Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([N:14](CC)CC)[CH3:13].ClCC#N>O1CCCC1>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][CH2:13][C:12]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOCc1ccccc1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: C1CCOC1
Product: N#CCNCCOCc1ccccc1

Procedure:
A mixture of 2-benzyloxyethylamine (40 g) and triethylamine (50 ml) in tetrahydrofuran (500 ml) was treated dropwise with chloroacetonitrile (23 g) at room temperature.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:15](Cl)=O.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:15]([C:14]3[CH:13]=[C:12]([F:11])[C:20]([F:21])=[C:19]([F:22])[CH:18]=3)[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: Fc1cc(-c2nc(-c3ccnnc3)no2)cc(F)c1F

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 3,4,5-trifluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 8.04-8.16 (m, 2 H), 8.38 (dd, J=5.4, 2.2 Hz, 1 H), 9.46 (dd, J=5.4, 1.4 Hz, 1 H), 9.86 (dd, J=2.4, 1.2 Hz, 1 H) ppm; MS (DCI/NH3) m/z=279 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH2:15]([O:22]CC1C=CC=CC=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na]>CS(C)=O.C(O)C1C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na]
Solvent: CS(C)=O
Solvent: OCc1ccccc1
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 866.3 %

Procedure:
To a solution containing 45.1 g (0.02 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene in 100 ml of DMSO was added dropwise at ambient temperature a solution containing 26 g (0.2 mole) of sodium benzyloxide in 75 ml of benzyl alcohol causing the temperature to rise 40° C. After 48 hours at ambient temperature, the reaction mixture was poured into ice water and extracted with ether, and the extract was dried and concentrated to about 200 ml. To the concentrated solution was added 200 ml of hexane and the resulting solution was cooled. Filtration gave 51.5 g (87%) of colorless crystalline solid; m.p. 112°-114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[O:5][CH2:6][CH2:7][Br:8].[O:13]=[S:14](Cl)Cl.OS(O)(=O)=O>N1C=CC=CC=1>[Br:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][C:11]2=[N:12][S:14](=[O:13])[N:1]=[C:2]2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(OCCBr)cc1N
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: O=S1N=c2ccc(OCCBr)cc2=N1
Temperature: 0 °C
Yield: 17 %

Procedure:
To a cooled (ice-water) solution of 2-(3,4-diaminophenoxy)ethyl bromide (2.03 g, 8.8 mmol) in pyridine (40 mL) was added dropwise 0.65 mL (8.9 mml) of SOCl2 with stirring. The resulting mixture was stirred at r.t for 2 h, then 4N H2SO4 was added dropwise with cooling. The acidic (pH 5) mixture was extracted with CHCl3 (4×50 mL). The CHCl3 solution was washed with brine, dried (Na2SO4), then evaporated to give 420 mg (17%) of 5-(2-bromoethoxy)-2,1,3-benzothiadiazol-2-one as an orange-yellow powder. 1H NMR (CDCl3): 3.737 (t, 2H, J=6), 4.407 (t, 2H, J=6), 7.195 (d, 1H, J=2), 7.341 (dd, 1H, J=9; 2), 7.874 (d, 1H, J=9).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]=1[CH3:23]>C1COCC1.CO>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:24])=[O:4])=[C:8]2[CH3:23])=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1c(C)n(-c2ccc(Cl)cc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)c2cccnc2n1-c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
1M Aqueous NaOH (0.5 mL) is added to a stirring solution of [1-(4-chloro-phenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (4 mg, 0.013 mmol) in 1:1 THF/MeOH (2 mL). After 18 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 1, and extracted with ethyl acetate. The organic layer is washed with water then brine, dried (MgSO4) then evaporated, to give [1-(4-chloro-phenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=301.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].[Cl:17]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([Cl:17])=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C=NNc1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(Cl)=NNc1ccc(OC)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Method A. A solution of [(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (33, 4.0 g, 18.0 mmol) in anhydrous THF (40 mL) was treated with N-chlorosuccinimide (NCS, 2.52 g, 18.9 mmol, 1.05 equiv) at 0-5° C. under N2, and the resulting reaction mixture was stirred at 0-5° C. for an additional 30 min before being gradually warmed to 25° C. for 12 h. When HPLC and TLC showed the reaction was deemed complete, the solvent was removed in vacuo. The residue was directly purified by column chromatography (SiO2, 0-25% EtOAc/hexane gradient elution) to afford the desired chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 3.51 g, 4.62 g theoretical, 76%) as pale-yellow solids, which was found to be essentially pure to do the following reaction without further purification. For 34, CIMS m/z 255/257 (M+−H, C11H13ClN2O3).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9]I>CO>[CH3:9][NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8]
Reactant: Nc1ccccc1N
Reactant: CI
Solvent: CO
Product: CNc1ccccc1N

Procedure:
To one liter of methanol were added 89 grams (0.82 mole) of o-phenylenediamine and 25.7 ml. (0.41 mole) of methyl iodide. The mixture was refluxed for 2 hours, and an additional 25.7 ml. (0.41 mole) of methyl iodide then were added. The total mixture was refluxed for 12 hours. The major portion of the methanol then was removed in vacuo. The residual brown oil was poured into two liters of crushed ice, and the pH of the mixture was raised to 9.0 by addition of potassium hydroxide. The resulting mixture then was extracted with ethyl ether, and the extract was dried over potassium carbonate. The ether was removed in vacuo, and the residue was distilled at about 120° C./8 mm. to obtain N-methyl-o-phenylenediamine as a yellow oil which turned brown upon standing.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].C[N+](C)(C)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(-c2ccc(O)cc2)cc1
Reaction time: 6 h
Yield: 75.9 %

Procedure:
A solution of 0.1 mol (21.4 g) of 4'-hydroxybiphenyl-4-carboxylic acid and 0.11 mol (19.9 g) of tetramethylammonium hydroxide (pentahydrate) in 200 ml of DMF was stirred for 2 hours. To this was then added 0.1 mol (17.1 g) of benzyl bromide and the mixture was stirred for 6 hours. The reaction solution was extracted with ether and the extract was dried and concentrated. The resulting crude product was purified by column chromatography to obtain 23.1 g of the objective ester compound of the following formula. (yield: 76%) ##STR98##
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC(OC)=O)C=CC=1OC.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[C:32]([C:34]1[CH:43]=[CH:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=1)=O.C(OP([CH2:57][C:58]#[N:59])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)=[CH:57][C:58]#[N:59])[CH:44]=[CH:45][C:46]=1[O:47][CH3:48]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc3ccccc3c2)cc1OC
Agent: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc3ccccc3c2)cc1OC
Yield: 92.9 %

Procedure:
3-(3,4-Dimethoxyphenyl)-3-naphth-2-ylacrylontrile was prepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using 2-(3,4-dimethoxybenzoyl)naphthalene (2.9 g, 10 mmol), diethylcyanomethylphosphonate (1.8 mL, 11 mmol) and lithium hexamethyldisilazide (8.5 mL, 11 mmol 1.3M) with a reaction time of 1 hour at reflux. The crude product was purified by chromatography (silica gel, methylene chloride) to afford 2.93 g (93%) of a mixture of the E and Z isomers as a white solid: mp 121–123° C.; 1H NMR (CDCl3) δ 8.11–6.78 (m, 20H), 5.76 (s, 1H), 5.75 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H); 13C NMR (CDCl3) δ 162.7, 162.7, 151.2, 150.6, 148.9, 148.7, 136.6, 134.5, 134.0, 133.8, 132.8, 131.5, 129.7, 129.4, 129.0, 128.6, 128.6, 128.3, 128.1, 127.7, 127.7, 127.4, 127.2, 126.8, 126.6, 125.4, 123.2, 122.2, 118.4, 118.2, 112.7, 111.1, 110.8, 93.9, 93.4, 56.0, 56.0, 55.9; Anal. Calcd for C21H17NO2. Theoretical: C, 79.98; H 5.43; N, 4.44. Found: C, 79.90; H, 5.65; N, 4.46.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:13][CH:14]([OH:16])[CH3:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])[CH3:2].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18]>Cl.O1CCOCC1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH:24]([C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[O:16][CH:14]([CH3:15])[CH2:13]2)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CC(C)O)cc1NC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1NC(C)=O)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Yield: 57.2 %

Procedure:
To a solution of compound 13 (0.23 g, 1.03 mmol) in 15 ml of HCl solution in 1,4-dioxane was added 4-nitrobenzaldehyde (0.16 g, 1.06 mmol) in one portion. After refluxing for 5 hours, the solvent was removed under reduced pressure. The residue was washed with cold ethanol three times, and dried to give the product 14 (0.21 g, 66%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[O:14][C:11]2=[N:12][CH:13]=1.B([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:30]([OH:32])=[O:31])(O)O>CN(C=O)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>[Cl:36][C:35]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=1[C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[O:14][C:11]2=[N:12][CH:13]=1
Reactant: O=C(O)c1ccc(Cl)c(B(O)O)c1
Reactant: Fc1ccc(-c2cc3cc(Br)cnc3o2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(Cl)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Temperature: 180 °C
Yield: 46.8 %

Procedure:
Cesium carbonate (167 mg, 0.514 mmol) was added to Pd(Ph3P)4 (40 mg, 0.034 mmol), 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (100 mg, 0.342 mmol), 3-borono-4-chlorobenzoic acid (103 mg, 0.514 mmol) in DMF (3 mL) and Water (0.3 mL) at room temperature. The mixture was degassed 3× and the reaction was heated to 180° C. in the microwave for 10 min. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was triturated with MeOH to give the expected product 4-chloro-3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (59 mg, 0.160 mmol, 47% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.22 (1H, br. s.), 8.36 (1H, d, J=2.26 Hz), 8.25 (1H, d, J=2.26 Hz), 8.03-8.11 (2H, m), 7.97-8.02 (2H, m), 7.77 (1H, d, J=7.78 Hz), 7.55 (1H, s), 7.41 (2H, t, J=8.78 Hz). LC-MS retention time: 1.15 min; m/z (MH+): 368. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([S:15][CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[CH2:6]Cl.[C-:17]#[N:18].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:17]#[N:18])[CH:8]=[C:9]([S:15][CH3:16])[C:10]=1[O:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCOc1c(OC)cc(CCl)cc1SC
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1c(OC)cc(CC#N)cc1SC
Reaction time: 48 h
Yield: 94 %

Procedure:
To 16 g of 3-methoxy-5-methylthio-4-propoxybenzyl chloride in 100 ml of dry DMF was added 5 g (0.10 mole) sodium cyanide. The mixture was stirred for about 48 hours at rom temperature under N2. The solution was filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography to yield 14.5 g of 3-methoxy-5-methylthio-4-propoxyphenyl acetonitrile as an oil. (95% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@@:8]2([CH3:21])[NH:17][C:16](=O)[C:11]3([CH2:15][CH:14]=[CH:13][CH2:12]3)[S:10](=[O:20])(=[O:19])[CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@@:8]2([CH3:21])[NH:17][C:16](=[S:32])[C:11]3([CH2:15][CH:14]=[CH:13][CH2:12]3)[S:10](=[O:20])(=[O:19])[CH2:9]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CC=CC2)C(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CC=CC2)C(=S)N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of (R)-8-(5-bromo-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-2-en-10-one (410 mg, 1.06 mmol, Eq: 1.00) and Lawesson's reagent (427 mg, 1.06 mmol, Eq: 1.00) in dioxane (10 ml) was stirred at 80° C. for 2 hours. More Lawesson's reagent (427 mg, 1.06 mmol, Eq: 1.00) was added and stirring continued at 85° C. for 16 hours. More Lawesson's reagent (427 mg, 1.06 mmol, Eq: 1.00) was added and stirring continued at 95° C. for 6 hours. The reaction mixture was poured into sat. NaHCO3-solution and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give light yellow oil. The residue was chromatographed on 20 g silica gel with dichloromethane/heptane to give (R)-8-(5-bromo-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-2-en-10-thione (305 mg, 754 μmol, 71.4% yield) as a light yellow foam. MS (ISP): m/z=404.1 [M+H]+ and 406.2 [M+2+H]+.
Reaction SMILES: [F:1][C:2]1[N:3]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[C:5](C=O)[N:6]=1.Cl.[CH3:29][O:30][NH2:31].N1C=CC=CC=1>CCO>[F:1][C:2]1[N:3]([C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:4][C:5](=[N:31][O:30][CH3:29])[N:6]=1
Reactant: CON
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C(F)=N1

Procedure:
2-Fluoro-4-formyl-1-triphenylmethylimidazole was reacted in EtOH with O-methylhydroxylamine hydrochloride and pyridine, to give 2-fluoro-4-methoxyimino-1-triphenylmethylimidazole, as a 3:1 mixture of geometrical isomers, having the following n.m.r. in CDCl3 : 3.87 (s, 0.75H); 3.93 (s, 0.25H); 7.05-7.5 (m, 17H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27]CO[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC([C:54]([O:56][CH3:57])=[O:55])C1>>[CH3:57][O:56][C:54]([CH:24]1[CH2:27][N:22]([C:7]2[C:8]3[N:13]=[N:12][N:11]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:9]=3[N:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[N:6]=2)[CH2:23]1)=[O:55]
Reactant: COC(=O)C1CNC1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: COC(=O)C1CN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and methyl azetidine-3-carboxylate. MS(m/e): 415.3 (MH+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:16]([NH:18][C:19]1([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:28][CH2:29][CH2:30][S:31][CH3:32])[C:20]1=[O:33])=[O:17]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:16]([NH:18][C:19]1([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([CH2:28][CH2:29][CH2:30][S:31]([CH3:32])=[O:9])[C:20]1=[O:33])=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CCCSC)c2ccccc21
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCC1(NC(=O)c2ccc(Cl)c(Cl)c2)C(=O)N(CCCS(C)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.22 g of m-chloroperbenzoic acid was added to a stirred solution of 2.05 g of ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-1-(3-methylthiopropyl)-2-oxo-1H-indol-3-yl]propionate in chloroform (80 ml) under ice cooling. The mixture was stirred at room temperature overnight. After removal of solvent, the residue was extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to dryness under reduced pressure. The residue was separated by silica gel column chromatography [ethyl acetate-hexane (1:2) to chloroform-methanol (20:1)] to afford ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-1-(3-methylsulfinylpropyl)-2-oxo-1H-indol-3-yl]propionate (a sulfinyl compound, Rf: small) and ethyl 3-[3-(3,4-dichlorobenzoylamino)-2,3-dihydro-1-(3-methylsulfonylpropyl)-2-oxo-1H-indol-3-yl]propionate (a sulfonyl compound, Rf: large). The sulfinyl compound was recrystallized from ethyl acetate-isopropyl ether to afford 1.07 g of the sulfinyl compound as colorless prism. Melting point: 154° to 159° C., IR (Nujol) (cm-1): 3220, 1720, 1655, 1610, FAB-MS (m/z): 527 & 525 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12](=[O:14])[CH3:13])[C:6]=2[C:5](=[O:15])[NH:4][C:3]1=[O:16].Cl[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23].S(=O)(=O)(O)O>>[OH:24][CH:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:4]1[C:5](=[O:15])[C:6]2[N:7]([CH2:11][C:12](=[O:14])[CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:16]
Reactant: CC(O)CCCCCl
Reactant: CC(=O)Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=S(=O)(O)O
Product: CC(=O)Cn1cnc2c1c(=O)n(CCCCC(C)O)c(=O)n2C

Procedure:
This compound was prepared starting from 3-methyl-7-(2-oxopropyl)-xanthine by alkylation with 1-chlorohexan-5-ol as described in Example 1; however, without the sulfuric acid treatment.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.Cl.[N:33]1([CH:38]2[CH2:42][CH2:41][NH:40][CH2:39]2)[CH:37]=[CH:36][N:35]=[N:34]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:40]4[CH2:41][CH2:42][CH:38]([N:33]5[CH:37]=[CH:36][N:35]=[N:34]5)[CH2:39]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 7580 °C

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (138.5 mg, 0.486 mmol), DBU (190 mg, 1.25 mmol), and 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride (216 mg, 1.25 mmol) in pyridine (8 ml) was heated for 20 h at 7580° C. and then pyridine was removed under vacuum. The residue was diluted with acetonitrile. The precipitated solid was washed with acetonitrile, ether and dried at 40° C. Yield: 65 mg (33%), m.p. 244°-246° C. (dec). 1H NMR (TFA) δ: 1.5 (m, 4H), 2.8 (m, 2H), 4.5 (m, 4H), 4.75 (bs, 1H), 5.8 (bs, 1H), 8.15 (d, 1H), 8.6 (s, 1H), 8.7 (s, 1H), 9.25 (s, 1H).
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:38]=[CH:37][C:22]([CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:21][CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:24]1([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=4[CH2:3][C:2]([NH2:1])=[O:43])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=3)=[CH:38][CH:37]=2)[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I98) (34 mg, 0.057 mmol) was dissolved in DCM (4 mL) and TFA (0.4 mL) was added. The resulting mixture was stirred for 16 hours at room temperature then concentrated under reduced pressure. The residue was suspended in 10% aqueous NaOH (2 mL) and brine (3 mL) then extracted with ethyl acetate (4×5 mL). The combined organic phases were washed with brine, dried (sodium sulphate) and evaporated to dryness. The residue was triturated with diethyl ether to give the title compound (25) (27.5 mg, 98%) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.17 (s, 1H), 8.66 (s, 1H), 7.72-7.66 (m, 2H), 726-7.20 (m, 3H), 7.20-7.13 (m, 3H), 6.90 (s, 1H), 3.49 (s, 2H), 3.37 (s, 2H), 3.14-2.98 (m, 4H), 2.67 (t, J=4.7 Hz, 4H), 2.26 (s, 4H). LCMS Method C: rt 4.52 min; m/z 499.1 [M+H]+; m/z 497.1 [M−H]−.