Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)=[CH:14]1>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]2[NH:27][CH:26]=[CH:25][N:24]=2)=[CH:14]1)=[O:9]
Reactant: NCCn1cc(Cc2ncc[nH]2)c2ccccc21
Reactant: O=C(O)c1ccccn1
Solvent: C1COCCO1
Product: O=C(NCCn1cc(Cc2ncc[nH]2)c2ccccc21)c1ccccn1
Yield: 29 %

Procedure:
A mixture of 2-picolinic acid (0.25 g) and N,N'-carbonyldiimidazole (0.33 g) was heated on a steam bath for 30 minutes in dioxan (10 ml) to give a clear solution. 1-(2-Aminoethyl)-3-(1-imidazolylmethyl) indole (0.48 g) in dioxan (2 ml) was added and the solution was heated on a steam bath for 1 hour and then evaporated. The residue was dissolved in ethyl acetate and the solution was washed with water and dried (NaSO4). Evaporation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform gave some impurity and pure product was eluted with a mixture of chloroform and methanol (20:1). Evaporation of the product containing fractions gave a solid which was crystallised from isopropanol/petrol to give 1-[2-(2-picolinoylamino) ethyl]-3-(1-imidazolylmethyl)indole (0.2 g), m.p. 183°-184° C. Found: C, 69.67; H, 5.6; N, 19.42. C20H19N5O requires: C, 69.54; H, 5.55; N, 20.28%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[CH3:30][O-:31].[Na+]>CN(C)C=O.[Cu]I>[F:28][C:25]([F:26])([F:27])[CH:24]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[CH3:23])[C:8]3=[N:9][C:10]=2[C:2]([O:31][CH3:30])=[CH:3][CH:4]=1)[OH:29]
Reactant: C[O-]
Reactant: COc1ccc(N2CCCn3c2nc2c(Br)ccc(C(O)C(F)(F)F)c23)c(C)c1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCn3c2nc2c(OC)ccc(C(O)C(F)(F)F)c23)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A mixture of 1-[9-bromo-1-(4-methoxy-2-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (200 mg, 0.425 mmol), sodium methoxide (28% methanol solution, 3 mL), copper (I) iodide (121 mg, 0.635 mmol) in N,N-dimethylformamide (3 mL) was stirred at 100° C. for 1 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 40-80% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless oil (96.6 mg, 0.229 mmol, 54%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:11]=2)=[O:8])=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:5]2[S:6][C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)=[CH:3][CH:4]=2)=[O:8])=[CH:11][C:12]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: COc1ccc(NC(=O)c2ccc(Br)s2)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccncc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2ccc(-c3ccncc3)s2)cc1N1CCN(C)CC1
Yield: 64.4 %

Procedure:
5-bromo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]thiophene-2-carboxamide (0.31 g;0.76 mmol) was stirred with 4-pyridylboronic acid (0.093 g;0.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g;5 mol %) and anhydrous sodium carbonate (0.089 g;0.84 mmol) in water (14 ml) and DME (14 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (30 ml) and extracted into CHCl3. The organic extracts were combined, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 4%MeOH/CHCl3 to yield a yellow, semi-solid residue which was triturated with acetone/Et2O. The solid that formed was collected by filtration and dried in vacuo to yield the tide compound as a yellow solid (0.2 g;65%), mp=191-194° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].CI.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19](C)=O>>[CH2:18]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:19]
Reactant: Oc1cccc(F)c1F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOc1cccc(F)c1F
Temperature: 70 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2,3-difluorophenol 21a (2.04 g, 14.5 mmol) in acetone (50 mL) were added methyl iodide (1.62 mL, 9.98 mmol) and potassium carbonate (3.18 g, 23.06 mmol) in turn at room temperature. The mixture was warmed up to 70° C. and stirred for 3 hours, and then filtered. To the mixture was added ethyl acetate (40 mL). The resulting mixture was washed with water (40 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 23b as yellow oil (2.42g, 100%). This material was not further purified. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.01-6.95 (m, 1H), 6.80-6.72 (m, 2H), 4.14 (q, 2H), 1.48 (t, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.CN1C[CH2:35][CH2:34][C:33]1=[O:37].C(Cl)(=O)CC>O>[Br:19][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]3[C:20]([Cl:23])=[CH:21][CH:22]=[C:4]([NH:3][C:33](=[O:37])[CH2:34][CH3:35])[C:5]=3[Cl:24])[C:10]2=[N:17][C:16]=1[CH3:18]
Reactant: CN1CCCC1=O
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Agent: CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (200 mg), pyridine (1 ml) and N-methylpyrrolidone (3 ml) was added propionyl chloride (78 mg) and the mixture was stirred at 60° C. for 1 hour. To the cooled mixture was added water, and the precipitate was collected by filtration and dissolved in chloroform. This organic solution was washed with water and brine respectively, dried with magnesium sulfate and concentrated in vacuo. The residue was collected by filtration and washed with ethyl acetate to give 3-bromo-8-(2,6-dichloro-3-propionylaminobenzyloxy)-2-methylimidazo [1,2-a]pyridine (158 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH2:25][CH3:26]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2c(F)cccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CCC1c2cccc(F)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][C:24]([O:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34])=[O:29])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:33]([C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[NH:30][C:28](=[O:29])[O:27][C:24]([CH3:25])([CH3:23])[CH3:26])=[O:34])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A mixture of Intermediate 7 (250 mg, 0,83 mmol) and 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)benzoic acid (196 mg, 0.83 mmol, e.g. available from Fluka) in N,N-dimethylformamide (4 ml) was treated with N,N-diisopropylethylamine (0.569 ml, 3.3 mmol) and (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (472 mg, 0.91 mmol) and allowed to stir at room temperature for 4 hours. An additional portion of (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (0.5 equiv., 0.41 mmol) was added and the mixture stirred for an additional hour. The solvent was evaporated and the residue dissolved in ethyl acetate (50 ml) and washed with aqueous sodium bicarbonate solution (2×50 ml); the organic fraction was dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel (50 g SPE cartridge), eluting with a gradient of 0-100% ethyl acetate/cyclohexane followed by a gradient of 0-20% methanol/ethyl acetate over 40 minutes. Fractions containing product were pooled and evaporated to give the title compound (292 mg). LCMS showed MH+=523; TRET=2.71 min.
Reaction SMILES: [Br:1]Br.[N:3]1[N:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[CH:6][CH:7]=1.CC([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O>[Br:1][C:6]1[CH:7]=[N:3][N:4]2[CH2:10][CH2:9][CH2:8][C:5]=12
Reactant: c1cc2n(n1)CCC2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1cnn2c1CCC2
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
Bromine (22.4 mL, 435 mmol) was added to a solution of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole 8 (47.2 g, 437 mmol) and NaOAc (36.2 g, 440 mmol) in AcOH (750 mL) drop wise at 0° C. The mixture was stirred at the same temperature for 10 minutes then neutralized by the addition of aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (5×200 mL) and the organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to afford 3-bromo-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (73.5 g).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:23]=[O:24])C.P(Cl)(Cl)(Cl)=O>O>[C:14]1([N:7]([C:1]2[CH:2]=[CH:3][C:4]([CH:23]=[O:24])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C=O
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 95 °C

Procedure:
101.4 g of triphenylamine and 35.5 mL of DMF were placed in a three-neck flask. While stirring and cooling in ice water, 84.4 mL of phosphorus oxychloride was dropped into the flask. The temperature was increased to 95° C. and the mixture was reacted for 5 hours. 4 L of warm water was poured into the flask and the mixture was stirred for one hour. A precipitate was collected and washed in a 1:1 mixture solution of ethanol/water. 4-(N,N-diphenylamino)benzaldehyde was obtained. The yield was 91.5 g (yield rate of 81.0%), and the melting point was 128.6°-130.1° C.
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:23][O:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[N:15][CH:14]=1.O>O1CCOCC1>[CH:5]1([CH2:8][NH:9][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:23][O:24][C:25]=3[C:26]([F:29])([F:28])[F:27])=[N:15][CH:14]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Reactant: NCC1CC1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC1CC1)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 529 μL, 1.1 mmol) was added dropwise (exothermic) to a solution of cyclopropanemethylamine (75 mg, 91 μL, 1.1 mmol) in dioxane (7 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.26 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 6 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (92 mg, 83%) which was obtained as an off white solid. MS: m/e=418.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:25]1[C:26](=[O:42])[N:27]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26](=[O:42])[N:27]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:39])[CH3:41])[CH:28]=[C:29]([N+:31]([O-:33])=[O:32])[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CC1
Reactant: C[Si](C)(C)CCOCn1cc([N+](=O)[O-])cc(I)c1=O
Product: CN1CCN(c2ccc3c(c2)cc(-c2cc([N+](=O)[O-])cn(COCC[Si](C)(C)C)c2=O)n3C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared by the route outlined in Scheme 10 and using the experimental from Example 37, Step 3, with intermediate (10c), 5-(4-methyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester (2.33 g, 7.4 mmol) and 3-iodo-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one (2.66 g, 6.7 mmol) which had been synthesised according to the protocol described for intermediate (6a) in example 20. The resultant solid was purified via trituration using diethyl ether, to afford the title compound as a pale brown solid, 1.73 g, 40%.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:34])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:23]=[C:22]([CH3:34])[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2ccc(Cl)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
33 mg (0.83 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 172 mg (0.85 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.85 mmol) 3-chloromethyl-6-(4-chloro-phenyl)-2-methyl-pyridine (EP 0 284 174) were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. The residue was dried at 40° C. in vacuum to give 305 mg (89%) of the title compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH3:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)(=[O:11])=[O:10])=[CH:5][C:4]=1[N+:26]([O-])=O.C1COCC1>CO.[Pd]>[NH2:26][C:4]1[CH:5]=[C:6]([S:9]([N:12]([CH3:25])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)(=[O:10])=[O:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(S(=O)(=O)N(C)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(C)c2cc(OC)c(OC)c(OC)c2)cc1N
Reaction time: 4 h

Procedure:
A solution of Example 52A (00 mg) in methanol:THF (1 mL:1 mL) was treated with 10% palladium on carbon, stirred under hydrogen (1 atm) for 4 hours, filtered through diatomaceous earth (Celite®), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2% methanol/dichloromethane to provide 31 mg of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C@H:11]([CH3:16])/[C:12](/[NH2:15])=[N:13]/[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](N1C=CN=C1)(=O)[CH3:19]>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:17])[NH:10][C@@H:11]([C:12]1[N:15]=[C:18]([CH3:19])[O:14][N:13]=1)[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)n1ccnc1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)/C(N)=N/O
Solvent: C1COCCO1
Product: Cc1nc([C@@H](C)NC(=O)OCc2ccccc2)no1
Temperature: 90 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
To a solution of benzyl[(1R,2Z)-2-amino-2-(hydroxyimino)-1-methylethyl]carbamate (2.25 g, 9.48 mmol) in dioxane (80 ml) was added 1-acetyl-1H-imidazole (3.13 g, 28.5 mmol) and the mixture heated to 90° C. After 16 h, the solution was concentrated and the residue was dissolved in 200 mL of dichloromethane. The mixture was washed with 100 mL of aquous saturated sodium bicarbonate (2×) and saturated aqueous sodium chloride (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) to give the title compound (1.1 g). MS 262.1 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.O>[CH2:19]([O:11][C:7]1[C:6]([Br:12])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:9][C:8]=1[Br:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Br)c(OCc2ccccc2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3,5-dibromo-4-hydroxyacetophenone from Example 45A (15 g, 51.2 mmol) in DMF (51 mL) was added K2CO3 (10.2 g, 74.1 mmol) and benzyl bromide (6.0 mL, 50.7 mmol). The reaction stirred at room temperature for 45 minutes. It was diluted with water (200 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were washed with 2M NaOH solution (2×75 mL), water (75 mL), and brine (75 mL) and then dried over MgSO4 and concentrated in vacuo to give 1-(4-benzyloxy-3,5-dibromo-phenyl)-ethanone as an off white solid (14.3 g, 37.2 mmol, 73% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1.O>[NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([C:32]1[CH:33]=[CH:34][C:35]([OH:36])=[C:30]([Cl:29])[CH:31]=1)[N:5]=2
Reactant: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(Cl)nc21
Reactant: OB(O)c1ccc(O)c(Cl)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(-c3ccc(O)c(Cl)c3)nc21
Temperature: 85 °C
Yield: 110 %

Procedure:
In a round bottom flask 0.3 g (0.71 mmol) 2-amino-7-chloro-1-ethyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-[1,8]naphthyridin-4-one, 0.185 g (1.07 mmol) 3-chloro-4-hydroxy-phenylboronic acid, 0.098 g (0.11 mmol) tris-(dibenzylidenacetone)dipalladium (0), 0.030 mg (0.0.11 mmol) tricyclohexyl phosphine, 0.303 g of potassium phosphate tribasic, and 8 mL of dioxane/water (50/50) (degassed) were stirred and heated at 85° C. for 8 h. The solvents were evaporated and the residue was purified by column chromatography (DCM/MeOH: 9/1) to yield 0.4 g of a brown solid. This solid was engaged without further purification in the next step.
Reaction SMILES: [I-].[Na+].[CH:3]([NH2:6])([CH3:5])[CH3:4].[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N:15]2[C:19](=[O:20])[CH2:18][CH2:17][C@@H:16]2[CH2:21]OS(C)(=O)=O)=[CH:10][C:9]=1[CH3:27]>C1COCC1>[Br:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([N:15]2[C@@H:16]([CH2:21][NH:6][CH:3]([CH3:5])[CH3:4])[CH2:17][CH2:18][C:19]2=[O:20])=[CH:10][C:9]=1[CH3:27]
Reactant: Cc1cc(N2C(=O)CC[C@@H]2COS(C)(=O)=O)cc(C)c1Br
Reactant: CC(C)N
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N2C(=O)CC[C@@H]2CNC(C)C)cc(C)c1Br
Temperature: 70 °C
Reaction time: 36 h
Yield: 61.3 %

Procedure:
Sodium iodide (catalytic amount) and isopropylamine (1.37 g, 23 mmol) were added to a solution of methanesulfonic acid (R)-1-(4-bromo-3,5-dimethyl-phenyl)-5-oxo-pyrrolidin-2-ylmethyl ester (150 mg, 0.399 mmol) in THF (3 ml) at room temperature, and the mixture was heated with stirring at 70° C. for 1.5 days. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give (R)-1-(4-bromo-3,5-dimethyl-phenyl)-5-(isopropylamino-methyl)-pyrrolidin-2-one (83 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Br)=[O:33])=[CH:30][CH:29]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[CH:9]=2)[C:13]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C(Br)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 308 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 4-trifluoromethyl benzoyl bromide. The compound of example 308 was used directly without isolation, for the preparation of compound of example 309.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:4]=1[NH2:5])#[N:2].[N:11]([O-])=O.[Na+].Cl>>[NH2:2][C:1]1[C:3]2[C:4](=[CH:6][CH:7]=[C:8]([F:10])[CH:9]=2)[NH:5][N:11]=1
Reactant: O=N[O-]
Reactant: N#Cc1cc(F)ccc1N
Agent: Cl
Agent: [Na+]
Product: Nc1n[nH]c2ccc(F)cc12

Procedure:
By the procedure of Example 2, 13.6 g. of 2-cyano-4-fluoroaniline is treated with 8.0 g. of sodium nitrite and concentrated hydrochloric acid, followed by stannous chloride to give 3-amino-5-fluoroindazole.