Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.CSC.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:9][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:5]([CH:13]2[CH:22]3[C:23](=[O:24])[O:25][CH2:26][CH:21]3[CH:20]([OH:27])[C:19]3[C:14]2=[CH:15][C:16]2[O:30][CH2:29][O:28][C:17]=2[CH:18]=3)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Agent: CS(=O)(=O)O
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C2c3cc4c(cc3C(O)C3COC(=O)C23)OCO4)cc(OC)c1O
Yield: 5.7 %

Procedure:
10 g (24 mmol) of podophyllotoxin are dissolved in 60 ml of trifluoroacetic acid. 5.4 ml (72 mmol) of dimethyl sulphide and 47 ml (72 mmol) of methanesulphonic acid are successively added. Stirring is maintained for 9 hours, 5.4 ml (72 mmol) of dimethyl sulphide are again added and stirring is maintained for 9 hours. The medium is run quickly onto ice (600 ml) and extracted with ethyl acetate (3×300 ml). The organic phases are washed with water and then with a NaHCO3 solution to neutrality. After drying over sodium sulphate, filtering and evaporating, 6.3 g of crude demethylation product are obtained. Flash chromatography on silica (elution: CH2Cl2/acetone 9/1) makes it possible to isolate 550 mg of 5-(4-hydroxy-3,5-dimethoxyphenyl)-9-hydroxy-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one, that is to say 4′-demethylepipodophyllotoxin of formula (Va). 1.10 g of 5-(3,4-dihydroxy-5-methoxyphenyl)-9-hydroxy-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one (Analysed: C20H18O8.0.15H2O; calculated: C % 61.74, H % 4.74. found: C % 61.67, H % 4.68), and then 1.9 g of 9-hydroxy-5-(3,4,5-trihydroxyphenyl)-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one are also isolated. The latter compound has a proton NMR spectrum with the following characteristics: 1H NMR (d6-DMSO) δ 8.65 (m, 2H), 7.95 (m, 1H), 6.71 (s, 1H, H5), 6.47 (s, 1H, H8), 5.98 (d, 2H, J=2 Hz, OCH2O), 5.93 (s, 2H, H2, H6′), 4.68 (d, 1H, J=3.2 Hz, H4), 4.34 (t, 1, J=8 Hz, H11), 4.29 (d, 1H, J=5.2 Hz, H1), 4.16 (dd, 1H, J=8 Hz, J′=10 Hz, H11b), 3.17 (dd, 1H, J=5.2 Hz and J′=14 Hz, H2), 2.76 (m, 1H, H3).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.[NH3:18].O>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:18])[N:3]=1
Reactant: N
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: O
Solvent: CC(C)O
Product: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reaction time: 8 h

Procedure:
2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (36.9 g) was heated with 2M ammonia in isopropanol (250 ml) at 50° C. for 5 hours. After standing at ambient temperature overnight, a further quantity of 2M ammonia in isopropanol (100 ml) was added to break up the resultant cake and the reaction mixture was heated for a further 9 hours until the reaction was complete. To the reaction mixture was added water (70 ml) and the yellow solid filtered off. The solid was washed with isopropyl alcohol:water (5:1 (v/v), 60 ml) and then air-dried under suction to give a first crop. The filtrate was re-filtered after standing overnight to isolate precipitate and both solids were dried in vacuo. The first crop was pure with the second crop material showing a very minor impurity (isolated broad signal 3.5 ppm not seen in first crop) but was otherwise identical. Solid first crop (28.4 g), solid second crop (3.42 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1.[H][H]>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCCN4)cc3)oc12
Yield: 7.3 %

Procedure:
2-(4-(Pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (100 mg, 0.3 mmol) and platinum (IV) oxide monohydrate (55 mg) in methanol (20 mL) was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by pre-HPLC. 7 mg of 2-(4-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained. Yield: 7%. 1H-NMR (400 MHz, DMSO-d6) δ 1.23 (s, 1H), 1.56-1.70 (m, 4H), 1.87 (brs, 2H), 2.88-2.91 (m, 1H), 4.02-4.04 (m, 1H); 7.48-7.52 (m, 1H); 7.72-7.74 (m, 2H); 7.82-7.98 (m, 4H); 8.30-8.32 (d, J=7.2 Hz, 2H); LC-MS (m/z) 316 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH3:30])[C:20]([N:23]2[CH2:28][CH2:27][NH:26][C@H:25]([CH3:29])[CH2:24]2)=[N:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Br:16][C:17]1[CH:18]=[C:19]([CH3:30])[C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:6]3[CH:5]=[C:4]([C:9]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=4)[N:3]=[C:2]([Cl:1])[N:7]=3)[C@H:25]([CH3:29])[CH2:24]2)=[N:21][CH:22]=1
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1
Reactant: Cc1cc(Br)cnc1N1CCN[C@H](C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(Cl)n2)[C@H](C)C1

Procedure:
Heat a mixture of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrimidine (6.0 g, 24.7 mmol), 1-(5-bromo-3-methyl-pyridin-2-yl)-3-(R)-methyl-piperazine (7.0 g, 25.9 mmol) and K2CO3 (6.8 g, 49.4 mmol) in DMA at 60° C. for 16 h. Partition the mixture between EtOAc and water, dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 15% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]#[N:19])=[CH:12][CH:11]=3)#[N:4].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([N:9]1[C:10]2[CH:11]=[CH:12][C:13]([C:18]#[N:19])=[CH:14][C:15]=2[C:16]2[C:8]1=[CH:7][CH:6]=[C:5]([C:3]#[N:4])[CH:17]=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N#Cc1ccc2[nH]c3ccc(C#N)cc3c2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)c1cc(C#N)ccc1n2Cc1ccccc1
Temperature: 110 °C
Yield: 79.8 %

Procedure:
A slurry of sodium hydride (50% in oil, 960 mg) in 100 ml of dimethylformamide is treated with 3,6-dicyanocarbazole (4.34 g, see Example 1) and heated at 110° C for two hours. The reaction mixture is then treated dropwise with benzylbromide (3.42 g) and heated at 110° C for an additional 18 hours. The reaction mixture is poured into water and extracted several times with dichloromethane. The combined dichloromethane extracts are dried over sodium sulfate and filtered through 200 ml of silica gel to yield 4.9 g of the title compound, melting point 265°-267° C.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[H-].[Na+].Br[CH2:25][C:26]1[CH:44]=[CH:43][C:29]([CH2:30][P:31](=[O:42])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:27]=1>CN(C=O)C>[C:38]([O:37][P:31]([CH2:30][C:29]1[CH:43]=[CH:44][C:26]([CH2:25][CH:2]([C:1]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[CH:27][CH:28]=1)([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:42])([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OP(=O)(Cc1ccc(CBr)cc1)OC(C)(C)C
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OP(=O)(Cc1ccc(CC(C(=O)OCc2ccccc2)C(=O)OCc2ccccc2)cc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a solution of dibenzyl malonate (0.5 g) in DMF (8 mL), was added sequentially NaH (0.06 g, 80% in mineral oil), di(tert-butyl) [4-(bromomethyl)benzyl]phosphonate(0.66 g). The reaction mixture was stirred at room temperature for 1 h, then quenched with 20 mL of saturated aqueous NH4OAc solution and extracted with 50 mL EtOAc. The extract was dried over Na2SO4 and concentrated. The sesidue was purified by silica gel chromatography eluted with to give the title compound (0.2 g).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:13][CH3:14])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:10](=[O:12])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:15])=[CH:8][CH:7]=2)[O:13][CH3:14])=[CH:20][CH:19]=1)#[N:16]
Reactant: COC(C(=O)O)c1ccc(N(C)C)cc1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(N(C)C)cc1

Procedure:
(RS)-(4-Dimethylamino-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(4-dimethylamino-phenyl)-2-methoxy-acetamide. Off-white solid. MS 324.2 ([M+H]+)
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:10]=1[NH2:11].[C:18]([NH:23][NH:24][C:25](Cl)=[O:26])([O:20][CH2:21][CH3:22])=[O:19]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:10]=1[NH:11][C:25](=[O:26])[NH:24][NH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)NNC(=O)Cl
Reactant: Nc1c(F)cc(F)cc1F
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)NNC(=O)Nc1c(F)cc(F)cc1F

Procedure:
A toluene solution of 2,4,6-trifluoroaniline is reacted with 2-carbethoxyhydrazinecarbonyl chloride as described above in Example 1b, mp 177°-178° (ethyl acetate/toluene).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH2:20]([N:22]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[N:23]1)[CH3:21]>>[CH2:20]([N:22]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:24]=[N:23]1)[CH3:21]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)CCOCCc1cccc(Br)c1
Product: CCn1cc(-c2cccc(CCOCCC(=O)OC(C)(C)C)c2)cn1

Procedure:
The subtitled compound (0.64 g) was prepared from tert-butyl 3-(3-bromophenethoxy)propanoate [Preparation 3, Step i)] and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using a similar method to that described in Example 18, Step i). MS[M+H-C4H8]+=289 (MultiMode+) 1H NMR (300 MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (s, 1H), 7.35-7.23 (m, 3H), 7.07 (d, J=7.5 Hz, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H), 3.68 (t, J=7.3 Hz, 2H), 2.89 (t, J=7.1 Hz, 2H), 2.49 (t, J=6.5 Hz, 2H), 1.53 (t, J=7.3 Hz, 3H), 1.43 (s, 9H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[N:10]1[CH:15]=[C:14](B(O)O)[CH:13]=[N:12][CH:11]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:8][C:6]1[N:7]=[C:2]([C:14]2[CH:15]=[N:10][CH:11]=[N:12][CH:13]=2)[CH:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Cc1nc(N)cc(Cl)n1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(N)cc(-c2cncnc2)n1
Temperature: 160 °C

Procedure:
To a microwave vial were added 6-chloro-2-methylpyrimidin-4-amine (700 mg, 4.88 mmol), pyrimidin-5-ylboronic acid (725 mg, 5.86 mmol), PdCl2(PPh3)2 (684 mg, 0.97 mmol), dioxane (10 mL) and Na2CO3 (2 M, 7 mL, 14 mmol) under Argon. The vial was microwave heated for 1 h at 160° C. Water was added, and extracted with 10% MeOH/CHCl3 (3*50 mL). The organic layers were combined and concentrated under reduced pressure and the crude was purified by silica gel chromatography to yield the title compound as a white solid; MS (m/z): [M+H]+188.2.
Reaction SMILES: [H-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:22][CH2:21]3)[CH2:14][CH2:13]2)=[CH:4]1.[CH3:32]I>O1CCCC1>[CH3:32][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:22][CH2:21]3)[CH2:14][CH2:13]2)=[CH:4]1
Reactant: CI
Reactant: c1ccc(N2CCN(CC[C@H]3CC[C@H](c4c[nH]c5ccccc54)CC3)CC2)nc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc([C@H]2CC[C@H](CCN3CCN(c4ccccn4)CC3)CC2)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of potassium hydride (0.24 g, 6 mmol) in tetrahydrofuran is cooled to 0° C. and a solution of trans 1-(2-{4-[1H-3-indolyl]cyclohexyl}ethyl)-4-(2-pyridinyl)piperazine (Example 1) (2.0 g, 5.14 mmol) in 20 mL of tetrahydrofuran is added. After 20 minutes 3 mL of methyl iodide is added and the reaction is warmed to room temperature overnight. The reaction is quenched with ammonium chloride and the tetrahydrofuran is removed under reduced pressure. The residue is partitioned between chloroform and ammonium chloride and the organics are dried with sodium sulfate and solvents are evaporated. The residue is chromatographed on silica gel (2% methanol in chloroform) to give the desired product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][OH:23])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].CCN(C(C)C)C(C)C.[S:40](Cl)([CH3:43])(=[O:42])=[O:41]>C(Cl)Cl>[CH3:43][S:40]([O:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:14][N:13]=2)[CH:16]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: COCc1cc(-c2nc(-c3cccc(CCO)c3)no2)ccc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCc1cc(-c2nc(-c3cccc(CCOS(C)(=O)=O)c3)no2)ccc1-c1ccccc1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)ethanol (0.2 mmol) in DCM (2 mL) at 0° C. was added DIEA (71 μL, 0.4 mmol) and mesyl chloride (17 μL, 0.22 mmol). The resulting mixture was stirred at 0° C. for 10 minutes, allowed to warm to RT and stirred for 2 hours. The mixture was diluted with DCM (20 mL) and washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM (3×20 mL). The combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was all used in the next step without further purification.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([N:24]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[CH:32]=[C:31]([F:33])[C:28]([CH:29]=O)=[C:27]([F:34])[CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:35]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[CH:32]=[C:31]([F:33])[C:28](/[CH:29]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:27]([F:34])[CH:26]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=Cc1c(F)cc(N(Cc2ccccc2)Cc2ccccc2)cc1F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(F)cc(N(Cc2ccccc2)Cc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
To an ice-cooled solution of ethyl diethylphosphonoacetate (7.71 g, 34.4 mmol) in tetrahydrofuran (80 mL) was added sodium hydride (60% in oil, 1.38 g, 34.4 mmol) and the mixture was stirred for 30 min. A solution of 4-(dibenzylamino)-2,6-difluorobenzaldehyde (9.28 g, 27.5 mmol) synthesized according to the method described in European Journal of Medicinal Chemistry, 1999, vol. 34, pp. 137-151 in tetrahydrofuran (100 mL) was added dropwise. The mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=97/3-hexane/ethyl acetate=60/40) to give the title compound (9.57 g, yield 85%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[C:12]([CH2:13]Cl)=[N:11][C:10]([C:15]([OH:17])=[O:16])=[N:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[N:21]1[C:2]2[N:3]=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]2[N:9]=[C:10]([C:15]([OH:17])=[O:16])[N:11]=[C:12]2[CH2:13]1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)c1nc(CCl)n(-c2cccnc2Cl)n1
Product: O=C(O)c1nc2n(n1)-c1cccnc1N(c1ccccc1Cl)C2

Procedure:
using 31.40 g (0.115 mol) of 1-(2-chloro-3-pyridyl)-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid and 206.00 g (1.61 mol) of 2-chloroaniline there is obtained 5-(2-chlorophenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid and the methyl ester thereof which, after recrystallisation from methylene chloride/isopropanol, melts at 155°-163°;
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH2:44][C@@:42]2([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]2[OH:45])[C@@:37]2([CH:46]=[O:47])[C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([O:48][CH3:49])=[CH:33][C:34]=1[CH2:35][CH2:36]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH2:44][C@@:42]2([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]2[O:45][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[C@@:37]2([CH:46]=[O:47])[C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([O:48][CH3:49])=[CH:33][C:34]=1[CH2:35][CH2:36]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc2c(c1)CC[C@]1(C=O)C2=C(CCCCCOCc2ccccc2)C[C@@]2(C)[C@H]1CC[C@@H]2O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CC[C@]1(C=O)C2=C(CCCCCOCc2ccccc2)C[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]21
Temperature: 25 °C
Yield: 93.2 %

Procedure:
4.46 g of imidazole and 9.66 g of tert-butyldimethylsilyl chloride are added in succession at 0° C. to a solution of 12.49 g of alcohol 5 in 160 ml of N,N-dimethylformamide and stirred at room temperature until the reaction is completed. For working-up, the aqueous phase is mixed with water and extracted several times with diethyl ether. The combined organic phases are washed with water and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. The residue is purified by column chromatography (cyclohexane/ethyl acetate) and yields 14.36 g of silyl ether 6 as a yellow, viscous mass (GC-MS: m/z theor.: 602, pract.: 602).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH:19]2[CH3:24])[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1>CN1CCCC1=O>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:27]=3)[CH2:20][CH:19]2[CH3:24])[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: CC1CNCCC1N(C(=O)c1ccc(-c2cnco2)cc1)C1CC1
Reactant: Clc1nc(-c2ccccc2)no1
Solvent: CN1CCCC1=O
Product: CC1CN(c2nc(-c3ccccc3)no2)CCC1N(C(=O)c1ccc(-c2cnco2)cc1)C1CC1

Procedure:
The title compound is prepared from N-cyclopropyl-N-(3-methyl-piperidin-4-yl)-4-oxazol-5-yl-benzamide and 5-chloro-3-phenyl-[1,2,4]oxadiazole following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 3): tR=2.01 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2OC(NC)=O)[CH2:3]1.C(OC1C=CC=CC=1[N+:28]([O-:30])=[O:29])C(=C)C>>[CH3:1][C:2]1([CH3:16])[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([N+:28]([O-:30])=[O:29])[C:9]=2[O:10]1
Reactant: C=C(C)COc1ccccc1[N+](=O)[O-]
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Product: CC1(C)Cc2cccc([N+](=O)[O-])c2O1

Procedure:
Carbofuran is a commercially available material. It is manufactured by the simultaneous thermal rearrangement and cyclization of 1-methallyloxy-2-nitrobenzene to form 2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran, which is then reduced to the amine, then diazotized and converted to 2,3-dihydro-2,2-dimethylbenzofuran-7-ol, and then esterified with methyl isocyanate. In an alternative procedure, 2-methallyloxyphenol is thermally rearranged and cyclized to form 2,3-dihydro-2,2-dimethylbenzofuran-7-ol, which is then treated simultaneously with methyl isocyanate and triethylamine. The starting material 2-methallyloxyphenol can be prepared by reacting catechol with potassium carbonate and potassium iodide in dry acetone under a nitrogen atmosphere. Further particulars of each of these procedures will be readily apparent to those skilled in the art.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[N:6]=[N:7][CH:8]=1.[OH-].[Na+]>O1CCOCC1>[N:10]1([CH2:9][C:5]2[NH:6][N:7]=[CH:8][C:3](=[O:2])[CH:4]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: COc1cnnc(Cn2ccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1cn[nH]c(Cn2ccnc2)c1
Temperature: 25 °C

Procedure:
The 5-methoxy-3-(imidazol-1-yl-methyl)-pyridazine (IX) is dissolved in dioxane and NaOH is added. The mixture is refluxed for about 7 hours, cooled to room temperature and quenched with HCl. The pH is adjusted to 8 with saturated solution of NaHCO3. The solvent is removed in vacuo and the residue is taken in MeOH. After filtration, the solvent is removed in vacuo and diluted with MeOH to provide the corresponding 6-(imidazol-1-yl-methyl)-1H-pyridazin-4-one (X).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH3:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]([CH3:8])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:8][C:6]1[CH:5]=[C:4]([S:9]([C:10]2[N:14]([CH3:15])[C:13]([CH3:16])=[N:12][C:11]=2[CH:17]([CH3:19])[CH3:18])=[O:28])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2C)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)cc(S(=O)c2c(C(C)C)nc(C)n2C)c1
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
In methylene chloride (10 ml)was dissolved 150 mg (0.55 mmol)of 5-(3,5-dimethylphenylthio)-4-isopropyl-1,2-dimethyl-1H-imidazole, followed by addition of 177 mg (0.82 mmol)of 80% metachloroperbenzoic acid under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction mixture, an aqueous solution of sodium thiosulfate and then, an aqueous sodium hydrogen carbonate solution was added, and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue purified by silica gel chromatography (ethyl acetate), and recrystallized from n-hexane to give 100 mg of Compound I-104 (yield 63%). mp 100-101° C.