropylethanol (101 g, 999 mmol) and the reaction mixture was heated at 110° C. under argon for 25 hours. The reaction mixture was diluted with isopropyl acetate, cooled to room temperature, and 3 M hydrochloric acid (400 mL) was added slowly. The mixture was stirred at room temperature for 20 minutes, and the layers were separated. The organic layer was washed with 1 M hydrochloric acid (200 mL) and brine, then dried over magnesium sulfate, filtered and concentrated under a vacuum to provide the desired product as a brown oil (159 g).
Reaction SMILES: [CH3:1][C:2]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[CH:16]1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.O1CCOCC1.CO>C(Cl)Cl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:17]=[CH:16]1
Reactant: CC(CCn1cnc(-c2ccccc2)c1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(CCn1cnc(-c2ccccc2)c1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.4 %

Procedure:
To a solution of 2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (24.3 mg, 0.058 mmol, 1 eq) in DCM (4 mL) was added 4M HCl in dioxane (0.290 mL, 1.16 mmol, 20 eq). The reaction mixture was allowed to stir at RT for 5 mins. MeOH (100 uL) was added to the mixture. The mixture was then concentrated to dryness to give N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(4-phenyl-1H-imidazol-1-yl)butanamide (8.1 mg, 37% yield). LC-MS M+H+338.5.
Reaction SMILES: [N:1]([CH2:4][C:5]([F:27])([F:26])[CH2:6][C@H:7]([N:17](C)[C:18](=O)OC(C)(C)C)[CH2:8][O:9]C(OC(C)(C)C)=O)=[N+:2]=[N-:3].[ClH:28]>CO>[N:1]([CH2:4][C:5]([F:26])([F:27])[CH2:6][C@H:7]([NH:17][CH3:18])[CH2:8][OH:9])=[N+:2]=[N-:3].[ClH:28]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)OC(C)(C)C)CC(F)(F)CN=[N+]=[N-]
Agent: Cl
Solvent: CO
Product: CN[C@H](CO)CC(F)(F)CN=[N+]=[N-]
Reaction time: 8 h

Procedure:
To a solution of (S)-tert-butyl 5-azido-1-(tert-butoxycarbonyloxy)-4,4-difluoropentan-2-yl(methyl)carbamate (95.6 mmol) in methanol (10 mL) was added Hydrogen chloride (4.0 M in 1,4-dioxane, 240 mL, 0.596 mol). The resulting solution was stirred for overnight. The solvent was removed, and the remaining residue was dried under reduced pressure to give (S)-5-azido-4,4-difluoro-2-(methylamino)pentan-1-ol as a HCl salt, which was used without further purification. LRMS (M+H+) m/z 195.3.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1>C(OP(OCCCC)(OCCCC)=O)CCC.OS(O)(=O)=O>[CH3:5][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:1]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:3][CH:4]=1
Reactant: Cc1cccc2ccccc12
Agent: CCCCOP(=O)(OCCCC)OCCCC
Agent: O=S(=O)(O)O
Product: Cc1ccc(-c2ccc(C)c3ccccc23)c2ccccc12
Reaction time: 26 h
Yield: 4.6 %

Procedure:
2 g (14 mmol) of 1-methylnaphthalene in 2 ml of tributylphosphate was allowed to react with electrochemically produced Ag(II) sulphate at 23° C. The electrolyte solution was composed of 0.02M Ag(I) sulphate in 1.5M H2SO4. The reaction was run for 26 hours at 200 mA. The organic material isolated from the run was placed on a silica gel column, which was eluted with petroleum ether (bp=60°-80° C.) then with a solution of 1% ether in petroleum ether. From this column there were obtained 1.2 g (8.4 mmol, 60%) of starting material and 92 mg (0.32 mmol, 4.6%) of 4,4'-dimethylbinaphthyl.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=1.ClC1C=CC(C(NC2C=CC=C(C3OCCO3)C=2)=O)=CC=1.N1CCC(C(OC)=O)C1.C([O:46][C:47]([CH:49]1[CH2:54][CH2:53][N:52]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([NH:62]C(=O)C3C=CC(Cl)=CC=3)[CH:57]=2)[CH2:51]C1)=[O:48])C>>[F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[C:7]([C:9]([NH:62][C:58]2[CH:57]=[C:56]([CH:61]=[CH:60][CH:59]=2)[CH2:55][N:52]2[CH2:53][CH2:54][CH:49]([C:47]([OH:46])=[O:48])[CH2:51]2)=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)n1
Agent: COC(=O)C1CCNC1
Agent: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Product: O=C(Nc1cccc(CN2CCC(C(=O)O)C2)c1)c1cccc(C(F)(F)F)n1

Procedure:
The title compound is prepared according to the reaction sequence 2.001a-2.001d described above using 6-(trifluoromethyl)picolinoyl chloride instead of 4-chlorobenzoyl chloride as in 2.001a and methyl pyrrolidine-3-carboxylate instead of ethyl isonipecotate as in 2.001c: LC-MS A: tR=0.64 min; [M+H]+=394.00.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:2].[CH2:19]([O:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH3:20].[Na].C(O)(=O)C>C(O)C.O>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)[CH2:24][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(C2CCCCC2)cc1
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCC(C(=O)OCC)c1ccc(C2CCCCC2)cc1
Reaction time: 8 h

Procedure:
A mixture of 15 g of para-cyclohexyl-phenylacetic acid ethyl ester and 6.7 g of acrylic acid ethyl ester is added dropwise to a solution of 1.5 g of sodium in 25 ml of ethanol. The solution is boiled overnight and then poured into a mixture of 5 ml of glacial acetic acid and 75 ml of water. The alcohol is distilled off and the batch extracted with ethyl acetate. The residue remaining on evaporation of the ethyl acetate is distilled in a high vacuum. There is obtained 2-(para-cyclohexylphenyl)-glutaric acid diethyl ester boiling at 184°-186°C under a pressure of 0.4 mm of Hg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[O:13][C:14]([C:21](O)=[O:22])=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=1.[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][N:30]=1>>[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:36])[C:29]1[N:30]=[CH:31][C:32]([NH:35][C:21]([C:14]2[O:13][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:16][C:15]=2[C:17]([F:18])([F:19])[F:20])=[O:22])=[CH:33][CH:34]=1
Reactant: COCCOc1ccccc1-c1nc(C(F)(F)F)c(C(=O)O)o1
Reactant: COCCN(C)c1ccc(N)cn1
Product: COCCOc1ccccc1-c1nc(C(F)(F)F)c(C(=O)Nc2ccc(N(C)CCOC)nc2)o1

Procedure:
With a procedure similar to example 1 above, 2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-[2-(2-methoxy-ethoxy)-phenyl]-4-trifluoromethyl-oxazole-5-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C23H25F3N4O5 (m/e) 494, obsd 495 (M+H).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][CH:5]([CH3:43])[CH:6]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:31]2)=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH:13]([C:19]([O:21]C)=[O:20])[CH2:14]2)=[O:8].Cl>C1COCC1.O>[CH3:4][CH:5]([CH3:43])[CH:6]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[N:31]2)=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH:13]([C:19]([OH:21])=[O:20])[CH2:14]2)=[O:8]
Reactant: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C(C)C)c2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(C(=O)Nc1cccc2c1CC(C(=O)O)C2)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
26 mg (0.63 mmol) of lithium hydroxide monohydrate were added to a solution of 170 mg (0.32 mmol) of methyl 4-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoyl)amino]-2,3-dihydro-1H-indene-2-carboxylate (Example 134A) in 11 ml of THF and 11 ml of water, and the mixture was stirred at 60° C. for 12 h. The reaction mixture was then adjusted to pH 2 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and then concentrated to dryness under reduced pressure. This gave 141 mg (content 98%, 0.26 mmol, 84% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[C:13]([Cl:15])[Cl:14])(=O)C.[OH-].[K+]>C(O)C>[Cl:14][C:13]([Cl:15])=[CH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1ccccc1C=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccccc1C=C(Cl)Cl
Reaction time: 2 h

Procedure:
133 g (0.54 mole) of 2-(2,2-dichlorovinyl)-benzyl acetate are dissolved in 200 ml of ethanol, and the solution is added, at room temperature, to 750 ml of an ethanolic KOH solution saturated at room temperature. After 2 hours, the mixture is evaporated down, the residue is taken up with H2O, the solution is extracted several times by shaking with ether, and the combined ether phases are washed with H2O, dried and evaporated down.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[CH3:26][CH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29](=O)[O:28]1>C1COCC1>[CH3:26][CH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2/[C:29](=[C:3]2\[C:2](=[O:10])[NH:1][C:9]3[C:4]\2=[CH:5][CH:6]=[CH:7][CH:8]=3)/[O:28]1
Reactant: CC1OC(=O)c2ccccc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1O/C(=C2/C(=O)Nc3ccccc32)c2ccccc21
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 15.2 %

Procedure:
To a solution of oxindole (119 mg, 0.891 mmol) in THF (2.0 ml) cooled at 0° C. was added 1.0M LiHMDS/THF (1.78 ml). The mixture was stirred for 4 minutes at 0° C., then allowed to warm to room temperature for an additional 6 minutes. A solution of 3-methyl-2-benzofuran-1(3 H)-one (119 mg, 0.802 mmol) in THF (0.5 ml) was added, and the reaction was rapidly stirred for 1.5 hours. The reaction was quenched into 10% HCl aqueous solution (30 ml). The resulting mixture was stirred 5 minutes, and then extracted into EtOAc. The combined organic layers were washed with water, brine, dried with anhydrous Na2SO4, and rotary evaporated to a yellow oil. Upon standing at room temperature overnight a yellow crystalline solid formed from the yellow oil. The remaining oil was removed by pipet and the solid was recrystallized from EtOAc to produce (3E)-3-(3-methyl-2-benzofuran-1(3 H)-ylidene)-1,3-dihydro-2H-indol-2-one as a yellow solid (32 mg, 15%).
Reaction SMILES: O.CS[C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1.[NH2:16][CH:17]([CH3:20])[CH2:18][OH:19]>C(OCC)C>[OH:19][CH2:18][CH:17]([NH:16][C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1)[CH3:20]
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Reactant: CC(N)CO
Solvent: CCOCC
Solvent: O
Product: CC(CO)NC1=NS(=O)(=O)c2cnccc2N1
Reaction time: 3 h

Procedure:
A suspension of 3-methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide monohydrate and 2-amino-1-propanol (0.75 mL) was refluxed for 90 min (until completion of the reaction; t.l.c.). After cooling, the addition of diethylether (20 mL) gave rise to the separation of an oily residue. After decantation of the etheral solution, the residue was solubilized in methanol (1 mL) and then supplemented with diethylether (15 mL). An oily residue separated again. After decantation of the supernatent, the oily residue was solubilized in acetone (6 mL). A fine precipitate readily appeared. After 3 h at +4° C., the resulting precipitate was collected by filtration, washed with acetone and dried (yield: 0.33 g); m.p. 213°-216° C. (Compound 19).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[NH:12][C:13](=[O:22])[O:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].O>CN(C=O)C.C(Cl)(Cl)Cl>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:13](=[O:22])[O:14][C:15]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1nc(-c2[nH]c(=O)oc2-c2ccccc2)ccc1=O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)oc1=O
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 2-isopropyl-6-(2-oxo-5-phenyl-2,3-dihydro-oxazol-4-yl)-3(2H)-pyridazinone (100 mg) was added to a suspension of NaH (60% dispersion in mineral oil) (14 mg) in DMF (0.3 ml) at 20-25° C. and the mixture was stirred at the same temperature for 30 minutes. Methyl bromoacetate (0.0035 ml) was added to the mixture and stirred at 70-75° C. for 7 hours. After an addition of water (5 ml), an aqueous solution was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give methyl [4-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-oxo-5-phenyl-oxazol-3(2H)-yl]-acetate as a solid (64 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([N+:15]([O-])=O)=[CH:4][N:3]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.[Fe]>[Br:1][C:2]1[N:3]=[CH:4][C:5]([NH2:15])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Nc1ccccc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cnc(Br)cc1Nc1ccccc1
Temperature: 75 °C
Yield: 91.6 %

Procedure:
The product from Step 3 (7.42 g, 25.2 mmol) in acetic acid (80 mL) was treated with iron powder (5.65 g, 100.95 mmol) portionwise over 1 h while the temperature was maintained between 70-80° C. The hot reaction mixture was quickly filtered through a pad of celite and washed with methanol. The combined filtrates concentrated to give a dark red residue was treated with NaHCO3 and extracted with ethyl acetate. The organic layers were washed brine, dried over Na2SO4 and concentrated to afford the title compound (6.1 g, 95%). MS (ES+) m/e 264/266 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]([S:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:39][N:38]=[N:37][N:24]=3)=[CH:13][CH:12]=2)[C:8]([S:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nnc(SCC2CCCCC2)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1nnc(SCC2CCCCC2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 60 %

Procedure:
Reaction of 3-n-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-5-(cyclohexylmethylthio)-4H-1,2,4-triazole (Step A) with trimethyltin azide according to the procedure of Example 18, Step B, gave a 60% yield of the title compound as a white solid, mp 89°-91° C., homogeneous by TLC in 4:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 488 (M+1)+.
Reaction SMILES: [H-].[Na+].[OH:3][NH:4][C:5](=[NH:7])[CH3:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH:27]3[CH2:28][CH:29]([C:31](OCC)=O)[CH2:30][CH:19]2[CH2:20][C:21]2([CH2:26]3)[O:25][CH2:24][CH2:23][O:22]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C1COCC1.CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH:27]3[CH2:28][CH:29]([C:31]4[O:3][N:4]=[C:5]([CH3:6])[N:7]=4)[CH2:30][CH:19]2[CH2:20][C:21]2([CH2:26]3)[O:25][CH2:24][CH2:23][O:22]2)(=[O:16])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(=N)NO
Reactant: CCOC(=O)C1CC2CC3(CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(C2CC3CC4(CC(C2)N3S(=O)(=O)c2ccc(Cl)cc2)OCCO4)n1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion, 43 mg, 1.09 mmol) was added to a solution of N-hydroxy acetamidine (81 mg, 1.09 mmol) in THF (2 mL) and the resulting mixture was stirred at 50° C. for 15 minutes. Ethyl 9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolane]-7-carboxylate (50) (0.394 g, 0.916 mmol) in THF (2 mL) was added to the reaction mixture and the resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc and washed with H2O. The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to yield 0.40 g (quant.) of compound 51. MS (ESI) 440.1 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl>C(#N)C>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4]1
Reactant: Fc1ccccc1CCl
Reactant: COC(=O)c1ccc2c(=O)[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc2c(=O)n(Cc3ccccc3F)cnc2c1
Yield: 70 %

Procedure:
Methyl 4-oxo-3,4-dihydroquinazoline-7-carboxlate 300 mg (1.37 mmol) was dissolved in acetonitrile (20 mL) followed by addition of K2CO3 (100 mg), KI (80 mg) and 2-flourobenzyl chloride (0.2 mL, 1.65 mmol). The mixture was refluxed over night. The reaction mixture was concentrated and the residue was purified by flash chromatography (Et2O:DCM, 1:1) to give methyl 3-(2-flourobenzyl)4-oxo-3,4-dihydroquinazoline-7-carboxylate in 70% yield.
Reaction SMILES: Cl[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4].[Br:8][C:9]1[CH:24]=[CH:23][C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.ClCCl>O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([N:13]([CH2:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)[C:2](=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:23][CH:24]=1
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1cc(C)cc(CNc2ccc(Br)cc2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)N(Cc1cc(C)cc(C)c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Methyl chloroglyoxylate (0.566 ml, 6.16 mmol) was added dropwise to a mixture of 4-bromo-N-(3,5-dimethylbenzyl)aniline (1.49 g, 5.13 mmol), triethylamine (1.08 ml, 7.70 mmol) and dichloromethane (20 ml) at 0°, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (1.66 g, 86%) as a pale yellow oil.