Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N.[C:17]1([N:23]2[CH:27]=[C:26](I)[N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][C:38](=O)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>O1CCOCC1.[Cu]I.O>[C:17]1([N:23]2[CH:27]=[C:26]([N:39]3[CH2:38][CH2:37][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:41][CH2:40]3)[N:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Ic1cn(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cn(-c3ccccc3)nn2)CC1
Temperature: 90 °C
Yield: 16.5 %

Procedure:
In a nitrogen atmosphere, 200 mg of tripotassium phosphate, 5 mg of copper(I) iodide and 0.1 ml of trans-1,2-diaminocyclohexane were successively added to a solution of 50 mg of 1-phenyl-4-iodo-1H-[1,2,3]triazole and 80 mg of 4-(tert-butyloxycarbonyl)piperazin-2-one in 2 ml of dioxane and the mixture was stirred for one night at 90° C. After addition of water, the product was extracted with ethyl acetate and the organic layer washed with water and dried over sodium sulfate. A borane methyl sulfide complex (0.1 ml) was added to the residue after evaporation of the solvent in vacuo and the mixture was stirred at room temperature for 1 hour. After addition of pyridine, the residue prepared by evaporation in vacuo was purified by a preparative thin-layer silica gel chromatography (hexane:ethyl acetate=3:1) to give 10 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[C:10]2[O:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2cccc(C)c2o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2cccc(CBr)c2o1

Procedure:
A solution of 7.38 g of methyl 7-methylbenzofuran-2-carboxylate in 300 ml of carbon tetrachloride is admixed at 70° C. with 6.96 g of N-bromosuccinimide and 1.42 g of dibenzoyl peroxide, heated to reflux with stirring and kept at reflux for 2 hours (succinimide crystallizes out). The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a red-orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.60 (dichloromethane); Rt=17.83 (II).
Reaction SMILES: [CH2:1]([C:4]1([CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[CH:6]=[C:5]1[O:15]C)[CH:2]=[CH2:3].[OH-].[Na+].Cl>CO>[CH2:1]([C:4]1([CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][C:5]1=[O:15])[CH:2]=[CH2:3]
Reactant: C=CCC1(C)C(OC)=CC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCC1(C)C(=O)C=C(O)c2ccccc21
Yield: 77.9 %

Procedure:
To a solution of Example 123C (2.69 g, 11.8 mmol) in methanol (75 ml) was added a solution of 1N aqueous sodium hydroxide (75 mL) and the resultant mixture heated to reflux for 16 hours. After cooling to room temperature a solution of 1N aqueous hydrochloride (80 mL) was added to make the mixture acidic which caused a precipitate to form. This solid was collected by filtration, washed with water (5×20 mL) and dried in a vacuum oven to provide the title compound as a light brown solid (1.97 g, 78%). 1H NMR (300 MHz, DMSO-d6): δ 1.44 (s, 3 H), 2.65 (dd, J=13.2, 7.0 Hz, 1 H), 2.80 (dd, J=13.6, 7.0 Hz, 1 H), 4.72 (m, 2 H), 5.08 m, 1 H), 5.66 (s, 1 H), 7.36 (dt, J=7.2, 1.3 Hz, 1 H), 7.56 m, 1 H), 7.65 (d, J=7.7 Hz, 1H), 7.89 (d, J=7.7 Hz, 1 H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[N:8]1[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=[C:9]1[CH2:20]Cl.[CH3:22][S:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[N:8]1[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=[C:9]1[CH2:20][N:26]([S:23]([CH3:22])(=[O:24])=[O:25])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Reactant: ClCc1nc2cnc3ccsc3c2n1[C@H]1CC2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1nc2cnc3ccsc3c2n1[C@H]1CC2CCC1C2)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[(2S)-bicyclo[2.2.1]hept-2-yl]-2-(chloromethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (0.10 g, 0.31 mmol) dissolved in N,N-dimethylformamide (1 mL) was added tert-butyl (methylsulfonyl)carbamate (0.092 g, 0.47 mmol) and potassium carbonate (0.087 g, 0.63 mmol). The mixture was stirred at 50° C. overnight, then diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give crude tert-butyl ({1-[(2S)-bicyclo[2.2. l]hept-2-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}methyl)(methylsulfonyl)carbamate. LCMS calculated for C22H29N4O4S2 (M+H)+: m/z=477.2. Found: 477.1. The crude intermediate was treated with trifluoroacetic acid (0.5 mL, 6 mmol) in methylene chloride (0.5 mL) at room temperature for 30 min, then the solvent was removed in vacuo. The residue was re-dissolved in MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (30 mg, 25%). LCMS calculated for C17H21N4O2S2 (M+H)+: m/z=377.1. Found: 377.0.
Reaction SMILES: [NH2:1][C:2]1([CH2:14][OH:15])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.CN.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22]>C1COCC1>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:1][C:2]1([CH2:14][OH:15])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[O:22]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: COc1ccc2c(c1)CCCC2(N)CO
Agent: CN
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCCC2(CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring mixture of 2.0 g (0.00965 mol) of the product of Step C, 976 mg (0.00965 mol) of methylamine in 30 mL of THF at 0° C. was added dropwise a solution of 2,6-difluorobenzoylchloride in 15 mL of THF. The reaction mixture was stirred at ambient temperature for 30 minutes. The precipitated triethylamine hydrochloride was filtered off and the filtrate concentrated. It was purified by passing through a silica gel column eluting with EtOAc:Hexane (2:3) to afford a white solid: mp 174°-175° C. 1H NMR (CDCl3) d 7.30 (m, 2H), 6.90 (t, 2H), 6.85 (dd, 1H), 6.60 (d, 1H), 6.35 (broad s, 1H), 4.80 (dd, 1H), 4.20 (dd, 1H), 3.77 (s, 3H), 3.75 (d, 2H), 2.80 (m, 2H), 2.30 (m, 2H), 1.90 (m, 2H).
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.[Br:29][C:30]1[CH:31]=[C:32]([CH2:36][C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=1.CI>C1COCC1>[Br:29][C:30]1[CH:31]=[C:32]([CH:36]([CH3:2])[C:37]([OH:39])=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C(=O)O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of LDA in THF/n-heptane/ethylbenzene (1.8M, 23.25 mL, 41.85 mmol) is cooled down to −78° C. and added a solution of 3-bromophenylacetic acid [3 g, 13.95 mmol, Intermediate (68)] in THF (7 mL) dropwise over 15 minutes. The mixture is stirred for 1 h at −78° C. and treated dropwise with methyl iodide (6.34 g, 44.64 mmol) over 15 minutes. The reaction mixture is warmed up to room temperature and after stirring overnight, the mixture is quenched with 2 N hydrochloric acid and concentrated to remove THF. The residue is diluted with ether, washed twice with 2 N hydrochloric acid (20 mL) and extracted twice with 10% sodium hydroxide (20 mL). The combined sodium hydroxide extracts are acidified with 6 N hydrochloric acid to pH=1 and extracted three times with ether (50 mL). Combined organic extracts are washed with brine, dried over sodium sulfate and concentrated to obtain 2-(3-bromo-phenyl)-propionic acid [3 g, 100%, Intermediate (69)] as a solid, which is used without further purification. LC/MS: 229 (M+H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH:22]=[CH2:23])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C[O:36]CC1>O.[OH-].[Na+].OO.C(OCC)(=O)C>[Si:1]([O:8][C@H:9]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:12]([CH2:22][CH2:23][OH:36])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=C[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1CCO
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-vinylpiperidine-1-carboxylate (Intermediate 188, 1.39 g) in THF (20 mL) at 0° C. was added 9-BBN (0.5 M, 15 mL). After 45 minutes, the reaction was diluted with water (3 mL), 3 N NaOH (12 mL) and 30% H2O2 (12 mL). After 15 minutes, the reaction was allowed to warm to room temperature. After 30 minutes, the reaction was diluted with ethyl acetate, washed with 1 N HCl, NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. Chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride gave 1.27 g of product.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:11]([CH2:27][CH3:28])=[N:12][N:13]3[C:18]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[CH:17][C:16](Cl)=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.[Pd]>[C:1]1([S:7]([C:10]2[C:11]([CH2:27][CH3:28])=[N:12][N:13]3[C:18]([N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[CH:17][CH:16]=[N:15][C:14]=23)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCc1nn2c(N3CCN(C)CC3)ccnc2c1S(=O)(=O)c1ccccc1
Reaction time: 4 h

Procedure:
0.1 g of Pd/C (10%) was added to a solution of 0.267 g (0.63 mmol) of 3-benzenesulphonyl-5-chloro-2-ethyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine in 40 ml of EtOH and the mixture was hydrogenated at RT for 4 hrs. The reaction mixture was filtered over Dicalite and the filtrate was evaporated. The residue was partitioned between CH2Cl2 and sat. NaHCO3 solution. The aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography of the residue (SiO2CH2Cl2/MeOH 19:1) and crystallization from EtOH yielded 0.2 g (53%) of as pale beige crystals, m.p. 206-207°.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[OH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([OH:28])([CH3:35])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC(C)(O)CC(=O)O
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (68 mg, 79%), MS (ISP) m/z=431.6 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 3-hydroxy-3-methyl-butanoic acid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([S:15](Cl)(=[O:17])=[O:16])=[CH:7]1>O1CCCC1>[C:1]([NH:5][S:15]([C:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:6][CH:7]=1)(=[O:16])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1csc2ccccc12
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1csc2ccccc12
Temperature: 0 °C

Procedure:
To 25 g of tert-butyl amine in 100 ml of dry tetrahydrofuran was added dropwise with cooling 34 g of benzothiophene-3-sulfonyl chloride. The reaction mixture was allowed to come to room temperature and then poured into 200 g of ice. The phases were separated and the organic portion was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue thus obtained melted at 146°-148° after recrystallization from alcohol. It showed an absorption peak by NMR at 1.34 δ (singlet), for tert-butyl and 7.4-8.4 δ (multiplet) for benzothiophene consistent for the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][O:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:15]/[C:14]([O:13][CH3:12])=[O:35])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc2cc[nH]c2c1
Yield: 72.4 %

Procedure:
To a solution of indole-6-carboxaldehyde (499 mg) in tetrahydrofuran (20 mL), methyl(triphenylphosphoranylidene)acetate (2.5 g) was added at room temperature, and then the reaction mixture was subjected to microwave irradiation at 200° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the titled compound (501 mg) as a yellow solid.
Reaction SMILES: N[C@H:2]([CH:7]=O)[CH2:3]CSC.[CH3:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[CH3:19])[C:15](=[O:20])[N:14]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH:13]2[CH2:27][CH2:28][O:29]S(C)(=O)=O.O>C(O)CC>[CH3:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[CH3:19])[C:15](=[O:20])[N:14]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH:13]2[CH2:27][CH2:28][O:29][CH2:3][CH2:2][CH3:7]
Reactant: Cc1cc2c(cc1C)C(CCOS(C)(=O)=O)N(c1cccnc1)C2=O
Reactant: CSCC[C@H](N)C=O
Solvent: O
Solvent: CCCO
Product: CCCOCCC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Temperature: 90 °C
Yield: 26.4 %

Procedure:
Metal sodium (6.4 mg, 0.28 mmol) was stirred with heating in propanol (2 ml) at 110° C. for 1 hr, and 5,6-dimethyl-2-(3-pyridyl)-3-mesyloxyethylisoindolin-1-one (50 mg, 0.14 mmol) was added thereto, followed by stirring with heating at 90° C. for 3 hrs. To the reaction solution was added water, and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:ethyl acetate=1:1) to give 12 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][C:16](=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCO.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][C:16](=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=O)NC2)cc1C1=CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CNC(=O)NC3)cc2C2=CCCCC2)n1
Reaction time: 8 h
Yield: 8 %

Procedure:
4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide (as prepared in the previous step, 14 mg, 0.026 mmol) was dissolved in DCM (1 mL), EtOH (30 μL) and TFA (0.3 mL). The resulting mixture was stirred overnight and concentrated. The residue obtained was subjected to RP-HPLC eluting with 20% to 100% CH3CN in 0.1% TFA/H2O over 20 min on a C18 column to obtain the title compound (1.1 mg, 8%): 1H-NMR (CD3OD/CDCl3; 400 MHz): δ 8.23 (d, 1H, J=8.0 Hz), 7.90 (s, 1H), 7.20 (dd, 1H, J=8.0, 2.2 Hz), 7.09 (d, 1H, J=2.2 Hz), 5.75 (br s, 1H), 3.47 (4H, m), 3.17 (m, 1H), 2.22-2.33 (m, 4H), 1.72-1.83 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H22N6O2, 391.3 (M+H). found 391.2.
Reaction SMILES: Br[C:2]1[N:18]=[C:5]2[CH:6]=[C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[CH:9][N:4]2[N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[N:18]=[C:5]3[CH:6]=[C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[CH:9][N:4]3[N:3]=2)[CH:20]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)Nc1ccn2nc(Br)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccn2nc(-c3cccnc3)nc2c1
Reaction time: 18 h
Yield: 55.1 %

Procedure:
Nitrogen is bubbled for 10 minutes through a mixture of tert-butyl 2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (1.39 g, 4.44 mmol) and pyridin-3-ylboronic acid (818 mg, 6.66 mmol) in dioxane (23.8 ml) and sat. aqueous sodium carbonate sol. (5.94 ml), then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (181 mg, 222 μmol) is added and the resulting mixture is fluxed for 18 hours under nitrogen atmosphere. The residue is diluted with dichloromethane and washed with water; the organic layer is separated, dried with magnesium sulfate and the solvent is removed under reduced pressure. The residue is loaded on silicagel and purified by chromatography on a 50 g silica column using heptane/ethyl acetate 50-100% as eluent affording tert-butyl 2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (762 mg, 55.1%) as a light brown foam. MS: m/z=312.4 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[N:15]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:14]=[CH:13][CH:12]=2)=[C:7]([CH3:24])[N:6]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:5]1=[O:35])([CH3:3])[CH3:2].[I:36]I.[N+]([O-])([O-])=O.[NH4+].[Ce].S([O-])(O)=O.[Na+]>C(#N)C.C(OCC)(=O)C>[I:36][C:12]1[CH:13]=[N:14][N:15]([C:16]2[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=2)[C:11]=1[C:8]1[C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:35])[N:6]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[C:7]=1[CH3:24]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: II
Agent: O=S([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(-c2c(I)cnn2-c2ccc(C#N)cc2)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 153.2 %

Procedure:
To a suspension of 4-(5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 42) (0.82 g) in acetonitrile (15 ml) were added iodine (0.26 g) and cerium ammonium nitrate (0.56 g) and the resulting mixture was stirred at 50° C. for one hour. The reaction mixture was cooled to room temperature, and thereto were added ethyl acetate (50 ml) and 5% aqueous sodium hydrogen sulfite solution (25 ml), and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-iodo-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (0.95 g) as white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O.Br[CH:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[CH:33][CH:32]=1)[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:26]([C:31]2[CH:32]=[CH:33][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[CH:35][CH:36]=2)[C:27]([O:29][CH3:30])=[O:28])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 3.75 g of 4-t-butylphenol in 40 ml of tetrahydrofuran was added 0.88 g of sodium hydride (oil dispersion). After stirring 30 minutes, 1 ml of hexamethylphosphoramide was added and a solution of 7.36 g of methyl α-bromo-α-[p-(p-nitrophenoxy)phenyl]acetate in 25 ml of tetrahydrofuran was added over a period of 30 minutes. The mixture was stirred at room temperature for 30 minutes and refluxed for 30 minutes. The mixture was poured into 130 ml of ice-water and extracted with dichloromethane. The extracts were washed with saturated sodium chloride solution and chilled. Filtration gave 2.1 g of product. The filtrate was concentrated to an oil under vacuum and chromatographed over silica gel (eluent-CCl4). From the first fractions there was obtained 4.3 g of solid which was dissolved in hot methanol and the volume reduced. Chilling gave 3.7 g of product as pale yellow crystals, mp 101°-103° C.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[C:9]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.N12CCCCC1C=NCCC2.Cl>C(#N)C.O>[CH:1]1([NH:4][S:5]([C:8]2[C:9]([S:14]([NH:17][C:25]([NH:26][C:27]3[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[N:32]=3)=[O:24])(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: NS(=O)(=O)c1ccccc1S(=O)(=O)NC1CC1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2S(=O)(=O)NC2CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 0.14 g of the product of Example 1 and 0.15 g of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate in 2 ml of dry acetonitrile was added 0.1 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). The solution was stirred for 15 minutes at room temperature, diluted with 2 ml of water and acidified with 5% hydrochloric acid. The precipitated product was collected by filtration, washed successively with water, diethyl ether, and 1-chlorobutane, and dried in vacuo at 40° C. to afford 0.19 g of the subject compound, m.p. 197.5°-199° C. (dec.).