Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:11].Br.CC(O)=[O:22]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[OH:22])=[O:11])=[CH:13][CH:14]=1
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Agent: Br
Product: O=C(c1ccc(Cl)cc1)c1ccc(O)cc1O

Procedure:
To a stirred solution of 4-chlorobenzoyl chloride (1.0 g, 5.8 mmol) and 1-chloro-3-methoxybenzene(823.7 mmol) in CH2Cl2 (150 mL) at 0° C. was added AlCl3 (841.5 mg, 6.4 mmol). The reaction mixture was warmed to room temperature. After 12h the reaction mixture was poured into aq. NaHCO3 and extracted with CH2Cl2 (twice). The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo to provide the crude product. Purification by silica gel chromatography provided (2-chloro-4-methoxyphenyl)(4-chlorophenyl)methanone(1.1 g, 4.1 mmol). (2-Chloro-4-methoxyphenyl)(4-chlorophenyl)methanone was dissolved in AcOH (60 mL) and 49% HBr (60 mL) was added. After 12h at 90° C. all volatiles were evaporated in vaccuo to afford (4-chlorophenyl)(2,4-dihydroxyphenyl)methanone in quantitative yield. This was dissolved in MeOH (30 mL) and THF (6 mL) and cooled to 0° C. Into the reaction mixture NaBH4 (235.5 mg, 6.2 mmol) was added. After 30 minutes the reaction was quenched with aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo. Without purification this was subjected to alkylation with 1,8-dibromoocatane (3.3 g, 12.3 mmol) and K2CO3 (1.7 g, 12.3 mmol) in DMF (45 mL). After 12h the reaction mixture was diluted with water (150 mL) and water phase was extracted with EtOAc (twice). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vaccuo to give the crude product. Purification by silica gel chromatography provided (4-(8-bromooctyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.6 g, 3.5 mmol). To a stirred solution of (4-(8-bromooctyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.6 g, 3.5 mmol) in THF (25 mL) was added N-methylprop-2-en-1-amine (746 mg, 10.5 mmol) and NaHCO3 (11.0 mmol). After 36h at room temperature the reaction mixture was filtered through a glass-filter. The filtrate was evaporated in vaccuo. Purification by silica gel chromatography provided (4-(8-(allyl(methyl)amino)octyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.5 g, 3.3 mmol); 1H-NMR (300 MHz, CDCl3); 7.29-7.17 ppm (m, 5H), 6.84 (d, J=10.1 Hz, 1H), 6.74 (s, 1H), 5.98-5.80 (m, 2H), 5.31-5.15 (m, 2H), 3.85 (t, J=7.6 Hz, 2H), 3.20-3.08 (m, 2H), 2.58-2.40 (m, 2H), 2.35 (s, 3H), 1.77-1.45 (m, 4H), 1.32-1.15 (m, 8H); 13C—NMR (75 MHz, CDCl3) 156.3 ppm, 138.3, 134.2, 131.8, 130.0, 129.6, 129.3, 116.2, 74.5, 68.8, 60.4, 43.8, 57.0, 29.6, 29.3, 28.1, 27.3, 25.9; ESI-MS calcd for C25H34Cl2NO2 [M+H]+: 450.2. found 450.2.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+:23]([O-])([OH:25])=[O:24]>O>[N+:23]([CH:2]([CH2:3][CH:4]([CH2:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:1])([O-:25])=[O:24]
Reactant: CCCCCCCCC(CCC)CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCCCCCCCC(CC(=O)Nc1ccccc1)CC(C)[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 2435.1 %

Procedure:
4-Dodecylacetanilide (252 g) was added portionwise over 45 minutes to a stirred solution of nitric acid (density 1.50 g. ml.) (210 ml) and water (23 ml) keeping the temperature between 35° and 40° C. The mixture was stirred for a further 30 minutes, drowned into cold water (1200 ml) and the precipitated solid filtered off, washed acid free with water, dried and recrystallised from ethanol to give 202 g of 2-nitro-4-dodecylacetanilide as fine needles, melting at 71°-2° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]1[S:20][C:19]2[C:18](=[O:21])[N:17]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:16](=[O:28])[N:15]([CH2:29][C:30]3[N:31]=[N:32][N:33]([CH2:35][CH3:36])[N:34]=3)[C:14]=2[CH:13]=1.[CH2:37]([O:39][C:40]1[C:49]([O:50][CH3:51])=[CH:48][C:47]2[C:46]([C:52]3[CH:60]=[CH:59][C:55]([C:56](O)=[O:57])=[CH:54][CH:53]=3)=[N:45][C@@H:44]3[CH2:61][CH2:62][S:63][CH2:64][C@@H:43]3[C:42]=2[CH:41]=1)[CH3:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]1[S:20][C:19]2[C:18](=[O:21])[N:17]([CH:22]3[CH2:27][CH2:26][N:25]([C:56]([C:55]4[CH:59]=[CH:60][C:52]([C:46]5[C:47]6[CH:48]=[C:49]([O:50][CH3:51])[C:40]([O:39][CH2:37][CH3:38])=[CH:41][C:42]=6[C@H:43]6[CH2:64][S:63][CH2:62][CH2:61][C@H:44]6[N:45]=5)=[CH:53][CH:54]=4)=[O:57])[CH2:24][CH2:23]3)[C:16](=[O:28])[N:15]([CH2:29][C:30]3[N:31]=[N:32][N:33]([CH2:35][CH3:36])[N:34]=3)[C:14]=2[CH:13]=1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4cc(OC)ccc4OC)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6cc(OC)ccc6OC)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
6-(2,5-dimethoxyphenyl)-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (137 mg; compound B80) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (145 mg; compound C10) and HBTU (102 mg) in DCM (10 ml) in the presence of DIPEA (264 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and preparative HPLC as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][CH2:12][C:13]([O:15]C)=O>C1COCC1.C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:13]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)([OH:15])[CH2:12][O:11][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)OC
Reactant: Fc1cccc([Mg]Br)c1
Solvent: O=CO
Solvent: C1CCOC1
Product: COCC(O)(c1cccc(F)c1)c1cccc(F)c1

Procedure:
A solution of 1,1-bis(3-fluorophenyl)-2-methoxyethanol (156.7 g) (obtained by the reaction of 3-fluorophenylmagnesium bromide with methyl 2-methoxyacetate in THF) in formic acid (160 cc) is heated to reflux for 16 hours, cooled and poured into a mixture of saturated sodium carbonate solution (800 cc) and ethyl acetate (500 cc). The organic phase is washed with water (2×500 cc) and with saturated sodium chloride solution (500 cc), then dried and concentrated to dryness under reduced pressure (2.7 kPa) to give bis(3-fluorophenyl)acetaldehyde (144.5 g) in the form of a yellow oil.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:11]1[C:18](Cl)=[N:17][C:15](Cl)=[N:14][C:12]=1[Cl:13]>CCOCC.C1C=CC=CC=1>[Cl:13][C:12]1[N:14]=[C:15]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:17]=[C:18]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=1
Reactant: Brc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: II
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reaction time: 8 h
Yield: 134.2 %

Procedure:
The procedure used was based on the method of Jones et al, AD 229453, Sept. 1959. A stirred mixture of magnesium turnings (24.3 g, 0.935 mol) and a crystal of iodine in ether (150 ml), was added a solution of bromobenzene (155.3 g, 0.985 mol) in ether (100 ml) under a nitrogen atmosphere over a period of 3.75 hr at such a rate as to maintain a gentle reflux. Thereafter, the mixture was refluxed for 2.5 hr. The Grignard reagent thus prepared was then cooled and transferred to an addition funnel and added with stirring to a solution of cyanuric chloride (70 g, 0.38 mol) in benzene (500 ml) at 4°-15° C. (ice bath cooling) over a period of 1.25 hr. After stirring overnight the mixture was refluxed for 4 hr, cooled, and filtered. The filtrate was evaporated to dryness using a Rinco evaporator yielding 136.5 g of crude product mixture. This mixture was distilled in vacuo at 0.007 mm. The desired product, bp 140°-152° C., 63.5 g(62% yield), was crystallized three times from heptane yielding pure 2-chloro-4,6-diphenyl-s-triazine, 46.1 g (45% yield), mp 136°-138° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:13])[N:8]([CH2:10][CH2:11][CH3:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18]>C(OCC)(=O)C.O>[Cl:22][C:21]([Cl:24])([Cl:23])[CH2:20][O:19][C:17](=[O:18])[NH:13][C:7]1[N:8]([CH2:10][CH2:11][CH3:12])[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCCn1nc(C(C)(C)C)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103.1 %

Procedure:
To a stirred mixture of Intermediate 23a (0.774 g, 4.27 mmol) in ethyl acetate (4 mL) and 1 M aqueous NaOH (7.7 mL, 7.7 mmol) was added 2,2,2-trichloroethyl chloroformate (0.62 mL, 4.50 mmol) and the mixture was stirred at room temperature for 1.5 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water and saturated aqueous NaCl, then evaporated to give the title compound (1.57 g) as an oil. LCMS (Method 3): Rt 4.28 min, m/z 356/358/360 [MH+]. 1H NMR (300 MHz, CDCl3): 0.90 (3H, t, J 7.5 Hz), 1.28 (9H, s), 1.78-1.87 (2H, m), 3.92 (2H, t, J 7.4 Hz), 4.83 (2H, s), 6.08 (1H, s), 6.46 (1H, s).
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)(=[O:5])=[O:4].[CH3:22][C:23]1[N:28]=[C:27]([CH:29]=[CH2:30])[CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[Na+].CO>O>[CH3:22][C:23]1[N:28]=[C:27]([CH2:29][CH2:30][N:19]2[CH2:20][CH2:21][CH:16]([S:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])=[CH:8][CH:9]=3)(=[O:15])=[O:14])[CH2:17][CH2:18]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: C=Cc1cccc(C)n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc(CCN2CCC(S(=O)(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)n1
Yield: 63.9 %

Procedure:
0.60 g (1.86 mmol) of 4-(4-methylsulfonylaminophenylsulfonyl)piperidine hydrochloride obtained in Example 5, 0.44 g (3.72 mmol) of 6-methyl-2-vinylpyridine and 0.31 g of sodium acetate were suspended in 10 ml of a mixture of methanol with water (1:1) and the suspension was refluxed for 2 h. The reaction liquid was filtered and the filtrate was concentrated to give a residue. After extraction with dichloromethane followed by washing with water, the organic layer was concentrated to precipitate white crystals. The crystals were collected by filtration and recrystallized from ethyl acetate to give 0.52 g (yield: 64%) of the intended compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1
Reactant: NN1CCOCC1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 78 %

Procedure:
As described for example 26b, 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (75 mg, 0.24 mmol) was converted, using N-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (74 mg, 78%) which was obtained as a white solid. MS: m/e=396.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][S:9]([NH:12][C:13](=O)OC(C)(C)C)(=[O:11])=[O:10])([O-:3])=[O:2].[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][S:9]([NH:12][CH2:13][CH3:23])(=[O:11])=[O:10])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCNS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude tert-butyl N-(3-nitrobenzylsulfamoyl)carbamate, triphenylphosphine (2 g) and diisopropyl azadicarboxylate (DIAD, 1.6 g) were dissolved in THF (20 mL) and ethanol (0.47 mL). The solution was stirred at ambient temperature overnight. The reaction solution was evaporated to dryness. The residue was dissolved in methanol (10 mL) and treated with 4.0 M HCl in dioxane (10 mL). It was stirred at rt overnight and then evaporated. The residue was diluted with ethyl acetate (100 mL) and washed with NaHCO3 aq. (2×100 mL). The organic solution was evaporated and purified by flash column chromatography (EtOAc/hexane=1/2, 1/1) to give N-(3-nitrobenzyl)-N′-ethylsulfamide. 1H NMR (DMSO-d6): δ 1.02 (t, J=7.2 Hz, 3H), 2.82 (p, J=6.9 Hz, 2H), 4.14 (d, J=6.6 Hz, 2H), 6.93 (t, J=5.4 Hz, 1H), 7.54 (t, J=6.3 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 8.20 (s, 1H); LCMS: purity: 1.2 g, 88.4%; MS (m/e): 260.16 (MH+).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][S:6]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[Cl:16])(=[O:8])=[O:7])#[N:2].O.[NH2:20][NH2:21]>C(O)C>[NH2:2][C:1]1[NH:21][N:20]=[C:4]([NH:5][S:6]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])(=[O:8])=[O:7])[N:3]=1
Reactant: CSC(=NC#N)NS(=O)(=O)c1cc(Cl)ccc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1nc(NS(=O)(=O)c2cc(Cl)ccc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.2 %

Procedure:
A mixture of 8.51 g (26.2 mmol) of N'-cyano-N-(2,5-dichlorophenylsulfonyl)-S-methylisothiourea and 10 ml (10 g, 0.20 mol) of hydrazine monohydrate in 85 ml of ethanol was heated at reflux for 30 minutes. After cooling to room temperature, the solid which separated was collected and suspended in 170 ml of H2O and the suspension was acidified with concentrated aqueous HCl. After stirring the suspension for 4 hours the solid was collected and dried in vacuo to yield 5.10 g (57 percent) of the desired product as a hydrochloride salt, mp 306°-308° C. IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[N:34]1([CH2:40][CH2:41][OH:42])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:37]4[CH2:38][CH2:39][N:34]([CH2:40][CH2:41][OH:42])[CH2:35][CH2:36]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: OCCN1CCNCC1
Product: O=C1N=C(N2CCN(CCO)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 2-piperazin-1-yl-ethanol following General Procedure C.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[F:11][C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:19]2)=[N:16][CH:17]=1.[F:32][C:33]1[C:42]2[C:37](=CC=CC=2)[C:36]([C:43](Cl)=[O:44])=[CH:35][CH:34]=1.Cl>C1COCC1.C(Cl)Cl>[F:32][C:33]1[CH:42]=[CH:37][C:36]([C:43]([CH:26]([CH2:25][CH2:24][N:21]2[CH2:20][CH2:19][N:18]([C:15]3[N:16]=[CH:17][C:12]([F:11])=[CH:13][N:14]=3)[CH2:23][CH2:22]2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:44])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(F)c2ccccc12
Reactant: CCOC(=O)CCCN1CCN(c2ncc(F)cn2)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(CCN1CCN(c2ncc(F)cn2)CC1)C(=O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a cold (-78° C.) solution of lithium 1,1,1,3,3,3-hexamethyl disilazane in tetrahydrofuran (27.4 mL, 1N, 27.4 mmol) kept under Ar atm was added dropwise (10 min) a solution of ethyl 4-(4-(5-fluoro-2-pyrimidinyl)piperazin-1-yl)butanoate (3.7 g, 12.5 mmol) in dry THF (12 mL). The reaction mixture was stirred 0.25 h at -78° C. and then treated dropwise (10 min) with a solution of 4-fluoro-1-naphthoyl chloride (2.6 g, 12.5 mmol) in dry THF (10 mL). The reaction was stirred -78° C. for 0.5 h then the cooling bath was removed. When the temperature of reaction mixture reached 0° C., HCl solution (40 mL, 0.3N) was added slowly followed by CH2Cl2 (350 mL); the organic phase was separated and aqueous phase was extracted with CH2Cl2 (120 mL). The organic extracts were combined, washed with water (2×45 mL) and brine, dried (MgSO4) and concentrated under reduced pressure to a crude mixture which was purified on a silica gel pad (8.7×2.5 cm). Evaporation of appropriate fractions gave 2.8 g (48%) of the desired product compound which was recrystallized from EtOH to give an analytical sample; mp 95°-6° C.; 1H NMR (CDCl3, 200 MHz) δ: 1.08 (t, J=7.1 Hz, CH3, 3H), 2.1-2.7 (m, 8H), 3.5-3.8 (m, 4H), 3.9-4.3 (m, 2H), 4.5-4.7 (m, 1H), 7.1-7.25 (m, 1H), 7.5-7.8 (m, 2H), 8.17 (s), 8.0-8.02 (s and m, 4H), 8.6-8.7 (m, 1H); IR (KBr) ν: 1740 (C=O, 1682, 1630, 1611, 1600, 1578, 1554, 1510 cm-1 ; UV (CH3CN) λ: 224 (ε 43570), 242 (ε 37740), 304 (ε 9084);
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([O:29]C)=[O:28])=[O:23])[CH:9]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[F:37][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:22]([C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=2)[C:27]([OH:29])=[O:28])=[O:23])[CH:9]=1
Reactant: COC(=O)c1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 30 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of methyl 3-((2-(6-(3-(trifluoromethyl)benzylamino)pyrimidin-4-yl)-4-chlorophenyl)carbamoyl)benzoate (400 mg, 0.74 mmol, 1.00 equiv) in tetrahydrofuran (30 mL), water (30 mL), and lithium hydroxide hydrate (317 mg, 7.55 mmol, 10.00 equiv). The resulting solution was stirred for 4 h at 30° C. in an oil bath. The solution was adjusted to pH 1 with hydrochloric acid (1 mol/L). The resulting solution was extracted with 20 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The product was obtained as 350 mg (90%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[O:11][N:10]=1.C(O[CH:24](N(C)C)[N:25]([CH3:27])[CH3:26])(C)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]=[CH:24][N:25]([CH3:27])[CH3:26])[O:11][N:10]=1
Reactant: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C=CN(C)C

Procedure:
To a solution of 0.1 g (0.3708 mmol) methyl 3-(2-chloro-6-Fluorophenyl)-5-methylisoxazole-4-carboxylate in 10 mL dry toluene, 0.15 mL (0.7417 mmol) tert-Butoxy-bis(dimethylamino)methane (Bredereck's reagent) were added. The reaction mixture was heated under reflux for 6 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:7]=[CH:6]2.ClN1C(=[O:24])CCC1=O.P(=O)(O)(O)O>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7](=[O:24])[CH2:6]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(ccn2-c2ccccc2)c1
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)CC(=O)N2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
The compound of step 1 (800 mg, 3.58 mmol) was dissolved in DCM (25 ml), and N-chlorosuccinimide (526 mg, 3.94 mmol) was added. The reaction mixture was stir at room temperature overnight. The solvent was removed, the resulting solid was dissolved in concentrated acetic acid (15 ml) and heated to 70° C. After the addition of phosphoric acid (3.04 ml, 44.6 mmol; 85%) the reaction mixture was heated to 130° C. for 2.5 h. The cooled mixture was diluted with water and extracted with EA. The extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/HEP 1:3). 557 mg of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[N:9]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>O1CCCC1>[O:13]=[C:12]1[N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:19](=[O:20])[N:9]2[CH:10]=[C:11]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnn(-c2ccccc2N)c1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(=O)[nH]c3ccccc3n2c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
24.7 g 1-(2-aminophenyl)-5-hydroxy-1H-pyrazole-4-carboxylic acid, ethyl ester and 16.2 g 1,1'-carbonyl-bis-[1H-imidazole] are dissolved in 300 ml tetrahydrofuran and stirred for 8 hours at room temperature and one hour at 90° C. The solid residue, after distilling off the solvent, is recrystallized from dimethylformamide to yield 21 g of 5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]-benzotriazine-2-carboxylic acid, ethyl ester having a melting point of 269°-271° C.; white-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Br:11])[N:3]=1.[K].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C)C=O>[Br:11][C:4]1[CH:5]=[C:6]([S:22][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[CH:7]=[C:2]([Br:1])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2cc(Br)nc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
0.48 g (0.0025 mol) of 2,6-dibromo-4-nitropyridine and 0.70 g (0.0024 mol) of 4-nitrothiophenol potassium salt were dissolved in 12.5 ml of dimethylformamide and stirred at room temperature for 3 hrs. The solvent was removed and the residue was partitioned in water and ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:19 and subsequently dried in a high vacuum. There was obtained 0.785 g (81%) of 2,6-dibromo-4-(4-nitrophenylsulphanyl)-pyridine as yellow crystals; m.p. 166-168° C.