Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:10]2[N:23]([CH3:24])[C:13]3=[N:14][CH:15]=[C:16]([S:18][C:19]([F:22])([F:21])[F:20])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:33])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[C:5]([C:10]2[N:23]([CH3:24])[C:13]3=[N:14][CH:15]=[C:16]([S:18][C:19]([F:22])([F:20])[F:21])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:33])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cccnc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1cccnc1-c1nc2cc(SC(F)(F)F)cnc2n1C
Yield: 42.7 %

Procedure:
A mixture of 2-(3-ethylsulfanyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (200 mg), m-chloroperbenzoic acid (purity: not less than 65%) (230 mg) and chloroform (10 ml) was stirred while ice-cooling for 5 hours. To the reaction mixture was poured saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-ethylsulfinyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (89 mg), which is hereinafter referred to as “the present compound 14”, and 2-(3-ethylsulfonyl-pyridin-2-yl)-3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine (130 mg), which is hereinafter referred to as “the present compound 15”.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:4](=[O:20])[N:3]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[F:8][C:7]1[C:2](=[NH:1])[N:3]([CH2:26][C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)[C:4](=[O:20])[N:5]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)(=[O:10])=[O:11])[CH:6]=1
Reactant: OCc1cccs1
Reactant: COc1ccc(S(=O)(=O)n2cc(F)c(N)nc2=O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(F)c(=N)n(Cc3cccs3)c2=O)cc1
Temperature: 25 °C

Procedure:
To a 25 mL vial with magnetic stirring were added 4-amino-5-fluoro-1-((4-methoxyphenyl)sulfonyl)pyrimidin-2(1H)-one (150 mg, 0.501 mmol), thiophen-2-ylmethanol (172 mg, 1.504 mmol), triphenylphosphine (Ph3P; 394 mg, 1.504 mmol) and dry tetrahydrofuran (THF; 4.204 mL). The reaction mixture was placed under nitrogen (N2) atmosphere and cooled to ice-bath temperature. After cooling 10 minutes (min), diethylazodicarboxylate (DEAD; 0.238 mL, 1.504 mmol) was added dropwise and the mixture was allowed to warm to room temperature overnight. The reaction mixture was evaporated to dryness. The crude residue was purified on SiO2 (EtOAc/hexanes gradient) to provide the title compound as a yellow-white wax (146 mg, 73.8%): 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=9.1 Hz, 2H), 7.84 (d, J=1.8 Hz, 1H), 7.67 (d, J=5.5 Hz, 1H), 7.17 (dd, J=5.2, 1.2 Hz, 1H), 7.13 (d, J=3.5 Hz, 1H), 7.02 (d, J=9.1 Hz, 2H), 6.88 (dd, J=5.1, 3.5 Hz, 1H), 5.28 (s, 2H), 3.91 (s, 3H);. UV (CH2Cl2) λmax: 259 nm; ESIMS m/z 396.5 ([M+H]+). Step 2: 5-Fluoro-4-imino-3-(thiophen-2-ylmethyl)-3,4-dihydropyrimidin-2(1H)-one (2). To a magnetically stirred mixture of 5-fluoro-4-imino-1-((4-methoxyphenyl)sulfonyl)-3-(thiophen-2-ylmethyl)-3,4-dihydropyrimidin-2(1H)-one (130 mg, 0.329 mmol) in dry TFA (2.529 mL) was added dimethyl sulfide (0.122 mL, 1.64 mmol) in a dry 25 mL vial under Argon atmosphere. The reaction mixture was stirred at 23° C. for 16 h. The reaction mixture was evaporated to dryness and the crude residue was diluted with ice-water and aqueous saturated sodium bicarbonate solution and extracted with CH2Cl2 (2×). The layers were separated, the combined organic extracts were evaporated, and the crude residue was purified on SiO2 (EtOAc/CH2Cl2 gradient) to afford the title compound as an off-white wax (15 mg, 19.2%): 1H NMR (400 MHz, CDCl3+D2O) δ 7.22 (br d, J=3.4 Hz, 1H), 7.21 (dd, J=5.2, 1.1 Hz, 1H), 6.94 (dd, J=5.1, 3.5 Hz, 1H), 6.72 (d, J=4.3 Hz, 1H), 5.38 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 152.48 (d, J=30.5 Hz), 151.06 (s), 138.17 (s), 137.82 (s), 128.48 (s), 126.30 (s), 125.76 (s), 115.39 (d, J=35.1 Hz), 39.30 (s); ESIMS m/z 226.3 ([M+H]+), 224.4 ([M−H]−).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.[CH:18]([NH2:21])([CH3:20])[CH3:19]>>[NH2:6][O:5][CH2:4][C:3]([NH:21][CH:18]([CH3:20])[CH3:19])=[O:2]
Reactant: COC(=O)CON1C(=O)c2ccccc2C1=O
Reactant: CC(C)N
Product: CC(C)NC(=O)CON

Procedure:
Using (1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-acetic acid methyl ester obtained in Step A of Example 19 and isopropylamine as an amine, synthesis was performed according to the procedure described in Step A of Example 20 to give 2-aminooxy-N-isopropyl-acetamide.
Reaction SMILES: [CH:1]1([C@H:4]([N:7]2[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[C:8]2=[O:15])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[N:22]([C:9]1[C:8](=[O:15])[N:7]([C@@H:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][CH3:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH2:21][CH2:20]2
Reactant: Clc1cc(Br)cc2c1NCC2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-[(1R)-1-cyclopropylpropyl]-3,5-dichloro-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 154–156° C.; 1H NMR (300 MHz, CDCl3) δ 7.31 (d, J=1.9 Hz, 1 H), 7.24 (d, J=1.8 Hz, 1 H), 7.01 (s, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 4.05 (app. q, J=8.2 Hz, 1 H), 3.14 (t, J=7.9 Hz, 2 H), 1.96–1.83 (m, 2 H), 1.07–1.00 (m, 1 H), 0.94 (t, J=7.3 Hz, 3 H), 0.81–0.75 (m, 1 H), 0.55–0.48 (m, 2 H), 0.35–0.28 (m, 1 H); HRMS (ESI) calcd for C18H19N3OBrCl2 (M+H)+: 442.0089; Found m/z 442.0102.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
To a suspension of NaH (0.395 g, 9.87 mmol, 60% in mineral oil) in DMF (20 mL) was added methyl 3-hydroxybenzoate (1.0 g, 6.58 mmol). After stirring for 15 min at room temperature, benzyl bromide (1.1 g, 6.58 mmol) was added. After stirring at room temperature for 3 h, the solution was partitioned between ethyl acetate and water. The organic layer was washed with water (2×75 mL), saturated aqueous sodium bicarbonate, and brine, then dried (MgSO4), filtered and concentrated to yield an off-white solid (1.013 g, 4.2 mmol). 1H NMR (400 MHz, CDCl3) δ 7.67 (m, 2H), 7.48-7.34 (m. 6H), 7.19 (m, 1H), 5.12 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[N:5][C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3]1.[Cl-].[CH3:15][C:16]1[N:21]2[N:22]=[C:23]([CH2:25][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:24]=[C:20]2[C:19]([CH3:45])=[CH:18][N:17]=1>>[CH3:15][C:16]1[N:21]2[N:22]=[C:23](/[CH:25]=[CH:7]/[C:6]3[N:2]([CH3:1])[N:3]=[C:4]([N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)[N:5]=3)[N:24]=[C:20]2[C:19]([CH3:45])=[CH:18][N:17]=1
Reactant: Cc1cnc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: Cn1nc(N2CCCC2)nc1C=O
Agent: [Cl-]
Product: Cc1cnc(C)n2nc(/C=C/c3nc(N4CCCC4)nn3C)nc12
Yield: 50.1 %

Procedure:
Was prepared in the same manner as described in Example 81a) using 1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole-5-carbaldehyde (30 mg, 166 μmol, Eq: 1.00) and ((5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (76.4 mg, 166 μmol, Eq: 1.00) (prepared as described in WO2011150156, pp 123-125, Expl. 24 g) affording 5,8-dimethyl-2-[(E)-2-(2-methyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-vinyl]-[1,2,4]triazolo[1,5-c]pyrimidine (27 mg, 50.0%) as light yellow amorphous. MS: m/z=325.6 (M+H+)
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][C:8]1=[O:17])[CH:4]([CH3:6])[CH3:5]>CO.C1COCC1>[CH2:3]([N:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]1=[O:17])[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)c1ccn(CC(C)C)c(=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cn1ccc(C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 81 %

Procedure:
To a mixed solution was added a 1M aqueous NaOH solution (4.1 ml) of methyl 1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylate (430 mg) in CH3OH-THF (4 ml-3 ml). The solution was stirred at room temperature for 10 hours, and then concentrated under reduced pressure, and water (10 ml) was added, and subsequently 1M HCl was added thereto until pH becomes 3. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (325 mg) as white powders.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)([O-])=O.C1COCC1.Cl>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(OCc2cc(Cl)ccc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2cc(Cl)ccc2N)cc1
Reaction time: 13 h
Yield: 100.4 %

Procedure:
A mixture of methyl 4-(2-nitro-5-chlorophenylmethoxy)benzoate (460 mg; prepared in Reference Example 9.), THF (10 ml), water (3 ml), 1N HCl (0.4 ml) and iron powder (500 mg) was stirred for 13 hours. The reaction mixture was filtered. The filtrate was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane-AcOEt) to give the title compound (419 mg) having the following physical data.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:18][CH2:19][C@@H:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=1)[OH:21]>>[OH:21][C@H:20]([C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=1)[CH2:19][NH:18][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C(O)Cc1ccc(N2CCC(=O)CC2)cc1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from [4-(4-oxo-piperidine-1-yl)-phenyl]-acetic acid (which was obtained in Example 149) and N-[5-(2-amino-(1 R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a pale yellowish solid; mp >140° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.25-1.40 (m, 2H), 1.75-1.95 (m, 2H), 2.50-3.60 (m, 7H), 2.88 (s, 3H), 3.16 (s, 2H), 4.47 (dd, J=8.0, 4.1 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 6.84 (d, J=8.3 Hz, 2H), 6.95 (dd, J=8.2, 1.7 Hz, 1H), 7.05 (d, J=8.3 Hz, 2H), 7.16 (d, J=1.7 Hz, 1H); MS (ES) m/z: 464.1 (MH+); HRMS Calcd. for C22H28N3O6S(M−H)−: 462.1704. Found: 462.1696.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][CH:17]3[CH2:19][CH2:18]3)(=[O:15])=[O:14])=[C:9]2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:28])C(=O)C1.O>C1COCC1>[Br:28][C:12]1[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:9]([CH3:20])=[C:10]([S:13]([NH:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH:11]=1
Reactant: Cc1c(S(=O)(=O)NC2CC2)ccn1CC1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(S(=O)(=O)NC2CC2)cc(Br)n1CC1CCCCC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of compound 3c (3.0 g, 10.0 mmol) in THF (80 mL) at −78° C. was added a solution of NBS (1.78 g, 10.0 mmol) in THF (50 mL) and the solution was stirred for 2 h at −78° C. Water was added and the solution was extracted with EA twice. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified CC (EA/PE=1/5) to give compound 3d (3.2 g, 85%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[O:10]1CCC[CH2:11]1>>[F:8][C:4]1[C:3]2[O:9][C:11](=[O:10])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C1CCOC1
Reactant: Nc1cccc(F)c1O
Product: O=c1[nH]c2cccc(F)c2o1
Temperature: 25 °C

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, 1,1-carbonyldiimidazole (15.6 g, 96 mmol) is added to a solution of 2-amino-6-fluorophenol 1 (4 g, 32 mmol) in 100 ml of anhydrous tetrahydrofuran at room temperature. The solution is refluxed for 1 h, cooled down to room temperature and concentrated in vacuo. The crude reaction mixture is purified by chromatography on silicagel (n-hexane/AcOEt:1/1 (v/v)) to afford 7-fluoro-1,3-benzoxazol-2(3H)-one 2.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].Cl[C:8]1[N:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:10]2[C:15]([C:16]=1[CH:17]=O)=[CH:14][CH:13]=[CH:12][CH:11]=2.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[C:2]([C:3]([O:5][CH3:6])=[O:4])[S:1][C:8]1=2
Reactant: COC(=O)CS
Reactant: COCCOCn1c(Cl)c(C=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COCCOCn1c2ccccc2c2cc(C(=O)OC)sc21
Reaction time: 8 h

Procedure:
400 μl of methyl 2-mercaptoacetate was added to a slurry of 1 g of (78) and 1.1 g of K2CO3 in 10 ml of MeOH. The reaction was stirred overnight, and then 20 ml of water was added. The mixture was extracted with EtOAc, and the organic layer washed with water, dried and evaporated to give (79) as a yellow oil. Yield 880 mg. 1H-NMR (ppm): 8.1(s, 1H); 7.8(d, 1H); 7.5(d, 1H); 7.3(m, 2H); 5.6(s, 2H); 3.9(s, 3H); 3.5(m, 4H); 3.35(s, 3H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[C:9]12([NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[NH:7]1)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: Nc1ccccc1N
Reactant: O=C1CCCCC1
Solvent: O
Product: c1ccc2c(c1)NC1(CCCCC1)N2
Yield: 59.5 %

Procedure:
In a procedure similar to that described by H. Suschitszky in Croatica Chemica Acta, 59, 57-77 (1986), o-phenylenediamine (108 g, 1.0 mol) was dissolved in 1 liter hot water on a steam bath. With vigorous stirring and heating, cyclohexanone (98 g, 1.0 mol) was added in a rapid stream. After 5 minutes a brown gum formed; after 15 minutes a solid resulted. Stirring was continued for a total of 35 minutes. The slurry was cooled in an ice bath and then filtered to yield 112 g (59.5%) 1,3-dihydrobenzimidazole-2-spirocyclohexane. To a stirred solution of this compound (50 g, 0.266 mol) in 1 liter dichloromethane chloride was added, in several portions, 100 g MnO2. The resulting slurry was stirred vigorously for 30 minutes and filtered. The solids were washed with dichloromethane and the filtrate evaporated to obtain an oil. The oil was dissolved in 200 ml, ligroin, and the solution cooled to -10° C. The resulting solid was filtered to yield 46 g (93%) 2H-benzimidazole-2 spirocyclohexane. A solution of 2 chloroethyl methyl sulfide (19.8 g, 0.20 mol) and thiourea (15.2 g, 0.20 mol) in 50 ml absolute alcohol was refluxed for 6 hours. To this was added a solution of KOH (22.4 g, 0.40 mol) in 100 ml methanol, and the resulting slurry refluxed for 45 minutes. After cooling to 30° , 37.2 g (0.20 mol) of freshly prepared 2H-benzimidazole-2-spirocyclohexane was added in portions. The mixture was stirred at room temperature for 10 minutes and then at reflux for 2 minutes. After cooling, the mixture was evaporated to a thick slurry; 100 ml dichloromethane was added and the mixture evaporated. This was repeated and the residue treated with 100 ml water and 200 ml dichloromethane. The organic layer was separated, washed with water, dried over MgSO4, filtered, and evaporated. The residue was chromatographed through silica gel using an increasingly polar mixture of dichloromethane and acetonitrile. Product fractions were combined and evaporated to give 7.0 g 5'-(2-methylthioethylthio) 1',2'-phenylenediamine. A stirred solution of the phenylenediamine (5.0 g, 0.027 mol) in 50 ml acetic acid was treated with sodium nitrite (2.6 g, 0.037 mol), in 5 ml water, over 30 seconds at room temperature. The mixture was stirred for 15 minutes and then evaporated. The residue was treated with 50 ml water and 50 ml dichloromethane. The organic layer was dried over MgSO4, filtered, and evaporated. Solid was chromatographed through silica gel using an increasingly polar mixture of dichloromethane chloride and acetone. The isolated product was recrystallized from ethyl acetate to yield 3.2 g (62%) 6'-(2-methyl thioethylthio)benzotriazole, I-139.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[C:33]#[N:34]>>[C:33]([C:32]1[CH:31]=[C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)[CH:37]=[CH:36][CH:35]=1)#[N:34]
Reactant: N#Cc1cccc(Br)c1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (359 mg, 0.92 mmol) is coupled to 3-bromobenzonitrile (200 mg, 1.10 mmol) using Method B to give the title compound.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[S:23][C:11]2[N:12]=[C:13]([NH2:22])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=1)=[O:7])C>C(O)C.O>[NH2:22][C:13]1[N:14]=[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[S:23][C:11]=2[N:12]=1
Reactant: CCOC(=O)c1cc2c(-c3ccccc3)nc(N)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccccc2)c2cc(C(=O)O)sc2n1
Temperature: 25 °C

Procedure:
Sodium Hydroxide (0.66 g; 16.5 mmol) was added to a suspension of 2-amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 1) (1.00 g; 3.34 mmol) in ethanol (20 ml) and water (2 ml). The mixture was heated at reflux for 1 hour (affording a homogeneous pale-yellow solution) and allowed to cool to ambient temperature. Solvents were removed in vacuo and the solid residue was dissolved in water (30 mL) and cooled with ice-water bath. The mixture was stirred and adjusted to pH 1-2 by drop-wise addition of concentrated Hydrochloric acid. The resulting precipitate was filtered, washed with water, then ethanol and finally diethyl ether. The off-white product was dried in vacuo to afford 2-amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid as a colourless solid (0.784 g; 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:8][NH:9][C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[N:8][N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][C:21]([F:20])([F:32])[F:33])[CH:24]=2)[C:10]=1[CH:11]1[CH2:12][CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C1CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Yield: 23 %

Procedure:
In analogy to the procedure described in Example 160C], 5-cyclopropyl-3-pyridin-4-yl-1H-pyrazole-4-carboxylic acid ethyl ester and 3-(trifluoromethoxy)benzeneboronic acid gave the title compound as a colorless oil (23%). MS: 418.3 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1>>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:14])[N:20]=1)[C:7](=[O:13])[NH:8]2
Reactant: Cc1cccc(C=O)n1
Reactant: O=C1Cc2c(CCO)cccc2N1
Product: Cc1cccc(C=C2C(=O)Nc3cccc(CCO)c32)n1

Procedure:
4-(2-Hydroxyethyl)-1,3-dihydroindol-2-one (89 mg, 0.5 mmol) was condensed with 6-methyl-2-pyridinecarbaldehyde (61 mg, 0.5 mmol) using method B to give 4-(2-hydroxyethyl)-3-(6-methylpyridin-2-ylmethylene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH2:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([CH2:12][CH2:13][CH3:14])[NH:10][N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1[nH]ncc1-c1ccccc1
Solvent: CC#N
Product: CCCc1[nH]nc(Br)c1-c1ccccc1
Temperature: 82 °C
Reaction time: 16 h
Yield: 15.2 %

Procedure:
To a solution of 4-phenyl-5-propyl-1H-pyrazole (1.43 g, 7.68 mmol) in acetonitrile (38.0 mL), was added N-bromosuccinimide (1.50 g, 8.45 mmol). The reaction mixture was stirred at 82° C. After 16 h, the reaction mixture was quenched with 2 M Na2CO3 (aq.) to pH 12 and the organics were separated. The aqueous layer was extracted with EtOAc (3×). The combined organics were dried over MgSO4, filtered and concentrated to give a dark oil. This oil was purified by silica gel flash chromatography to give the title compound as a yellow oil (0.310 g). LCMS m/z=265.1, 267.1 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1>C(OCC)C>[CH3:8][C:9]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]1[N:17]([C:1](=[O:3])[CH3:2])[CH2:16][CH2:15][N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Solvent: CCOCC
Product: CC(=O)N1CCN=C1COc1cccc(C)c1C
Reaction time: 2 h

Procedure:
A solution of acetic anhydride (3.0 ml; 0.032 moles) in diethyl ether (10 ml) was added dropwise, during 10 minutes, to a stirred suspension of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (6.12 g; 0.030 mole) (prepared from O-ethyl-2,3-dimethylphenoxyacetimidate and ethylene diamine) in diethyl ether (100 ml) cooling the mixture to keep its temperature below 20° C. After stirring for 2 hours the reaction mixture was filtered and the precipitate recrystallised from acetone to yield white crystals of 2-(2,3-dimethylphenoxymethyl)-1-acetyl-2-imidazoline, m.p. 127°-130° C. Analysis: Calculated C 68.27, H 7.37, N 11.37% Found: C 68.13, H 7.44, N 11.13%.