Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8][CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].CO>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[CH2:11][CH2:12][C:20]([C:19]2[CH:27]=[CH:28][C:16]([Cl:15])=[CH:17][CH:18]=2)([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: Clc1ccc(Cc2ccncc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccncc2)(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 0.7 %

Procedure:
Under nitrogen, a solution of bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester* (1.54 g, 6.36 mmol) in toluene (10 mL) was cooled in ice. 4-(4-Chloro-benzyl)-pyridine (1.30 g, 6.36 mmol) was added, followed over two minutes by sodium hexamethyldisilazide solution (10 mL, 20 mmol, 2M in THF). The mixture was stirred at 0° C. for 3.5 hours then allowed to warm to room temperature and stirred for a further 20 hours. Methanol was added then the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 1N hydrochloric acid (×3) and brine, dried (MgSO4), filtered and concentrated to afford a residue which was purified by column chromatography (SiO2), eluting with gradient of 2M methanolic ammonia in dichloromethane (1% to 5%). A second purification by column chromatography (SiO2), eluting with 50% ethyl acetate/petrol gave the title compound (16 mg, 0.7%). LCMS (PS-A2) Rt 2.65 min [M+H]+ 373. * This starting material can be made by the method described in J. Chem. Soc., Perkin Trans 1, 2000, p 3444-3450
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=O)[N:16]=3)=[C:9]([F:30])[CH:8]=1.[CH3:31][Si](C[Mg]Cl)(C)C.CC(C)([O-])C.[K+]>C1COCC1>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]([CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH2:31])[N:16]=3)=[C:9]([F:30])[CH:8]=1
Reactant: O=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCOCC1
Reactant: C[Si](C)(C)C[Mg]Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a slurry of (2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)thiazolo[5,4-b]pyridine-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (0.408 g, 0.952 mmol) in 20 mL THF at ambient temp was added trimethylsilylmethylmagnesium chloride, 1.1 M solution in THF (1.472 mL, 1.619 mmol) dropwise via syringe. The reaction mixture became clear and dark brown. After 10 min, the reaction mixture became light orange and was cooled to 0° C. and was quenched by careful dropwise addition of sat'd aq NH4Cl. The reaction mixture was partitioned between satd NH4Cl and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an orange solid. The crude was taken up in 10 mL THF and potassium tert-butoxide (0.128 g, 1.143 mmol) was added. The reaction mixture became dark brown. After 2 h, additional potassium tert-butoxide (0.128 g, 1.143 mmol) was added. After 2 h, the reaction mixture was partitioned between sat'd aq. NH4Cl and DCM. The aqueous layer was extracted with DCM, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The solid was suspended in a minimum amount of MeOH and filtered, rinsing with MeOH to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)vinyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: Calculated: 426.1; Observed: 427.1 (M++1).
Reaction SMILES: C(OC(=O)[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C-:19]#[N:20].[K+].C(O)C>O>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][CH:11]([C:19]#[N:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:10]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
120 g of benzalmalonic acid diethyl ester, 33.6 g of potassium cyanide, 1600 cc of ethanol and 160 cc of water are stirred at a bath temperature of 60° for 12 to 14 hours. The reaction mixture is then cooled with ice water, the potassium bicarbonate which crystallizes is filtered off, the filtrate is made neutral with about 15 cc of 1 N hydrochloric acid, air is passed through the solution with a water jet vacuum pump for 1 hour, the solvent is distilled off on a rotary evaporator, 100 cc of water are added to the oily residue, and extraction is effected 6 times with 250 cc amounts of ether. The 3-cyano-3-phenyl-propionic acid ethyl ester, obtained after distilling off the ether, is purified by vacuum distillation. B.P. 125°-130°/0.15 mm Hg.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]1([Mg]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[NH4+]>C(OCC)C>[CH3:4][CH:3]([CH3:5])[CH2:2][CH:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CC(O)c1ccccc1
Temperature: 0 °C

Procedure:
To a time-dried flask under an argon atmosphere is added 0.50 mL of commercially available isovaleraldehyde and charged with 15 mL of diethyl ether. The solution is cooled to 0° C. and is treated with 2.0 mL (3.0 M in diethyl ether) of phenylmagnesium bromide. The reaction mixture is left to warm to room temperature overnight and then partioned between diethyl ether and saturated ammonium chloride. The aqueous phases are extracted with diethyl ether and the combined organic layers are dried (magnesium sulfate) and finally concentrated under reduced pressure. The residue is flash column chromatographed using 20% diethyl ether in hexanes to yield 800 mg of the title product as a clear, colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:9][CH:10]2[CH2:22][S:21][C:13]3[NH:14][C:15]4[C:20]([C:12]=3[C:11]2=[O:23])=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:6]=[CH:7][N:8]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C)C=O.C(O)C>[CH3:3][C:4]1[N:5]([CH2:9][CH:10]2[CH2:22][S:21][C:13]3[N:14]([S:25]([CH3:24])(=[O:27])=[O:26])[C:15]4[C:20]([C:12]=3[C:11]2=[O:23])=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:6]=[CH:7][N:8]=1
Reactant: Cc1nccn1CC1CSc2[nH]c3ccccc3c2C1=O
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1nccn1CC1CSc2c(c3ccccc3n2S(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.20 g (0.0042 mol) of sodium hydride, at a concentration of 50% in oil, is added in the course of 30 minutes and under a nitrogen atmosphere to a solution of 1.19 g (0.004 mol) of 3-[(2-methyl-1-imidazolyl)methyl]-4-oxo-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole in 20 ml of dimethylformamide, and 0.325 ml (0.0042 mol) of methanesulfonyl chloride is then added. The mixture is stirred for 4 hours at room temperature, 150 ml of 2N sodium carbonate solution are added and the resulting mixture is extracted three times with ethyl acetate. The organic phases are combined, dried and evaporated. The residue (1.35 g) is chromatographed on silica gel, eluting with a methylene chloride/ethanol mixture (92:8). The residue obtained is dissolved in 20 ml of ethanol and the solution is treated with 3 ml of an ethereal solution of hydrochloric acid at 10° C. for 1 hour. The precipitate is drained, washed with ethyl ether and recrystallized in acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])[N:3]=1.C(O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>[Cu]I.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.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])[N:3]=1
Reactant: CN(C)C=Nc1ncc(I)c(Cl)n1
Reactant: C#Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C=Nc1ncc(C#Cc2ccc(Cl)cc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 1-liter, 3-neck-round-bottom flask was equipped with an air stirrer, reflux condenser, and a nitrogen inlet. The 4-chloro-2-(dimethylaminomethyleneamino)-5-iodopyrimidine (65.2 g), ethanol (84 mL), and triethylamine (336 mL) were charged and heated to reflux. Copper (I) iodide (105 mg) and dichlorobis(triphenyl)phosphine palladium II (386 mg) were added. Neat 1-chloro-4-ethynylbenzene (30.1 g) was added and the mixture was refluxed approximately 2.5 hours. The mixture was cooled to ambient temperature, stirred for 1.5 hours and filtered. The filter cake was slurried in water:ethanol (4:1 v/v, 120 mL), filtered and dried in vacuo at 50° C. to give 4-chloro-5-(4-chlorophenylethynyl)-2-dimethylaminomethyleneaminopyrimidine as a yellow solid: 55.7 g m.p. 195–197° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:12]4[S:19][C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[CH:27](Cl)[O:28]C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[C:20]1([C:18]2[S:19][C:12]3[C:11]([NH:10][C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[NH:1][CH:2]=[C:3]5[CH:27]=[O:28])=[N:16][CH:15]=[N:14][C:13]=3[CH:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(Cl)Cl
Reactant: c1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1c[nH]c2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of (1H-Indol-5-yl)-(6-phenyl-thieno[3,2-d]pyrimidin-4-yl)-amine (481 mg, 1.4 mmol) in 3 mL of methylene chloride in a 3-neck flask with dropping funnel under nitrogen at 0° C. was added titanium tetrachloride (461 mL, 4.2 mmol) dropwise. The mixture was stirred for 30 minutes and then dichloromethoxy methane (380 mL, 4.2 mmol) was added dropwise. The reaction was warmed to room temperature and concentrated in vacuo. The resulting residue was pre-absorbed onto silica gel (10 gm) and purified by flash chromatography using a 5% methanol/methylene chloride to afford the title compound in 92% yield. RP18-HPLC RT: 4.80 minutes; API MS: 371.20 (M+1); MP: 174-175° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.[C:16]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C(O)(C)C>[C:16]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3[CH:15]=[CH:14][C:9]4[NH:10][C:11](=[O:13])[O:12][C:8]=4[CH:7]=3)[CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: O=c1[nH]c2ccc(CCCCCl)cc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=c1[nH]c2ccc(CCCCN3CCN(c4cccc5ccccc45)CC3)cc2o1
Yield: 543.1 %

Procedure:
To a 100 ml round-bottom flask equipped with condenser and nitrogen inlet were added 0.658 grams (3.10 mmol) of 6-(4-chlorobutyl)-benzoxazolone, 0.7 grams (3.10 mmol) of N-(1-naphthyl)piperazine, 0.328 grams sodium carbonate, 2 mg sodium iodide, and 50 ml isopropanol. The reaction was refluxed for 3 days, evaporated, taken up in methylene chloride, washed with water, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate as eluent, and the product dissolved in acetone, precipitated with ethereal HCl, and the white solid filtered, washed with acetone, and dried to afford 6.76 grams (46.0%) of a white solid, m.p. 231°-233° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([Cl:17])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(C(=O)O)c1ccc(F)cc1
Solvent: c1ccccc1
Product: CC(C)C(C(=O)Cl)c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
50 g of 2-(p-fluorophenyl)-3-methylbutyric acid were dissolved in 200 ml of benzene and treated with 54.2 g of thionyl chloride. The mixture was stirred at 60° for 45 minutes and subsequently heated to reflux for 2 hours. After evaporation of the solvent the residue was distilled, whereby 2-(4-fluorophenyl)-3-methyl-butyryl chloride, b.p. 70°/93 Pa, was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:44][O:45][C:46]1[C:51]2[N:52]=[C:53]([NH2:55])[S:54][C:50]=2[C:49]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)=[CH:48][CH:47]=1>C1COCC1.O1CCOCC1.CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:55][C:53]2[S:54][C:50]3[C:49]([N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)=[CH:48][CH:47]=[C:46]([O:45][CH3:44])[C:51]=3[N:52]=2)=[O:8])=[CH:4][N:3]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a stirred solution of 1.89 g (7.54 mmol) 6-chloro-nicotinic acid in 20 ml THF were added 2.87 g (7.54 mmol) HATU and 1.28 ml (7.54 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 30 minutes. A solution of 2.00 g (7.54 mmol) 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine in 20 ml dioxane and 4 ml DMF was then added and stirring continued at room temperature for 16 h. The reaction mixture was then poured into 350 ml water and the mixture stirred for 30 min. The resulting crystals were collected by filtration, washed with methanol and then with ether, and dried in vacuo to afford 3.03 g (99%) 6-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-nicotinamide as a yellow crystalline solid. ES-MS m/e (%): 429 (M{37Cl}+Na+, 15), 427 (M{35Cl}+Na+, 38). 407 (M{37Cl}+H+, 40), 405 (M{31Cl}+H+, 100)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH:18]([CH3:20])[CH3:19])[NH:5][C:6]([O:8]C1C=CC([N+]([O-])=O)=CC=1)=O.[CH:22]([C:25]1[O:26][CH:27]=[C:28]([CH2:30][NH:31][CH3:32])[N:29]=1)([CH3:24])[CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH:18]([CH3:19])[CH3:20])[NH:5][C:6]([N:31]([CH3:32])[CH2:30][C:28]1[N:29]=[C:25]([CH:22]([CH3:23])[CH3:24])[O:26][CH:27]=1)=[O:8]
Reactant: CNCc1coc(C(C)C)n1
Reactant: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)N(C)Cc1coc(C(C)C)n1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A solution of N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester (0.903 g, 0.00305 mol) in anhydrous DMF (6 mL) was added to a solution of 2-isopropyl-4-(((N-methyl)amino)methyl)oxazole (9, 0.470 g, 0.00305 mol) in anhydrous DMF (6 mL) under argon, and the yellow solution was stirred at room temperature for 30 min. Solvent was removed by rotary evaporation in vacuo and the resulting oil dried on high vacuum for 1 hr. The residue was applied to a 150 g SiO2 flash column and eluted with 20% EtOAc/CH2Cl2 and 3% MeOH/CH2Cl2. The material obtained after concentration of the product fractions was repurified on a 100 g SiO2 flash column with a gradient of MeOH/CH2Cl2 (1%, 2%, 3%) to obtain the desired compound as an oil (0.515 g, 0.00165 mol, 54 %): 1H NMR (CDCl3) δ 0.97 (dd, J1=9 Hz, J2=6.9 Hz, 6H), 1.33 (d, J=6.9 Hz, 6H), 2.11-2.23 (m, 1H), 2.98 (s, 3H), 3.00-3.13 (m, 1H), 3.77 (s, 3H), 4.23-4.36 (m, 2H), 4.36-4.42 (m, 1H), 5.79-5.86 (br d, 1H), 7.46 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])=[O:24].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:19])([F:20])[CH2:15]2)[C:8]2[C:9](=[N:11][N:12]([CH2:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[O:24])[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3Cl)nc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.6 %

Procedure:
A mixture of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (11.6 mg, 41.1 μmol), 2-bromo-1-(2-chlorophenyl)ethanone (11.5 mg, 7.19 μl, 49.3 μmol) and DIPEA (10.6 mg, 14.4 μl, 82.2 μmol) were combined with DCM (250 μl) to give a light yellow solution. The reaction mixture was stirred at r.t. for 4 h and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 1.9 mg (11%) of the title compound as yellow gum. MS (m/e): 435.3 (MH+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20](C(O)=O)[CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[O:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19][CH2:18]4)=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=C(O)N1CCN(c2ccc(N3CCC4(CC3)OCCO4)cn2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(c1)NCCN2c1ccc(N2CCC3(CC2)OCCO3)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.7 g of tert-butyl ester of 4-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is put in 30 ml of dioxane, then 22.37 ml of 4N HCl in dioxane is added. The reaction mixture is stirred for 48 h in a closed environment at room temperature. After concentration to dryness, the reaction mixture is diluted with 200 ml of a saturated aqueous solution of sodium hydrogen carbonate and extracted twice with 200 ml of dichloromethane. The resultant organic phases are combined, washed with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate, and with 100 ml of a saturated aqueous solution of sodium chloride, dried over MgSO4 and concentrated to dryness. 2.1 g of 1-[5-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+].C(O)C>O>[CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[N:15]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:16]=[N:17][N:18]=3)=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnn[nH]3)oc12
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnnn3Cc3ccccc3)oc12

Procedure:
A mixture of 30 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole, 16.6 parts of benzyl bromide, 3.53 parts of sodium hydroxide, 120 parts of ethanol and 60 parts of water was refluxed for 64 hours. The mixture was cooled, was extracted with chloroform and the chloroform extract washed with sodium bicarbonate solution and water. Evaporation of the chloroform gave a residue which was chromatographed on silica gel. Elution with 3 : 1 toluene/acetic acid and chloroform gave, after crystallisation from ethanol, a total of 7.31 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]-N-benzyltetrazole, m.p. 92.5-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]([OH:21])=O)[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>>[NH:36]1[C:35]([NH:34][C:19]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)[N:6]=2)=[O:21])=[N:39][N:38]=[N:37]1
Reactant: COc1cc(C(=O)O)nc(-c2ccc(NC(C)=O)cc2)c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc(NC(C)=O)cc2)c1
Yield: 84.5 %

Procedure:
In the same manner as described in Example 1-(1), 4-methoxy-6-(4-acetylaminophenyl)-2-pyridinecarboxylic acid (0.46 g), carbonyldiimidazole (0.29 g) and 5-aminotetrazole (0.15 g) are reacted to give N-(5-tetrazolyl)-4-methoxy-6-(4-acetylaminophenyl)-2-pyridinecarboxamide (0.48 g). M.P. 286°-288° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:45])=[C:15]([C:19]2[N:20]=[C:21]([C:31]3([CH3:44])[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10].C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]=[C:21]([C:31]3([CH3:44])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[N:25]=2)[C:14]=1[F:45])(=[O:10])=[O:11]
Reactant: Cc1nccc(-c2sc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nccc(-c2sc(C3(C)CCNCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-5-(2-methyl-4-pyrimidinyl)-1,3-thiazol-2-yl]-4-methyl-1-piperidinecarboxylate (72 mg, 0.109 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. The reaction was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to obtain the title compound (38 mg). MS (ESI): 560.0 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH3:14])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:8]=2[CH:23]=1)(=O)[NH2:2]>ClCCl.C(N(CC)CC)C.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:9]1[C:8]2[CH:23]=[C:4]([C:1]#[N:2])[CH:5]=[CH:6][C:7]=2[N:11]=[C:10]1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1nc2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1nc2ccc(C#N)cc2n1Cc1ccccc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of 1 mol of titanium tetrachloride in 0.14 ml of dichloromethane and 0.36 ml of triethylamine were added to a solution of 200 mg of 6-carbamoyl-1-(2-chlorobenzyl)-2-n-propylbenzimidazole in 4 ml of tetrahydrofuran at 0°C., and the mixture was stirred at 20° C. for 2 hours. The reaction mixture was separated with ethyl acetate and with water. The organic layer was washed with water, dried, and then concentrated under reduced pressure. The residue was developed and purified through column chromatography using a mixture of ethyl acetate and hexane (at a ratio of from 1:10 to 1:3), and was further recrystallized from a mixture of ethyl acetate and hexane to give 140 mg of 1-(2-chlorobenzyl)-6-cyano-2-n-propylbenzimidazole (87).