Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[N:4]([C:8]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:9])[CH2:5][C:6]#[CH:7].O>O1CCCC1>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[N:4]([CH:5]=[C:6]=[CH2:7])[C:8]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:9]
Reactant: C#CCN(C(=O)c1ccco1)c1c(C)cccc1C
Solvent: C1CCOC1
Solvent: O
Product: C=C=CN(C(=O)c1ccco1)c1c(C)cccc1C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
50 g (0.2 mol) of 2,6-dimethyl-N-(2-furoyl)-N-propargyl-aniline were dissolved in 200 ml of anhydrous tetrahydrofuran, and 150 mg of potassium tert.-butylate were added. During this procedure, the temperature of the solution rose to about 50° C., the solution becoming colored. The reaction mixture was left to stand for 2 hours and then poured onto 500 ml of water. The crystalline product which had precipitated was filtered off, dried and recrystallized from ethyl acetate/petroleum ether. 24 g (48% of theory) of 2,6-dimethyl-N-allenyl-N-(2-furoyl)-aniline of melting point 138°-41° C. were obtained. (The 1H-NMR spectrum indicated complete isomerization.) ##STR100##
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30](O)[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36]2)=[CH:23]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>>[Si:14]([O:21][C@H:22]1[CH2:31][C@H:30]([O:10][C:9](=[O:11])[CH:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][CH3:13])[C@H:29]2[C:24]([CH:25]=[CH:26][C@H:27]([CH3:50])[C@@H:28]2[CH2:33][CH2:34][C@H:35]2[O:40][C:39](=[O:41])[CH2:38][C@H:37]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:44])[CH3:45])[CH2:36]2)=[CH:23]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1ccccc1)C(=O)O
Product: CCC(Oc1ccccc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 92.7 %

Procedure:
A procedure similar to that described in Example 10, above, was followed, but using 0.66 g of (2RS)-2-phenoxybutyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as describe in Example B, above], to give 1.20 g of the title compound as a colorless foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4]=1[CH2:10][CH3:11])[CH3:2].[CH2:12]([N:30]1[C:35]([CH3:37])([CH3:36])CC(O)[CH2:32][C:31]1([CH3:40])[CH3:39])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:12]([N:30]1[C:31]([CH3:32])([CH3:40])[CH2:39][CH:1]([C:3]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4]=2[CH:10]2[CH2:40][C:31]([CH3:32])([CH3:39])[N:30]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:35]([CH3:36])([CH3:37])[CH2:11]2)[CH2:2][C:35]1([CH3:36])[CH3:37])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCCCCCCCCCN1C(C)(C)CC(O)CC1(C)C
Reactant: CCC1=C(CC)C2CCC1C2
Product: CCCCCCCCCCCCCCCCCCN1C(C)(C)CC(C2=C(C3CC(C)(C)N(CCCCCCCCCCCCCCCCCC)C(C)(C)C3)C3CCC2C3)CC1(C)C

Procedure:
In an analogous manner is also reacted diethyl bicyclo [2.2.1]hept-5-ene-endo,exo-2,3-dicarboxylate with 1-n-octadecyl-2,2,6,6-tetramethyl-4-piperidinol to give wax-like bis-(1-n-octadecyl-2,2,6,6-tetramethyl-4-piperidyl) bicyclo[2.2.1]hept-5-ene-endo,exo-2,3-dicarboxylate. (Example 9)
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.O[C:10]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=1[NH2:12].N1C=CC=CC=1>C1CCCCC1.C(OCC)(=O)C>[C:2]([C:1]1[O:6][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc2ccc(O)cc2o1

Procedure:
A mixture of 1.01 ml of pivaloyl chloride, 808 mg 2,4-dihydroxyaniline hydrochloride (formula V) and 0.4 ml of pyridine is heated at about 210° for about 18 hours. The mixture obtained is dispersed in a mixture of cyclohexane and ethyl acetate and purified by chromatography. The title compound is obtained (m.p. 204-210°).
Reaction SMILES: C([Li])CCC.CC(NC(C)C)C.CN1CCC(=[C:20]2[C:26]3[CH:27]=[CH:28][S:29][C:25]=3C=[CH:23][N:22]3[CH:30]=[N:31][N:32]=[C:21]23)CC1.[CH3:33][N:34]1[CH2:39][CH2:38][CH:37]([C:40]([O:42]CC)=O)[CH2:36][CH2:35]1>CCCCCC.O1CCCC1.O>[CH3:33][N:34]1[CH2:35][CH2:36][CH:37]([C:40]([C:23]2[N:32]([CH2:21][CH2:20][C:26]3[CH:27]=[CH:28][S:29][CH:25]=3)[N:31]=[CH:30][N:22]=2)=[O:42])[CH2:38][CH2:39]1
Reactant: CN1CCC(=C2c3ccsc3C=Cn3cnnc32)CC1
Reactant: CCOC(=O)C1CCN(C)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCC(C(=O)c2ncnn2CCc2ccsc2)CC1
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
Butyllithium in hexane (192 ml) was added dropwise at -70° C. under nitrogen to a solution of N-(1-methylethyl)-2-propanamine (43.4 ml) in tetrahydrofuran (400 ml) and the mixture was stirred for 30 minutes. A solution of intermediate (1) (0.236 mol) in tetrahydrofuran (50 ml) was added dropwise and the mixture was stirrred at -70° C. for 1 hour. Ethyl 1-methyl-4-piperidinecarboxylate (0.284 mol) in tetrahydrofuran (50 ml) was added and after the addition was completed, the mixture was stirred at -70° C. for 1 hour. The mixture was brought slowly to room temperature. The mixture was poured into water and extracted with 1,1'-oxybisethane/dichloromethane. The organic layer was dried (MgSO4) and evaporated. The residue (64.3 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 96/4/0.1 to 90/10/0.1) (35-70 μm). The pure fractions were collected and evaporated, yielding 29.55 g (41% ) of (1-methyl-4-piperidinyl)[2-[2-(3-thienyl)ethyl]-2H-1,2,4-triazol-3-yl]methanone (interm. 3);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][CH:20]=[C:19]3/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)O)=[CH:5][CH:4]=1.C([SiH](CC)CC)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][CH:20]=[C:19]3/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(O)(c2ccc3nccc(/C=C/c4ccccc4)c3c2)c2nccs2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: COc1ccc(C(c2ccc3nccc(/C=C/c4ccccc4)c3c2)c2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (E)-(4-methoxyphenyl)(4-styrylquinolin-6-yl)(thiazol-2-yl)methanol (33 mg, 0.0732 mmol) and triethylsilane (0.035 mL, 0.22 mmol) in CH2Cl2 (2 mL) at −78° C. was added dropwise TiCl4 (0.22 mL, 0.22 mmol). The resulting mixture (turned to dark green suspension) was kept at −78° C. for 20 min and then warmed to 0° C. The reaction was maintained at 0° C. for 1 hr and then quenched with ice, CH2Cl2 and aqueous NaOH until the aqueous layer became basic. The aqueous layer was extracted with CH2Cl2 twice. The combined organics were concentrated and purified by chromatography (silica column, 25% EtOAc/CH2Cl2) to yield (E)-2-((4-methoxyphenyl)(4-styrylquinolin-6-yl)methyl)thiazole.
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC=CC=1)([O-])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21].Cl>O.C(#N)C>[C:19]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: NCCCC(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Solvent: CC#N
Product: C=C(C)C(=O)NCCCC(=O)O
Temperature: 0 °C
Yield: 93 %

Procedure:
In a mixture composed of 80 g (2.0 mol) of sodium hydroxide, 400 ml of water and 4 ml of nitrobenzene was dissolved with stirring 214 g (2.0 mol) of γ-aminobutyric acid and the mixture was cooled to 0° C. To the aqueous solution, there were simultaneously added dropwise 230 g (2.2 mol) of methacrylic chloride and an aqueous solution containing 96 g (2.4 mol) of sodium hydroxide dissolved in 200 ml of water. After the completion of the reaction, 800 ml of acetonitrile was added to the reaction solution and the mixture was then acidified by adding 160 ml of concentrated hydrochloric acid and extracted with acetonitrile. The acetonitrile solution was concentrated to obtain 318.4 g of N-methacryloyl-γ-aminobutyric acid as an oily product.
Reaction SMILES: [O:1]=[S:2]1(=[O:36])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:29]4[O:30][CH2:31][CH2:32][O:33][C:28]=4[CH:27]=3)=[CH:20][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:3]1.[Li+].[OH-].Cl.O>C1COCC1.CO.O>[O:36]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:11][C@@H:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:29]4[O:30][CH2:31][CH2:32][O:33][C:28]=4[CH:27]=3)=[CH:22][CH:23]=2)[C:13]([OH:15])=[O:14])=[N:3]1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccc3c(c2)OCCO3)cc1)NC1=NS(=O)(=O)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@H](Cc1ccc(OCc2ccc3c(c2)OCCO3)cc1)NC1=NS(=O)(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
The crude product from Step A was dissolved in a THF/MeOH/H2O mixture (6:0.1:1; 2 ml). Aqueous 1M LiOH solution (1.6 ml) was added and the mixture was stirred for 3 days at room temperature. Then the reaction mixture was neutralized with 1M HCl, a small amount of water was added and the mixture extracted with ethyl acetate. The solvent was evaporated. The product was purified by chromatography (SiO2/ethyl acetate/hexane). The yield was 48%.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[O:3]1.B(Br)(Br)Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1([CH3:26])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[O:3]1
Reactant: COc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC(C)(C)C2=O)cc1
Agent: BrB(Br)Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(O)cc2)C1=O
Yield: 86.6 %

Procedure:
30 mg of 2,2-dimethyl-4-(4methoxyphenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (Example 3) in 30 ml dichloromethane was stirred with 0.1 ml boron tribromide (1.0 M solution in CH2Cl2) at room temperature for 4 hours. And then 10 ml aqueous sodium thiosulfate was added to the reaction mixture. The mixed solution was concentrated in vacuo and was extracted with 50 ml water and dichloromethane (50 ml×3). The organic layer was concentrated under reduced pressure and was purified by column chromatography (ethylacetate) to afford 25 mg of 2,2-dimethyl-4-(4-hydroxyphenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone. mp: 150-152° C. NMR: δ1.56 (s, 6H), 2.77 (s, 1H), 3.07 (s, 3H), 6.81 (d, J=8.7 Hz, 2H), 7.14 (d, J=8.7 Hz, 2H), 7.90 (m, 4H). IR (cm−1): 3492, 2929, 1696, 1597, 1393, 1151, 914, 744.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][N:5]=[C:4]([S:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])(=[O:9])=[O:8])[CH2:3]1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:29])(=O)=O)=CC=1>C1COCC1>[F:29][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([S:7]([C:4]1[CH2:3][C:2]([CH3:1])([CH3:18])[O:6][N:5]=1)(=[O:9])=[O:8])[CH3:11]
Reactant: CC(c1ccccc1)S(=O)(=O)C1=NOC(C)(C)C1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CC(S(=O)(=O)C(C)(F)c2ccccc2)=NO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
Phosphazene base 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2-lambda5-5,4-lambda5-5-catenadi(phosphazene) (P2-tBu) (2M in THF) (0.3 ml, 0.6 mmol) was added to a solution of 5,5-dimethyl-3-(1-phenyl-ethanesulfonyl)-4,5-dihydroisoxazole (150 mg, 0.56 mmol) in THF (8 ml) at room temperature. After 10 minutes N-fluorobenzene-sulfonimide (NFSI) (190 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 15 minutes. The mixture was absorbed onto silica gel and purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 1.138 of Table 27) as a white solid (89 mg, yield 56%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH2:2][CH3:3].S(=O)(=O)(O)O.[CH3:39]O>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([O:33][CH3:39])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of 2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (465 mg) and conc. sulfuric acid (7.2 g) in methanol (60 ml) was heated for 24 hours under reflux. After removal of solvent, the residue was suspended with water, to which was added 1N-NaOH to adjust to pH 3-4, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, followed by evaporation of the solvent. The residue was purified by column chromatography on silica gel. Recrystallization from ethanol afforded colorless prisms (310 mg), m.p. 195°-196° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:9][CH2:8]1)(C)(C)C.Br[CH2:22][C:23]1[O:24][C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[C:27]=1[CH3:28]>>[OH:6][CH:7]1[CH2:8][CH2:9][CH:10]([N:13]2[CH2:17][CH2:16][CH:15]([CH2:22][C:23]3[O:24][C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[C:27]=3[CH3:28])[C:14]2=[O:18])[CH2:11][CH2:12]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(N2CCCC2=O)CC1
Reactant: Cc1c(CBr)oc2ccccc12
Product: Cc1c(CC2CCN(C3CCC(O)CC3)C2=O)oc2ccccc12
Yield: 53.6 %

Procedure:
Using the procedure to synthesize Example 3 and using reagents 1-[4-(tert-butyldimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (500 mg, 1.68 mmol) and 2-bromomethyl-3-methyl-benzofuran (567 g, 2.52 mmol) afford the title compound as a tan powder (295 mg, 54%): Mass spectrum (apci) m/z=328.1 (M+H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[S:11][C:10]([C:12]3[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Na].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.[OH-].[Na+]>O.C(O)(=O)C>[N:1]1([CH2:6][C:7]2[S:11][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:18])[NH:16][N:17]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C1CCC(c2ccc(Cn3cccn3)s2)=NN1
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc(-c2ccc(Cn3cccn3)s2)n[nH]1

Procedure:
Analoguous to Example 4, the reaction is carried out with 20 g of 4.5-dihydro-6-[5-(pyrazol-1-yl-methyl)-thien-2-yl]-3(2H)-pyridazinone (Example 3), 19.2 g of the sodium salt of 3-nitrobenzenesulfonic acid and 13.5 g of sodium hydroxide in 200 ml of water. The reaction mixture is neutralized by the addition of 16 ml of acetic acid.
Reaction SMILES: CS(O[CH2:6][C:7]1([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:8]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:6][C:7]1([NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)=[N+:22]=[N-:23]
Reactant: CS(=O)(=O)OCC1(NC(=O)OCc2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (1-(benzyloxycarbonylamino)cyclopropyl)methyl methanesulfonate (5 g, 16.7 mmol) in 100 mL of DMF was added NaN3 (3 g, 46.15 mmol) in one portion at room temperature. Then the reaction mixture was stirred at 70° C. for 16 hours. The mixture was poured into 400 mL of water, extracted with ethyl acetate (600 mL). The organic phase was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was evaporated at 40° C. under reduced pressure to give a crude product as colorless oil, which was used in the next step without further purification MS: (M+H)+=247.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][C:8]=2[N+:15]([O-:17])=[O:16])(=O)[CH3:2].[CH3:18][NH:19][NH2:20]>C(Cl)CCl>[CH3:18][N:19]1[C:1]([CH3:2])=[C:4]2[CH:5]=[N:6][C:7]3[C:8]([N+:15]([O-:17])=[O:16])=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]2=[N:20]1
Reactant: CC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: CNN
Solvent: ClCCCl
Product: Cc1c2cnc3c([N+](=O)[O-])cccc3c2nn1C
Yield: 45.2 %

Procedure:
A mixture of 3-acetyl-4-chloro-8-nitroquinoline (140 mg) and methylhydrazine (77.2 mg) in ethylene chloride was refluxed for 30 minutes. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (methanol-dichloroethane) to give 2,3-dimethyl-6-nitro-2H-pyrazolo[4,3-c]quinoline (61.2 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.CN(CCN(C)C)C.[Li]CCCC.[I:29]I.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:3]=1[I:29]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1I
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution tert-butyl 4-chloropyridin-2-ylcarbamate (2.29 g, 10 mmol), TMEDA (2.32 g, 20 mmol) in anhydrous THF (30 mL) was added n-BuLi (8 ml, 20 mmol). The resulting mixture was allowed to stir at −78° C. for 0.5 h which was added the solution of I2 (2.54 g, 10 mmol) in THF (8 mL) dropwise at −78° C. The reaction mixture was stirred for another 4 h. To the solution was added NH4Cl aq (5 mL), extracted with EtOAc (3×20 mL), dried over Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography to afford the title compound as a yellow solid. LC/MS m/z=355.19 [M+H]+
Reaction SMILES: [F:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[CH:6](Cl)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CC(C)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[CH:6]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: Fc1cc2c(cc1Cl)C(Cl)Cc1ccccc1S2
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: OCCN1CCN(C2Cc3ccccc3Sc3cc(F)c(Cl)cc32)CC1

Procedure:
A mixture of 7-fluoro-8,10-dichloro-10,11-dihydrodibenzo(b,f)thiepine (the preparation of which is described in Example 19) (4.5 g), 1-(2-hydroxyethyl)piperazine (4.1 g) and chloroform (5 ml) was refluxed for 7.5 hours. The reaction mixture was then diluted with chloroform (50 ml) and the solution washed with water. The chloroform was evaporated the residue dissolved in benzene (200 ml) and the solution shaken with 3 N-HCl (60 ml). The separated hydrochloride was filtered, suspended in the aqueous layer of the filtrate and the suspension made basic with ammonium hydroxide. The liberated base was taken up in chloroform and isolated as usual; m.p. 150°-152° C. (acetone), yield 4.8 g (81%).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(I)cn1
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(N)nc3)cn2n1

Procedure:
The title compound, off white solid, MS: m/e=292.1 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 5-iodopyridin-2-amine.
Reaction SMILES: [N:1]1([C:6]2[O:10][C:9]([C:11](O)=O)=[C:8]([CH3:14])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[N:1]1([C:6]2[O:10][C:9]([C:11]3[NH:15][C:16]4[CH:17]=[C:18]([C:19](=[O:20])[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH:27]=[CH:28][C:29]=4[N:30]=3)=[C:8]([CH3:14])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: Cc1cc(N2CCCC2)oc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(N2CCCC2)oc1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
5-Pyrrolidine-1-yl-methyl-furan-2-carboxylic acid (62% purity, 223 mg, 0.71 mmol) was added to a pyridine (3 ml) solution of 3,4-diaminobenzophenone (150 mg, 0.71 mmol). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (149 mg, 0.78 mmol) and 1-hydroxybenzotriazole monohydrate (119 mg, 0.78 mmol) were further added, and the reaction mixture was heated to 70° C. and stirred overnight. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2), and the obtained residue was dissolved in acetic acid (3 ml) and stirred at 100° C. for 8 hours. The solution was allowed to cool to room temperature with stirring, and then the solvent was evaporated. The residue was purified using medium pressure silica gel flash column chromatography (NH silica gel, chloroform:methanol=98:2), to afford 2-(5-pyrrolidine-1-yl-methyl-furan-2-yl)-5-benzoylbenzimidazole (143 mg, 55% in two steps) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:15]=1B(O)O)[CH3:13].C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCOC(C)=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.C(O)C>[CH2:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:15]=1[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1)[CH3:13]
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CCc1cccc(CC)c1B(O)O
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: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCc1cccc(CC)c1-c1cc(C)c([N+](=O)[O-])cn1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-4-methyl-5-nitro-pyridine (5.0 g, 29.0 mmol), 2,6-diethylphenylboronic acid (7.7 g, 43.3 mmol), Pd(PPh3)4, (1.0 g, 0.9 mmol), Na2CO3 (9.1 g, 86.5 mmol) in a mixture of toluene (200 mL), water (43 mL) and ethanol (10 mL) is heated at 100° C. under nitrogen overnight. The mixture is cooled to room temperature, diluted with EtOAc, washed with water, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (Hexane/EtOAc, 6:1) to afford 2-(2,6-diethyl-phenyl)-4-methyl-5-nitro-pyridine as a colorless oil.