Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@:9]2([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])[C:11]([OH:13])=O)=[CH:4][CH:3]=1.C([N:32]1CCOCC1)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@:9]2([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[O:16])[C:11](=[O:13])[NH2:32])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@]1(C(=O)O)C[C@@H]1c1ccc(Br)cc1
Reactant: CCN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@]1(C(N)=O)C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(1R,2R)-2-(4-Bromophenyl)-1-((S)-1-(tert-butoxycarbonyl)piperidine-2-carboxamido)cyclopropanecarboxylic acid (3 g) was dissolved in DMF (17 mL) and to the solution was added N-ethylmorpholine (1.219 mL) followed by TBTU (3.09 g). The reaction mixture was stirred at RT for 20 min then it was cooled to 0° C. Aqueous ammonia (1.461 mL) was added and the mixture was allowed to reach RT over 1 h. The reaction appeared to have proceeded ˜70%, so it was left to stir for a further 2 h. LCMS showed little change so further TBTU (400 mg) and ammonia (0.3 mL) were added, and the mixture stirred for a further 2 h. The reaction mixture was partitioned between ethyl acetate and diluted brine, and reextracted into ethyl acetate twice more. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (2.75 g) as a pale gum.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([O:10][C:11]2[CH:12]=[CH:13][CH:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=3)[C:15]3[C:19]=2[N:18]=[C:17]2[CH2:20][CH2:21][CH2:22][CH2:23][C:16]=32)=[CH:8][CH:9]=1)=[O:4].O[Li].O.Cl>O1CCCC1.O>[Br:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:14]2[C:15]3=[C:16]4[CH2:23][CH2:22][CH2:21][CH2:20][C:17]4=[N:18][C:19]3=[C:11]([O:10][C:7]3[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)[CH:12]=[CH:13]2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(OC2=C3N=C4CCCCC4=C3C(Cc3ccc(Br)cc3)C=C2)o1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OC2=C3N=C4CCCCC4=C3C(Cc3ccc(Br)cc3)C=C2)o1
Temperature: 25 °C
Reaction time: 28 h
Yield: 40.1 %

Procedure:
A solution of the methyl ester (0.9 g) from Example 114 in 10 mL of tetrahydrofuran was treated with a solution of 0.8 g of LiOH.H2O in 10 mL water. The reaction mixture was stirred at room temperature for 28 h, diluted with water, acidified with 2N-HCl and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 5-[[1,2,3,4-tetrahydro-9-(4-bromophenyl)methyl-9H-dibenzo[b,d]pyrrol-6-yl]oxy]-2-furancarboxylic acid (0.35 g; 40.0%) as a white solid after repeated crystallizations from ethyl acetate, mp 155.5°-157.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][OH:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26].Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:25]([O:17][CH2:16][C:11]1[N:12]=[C:13]([CH3:15])[NH:14][C:10]=1[S:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)(=[O:27])[CH3:26]
Reactant: Cc1cc(C)cc(Sc2[nH]c(C)nc2CO)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1nc(C)[nH]c1Sc1cc(C)cc(C)c1
Yield: 78 %

Procedure:
In dry methylene chloride (85 ml) was dissolved 1.7 g (6.8 mmol) of [5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazol-4-yl]methanol (41d), followed by addition of 2.10 g (20.8 mmol) of triethylamine. To this solution, acetyl chloride was added dropwise with stirring under ice-cooling. At the same temperature, the mixture was stirred for 30 minutes, then, 8.3 ml of 6N hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to neutralize, and extracted with methylene chloride. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate) to obtain 1.55 g of [5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazol-4-yl]methyl acetate (41b) as oil (yield 78%).
Reaction SMILES: Cl.Cl.[NH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[NH2:4].C(N(CC)C(C)C)(C)C.[C:20]1([C:26]2[O:27][CH2:28][C:29](=O)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:20]1([C:26]2[N:30]=[C:29]([CH2:28][OH:27])[N:3]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=3)[N:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNc1cccnc1
Reactant: O=C1COC(c2ccccc2)=N1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: OCc1nc(-c2ccccc2)nn1-c1cccnc1

Procedure:
To a solution of 3-hydrazinylpyridine dihydrochloride (336 mg, 1.84 mmol) and N,N-diisopropylethylamine (476 mg, 644 μL, 3.69 mmol) in ethanol (7 mL) was added 2-phenyloxazol-4(5H)-one (300 mg, 1.68 mmol, example 55, step 1) and the reaction mixture was refluxed for 2 h. All volatiles were removed in vacuo, and the product was obtained after purification by flash chromatography (using silica gel and a methanol/ethyl acetate gradient) as light yellow solid (390 mg, 1.546 mmol, 92.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[C:21]2[C:16](=[N:17][C:18]([NH2:22])=[N:19][CH:20]=2)[N:15]([CH3:23])[N:14]=1.[Cl:24]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>S(=O)(=O)(O)O>[Cl:24][C:8]1[C:3]([O:2][CH3:1])=[C:4]([C:13]2[C:21]3[C:16](=[N:17][C:18]([NH2:22])=[N:19][CH:20]=3)[N:15]([CH3:23])[N:14]=2)[CH:5]=[C:6]([C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: COc1ccc(C(F)(F)F)cc1-c1nn(C)c2nc(N)ncc12
Agent: O=S(=O)(O)O
Product: COc1c(Cl)cc(C(F)(F)F)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-(2-Methoxy-5-trifluoromethyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 88) (526 mg, 1.62 mmol) is dissolved in concentrated sulfuric acid (98%, 15 ml) and trichloroisocyanuric acid (126 mg, 0.54 mmol) is added. The reaction mixture is stirred at room temperature for 3 days, poured onto ice water (100 ml) and stirred for 30 minutes. The resulting precipitate is collected by filtration and dried under vacuum to afford the title compound as the sulfate salt.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.CCO/[CH:12]=[C:13](/[CH:15]=O)\[CH3:14]>C(O)(=O)C>[CH3:15][C:13]1[CH:12]=[N:1][C:2]2[N:6]([N:5]=[C:4]([CH2:7][OH:8])[N:3]=2)[CH:14]=1
Reactant: Nc1nc(CO)n[nH]1
Reactant: CCO/C=C(\C)C=O
Solvent: CC(=O)O
Product: Cc1cnc2nc(CO)nn2c1
Temperature: 80 °C

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (16.6 g, 87.6 mmol) from step 6 of example A(1) in acetic acid was added 3-ethoxymethacrolein (10 g, 87.6 mmol). The mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction, the product cyrstallized out of solution. The collected product was a white solid (14 g, 92%). 1H NMR (300 MHz, DMSO-d6): δ 2.38 (s, 3 H), 4.63 (s, 2 H), 5.52 (s, 1 H), 8.75 (s, 1 H), 9.21 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3]1.[Li]CCCC.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](Cl)=[O:25])=[CH:16]1>C1COCC1.CCCCCC>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([O:9][CH2:8][CH2:7][CH:6]2[CH2:5][CH2:4][CH2:3][N:2]2[CH3:1])=[O:25])=[CH:16]1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: CN1CCCC1CCO
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCCC1CCOC(=O)c1c[nH]c2ccccc12
Reaction time: 0.5 h

Procedure:
To a dry THF solution (30 ml) of 2-(1-methyl-2-pyrrolidine)ethanol at -10° to 5° C. was dropwise added a 1.5M hexane solution of n-BuLi (16.0 ml, 24.0 mmol) over a period of 10 min. Stirring was continued for 30 min. To a mixture was then dropwise added at -5° to 5° C. a dry THF solution (20 ml) of indole-3-carboxylic acid chloride (4.20 g, 24.0 mmol) over a period of 45 min. The cooling bath was removed. After stirring overnight at room temperature, a reaction solution was poured onto a cold diluted hydrochloric acid, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted with saturated aqueous sodium bicarbonate to a pH of >10 and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.91 g of the title compound as a yellow viscous material. A foamy solid;
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[C:3]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:16][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1cc(Cl)ccc1N1CCNCC1
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)N1CCN(c2ccc(Cl)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a mixture of 1-(2-tert-butyl-4-chlorophenyl)piperazine dihydrochloride (Reference Example 20, 0.50 g, 1.54 mmol) and triethylamine (0.48 g, 4.77 mmol) in THF (30 mL) was added ethyl chloro(oxo)acetate (0.23 g, 1.69 mmol). The mixture was stirred at room temperature for 1 h, filtered and concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, died over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 9:1-3:7, hexane/ethyl acetate) to give the title compound (0.49 g) as a colorless solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[N:3]=1.Cl.[CH:18]1([N:22]([CH3:29])[CH2:23]/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:26](=[O:27])/[CH:25]=[CH:24]/[CH2:23][N:22]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[CH3:29])[CH2:13]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CN(C/C=C/C(=O)O)C1CCC1
Reactant: Nc1ncnc2c1c(I)nn2[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(I)c3c(N)ncnc32)C1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.4 %

Procedure:
To a cooled solution of (R)-3-iodo-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4) (990 mg, 3.0 mmol), (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid (21) (871 mg, 3.0 mmol) and DIPEA (3.1 mL, 18 mmol) in DMF (15 mL) was added HBTU (1.74 g, 4.5 mmol). The resulting solution was stirred at RT overnight, then quenched with water. The layers were separated and the aqueous layer was extracted with 85% DCM/IPA(3×). The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to provided (R,E)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one (22) (1.71 g, quant. yield) as a white solid. LC-MS (ESI): m/z (M+1) 482.0.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[CH:23][N:22]=1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:24]=[CH:23][N:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cc1cc(C=O)ccn1
Product: Cc1cc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)ccn1
Yield: 61 %

Procedure:
Obtained in 61% yield by General Synthetic Method 5, starting from 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine and 2-methylpyridine-4-carboxaldehyde
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.Cl.[Cl:19][C:20]1[C:21]([CH3:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24].C(N(CC)CC)C>O1CCCC1>[Cl:19][C:20]1[C:21]([CH3:28])=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: Cc1c(Cl)cccc1CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cccc(Cl)c2C)c(=O)c1=O
Yield: 89.8 %

Procedure:
Tetrahydrofuran (10 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5.0 mmol, Example 3), 3-chloro-2-methylbenzylamine hydrochloride (0.96 g, 5.0 mmol, Example 96, Step 1), and triethylamine (0.51 g, 5.0 mmol) were stirred together at room temperature for 65 hours. Processing the reaction mixture as in Example 96, Step 2 provided 1.44 g of a white solid. Two recrystallizations of the crude product from methanol gave 1.12 g of the title compound as a fluffy, white solid: mp 236°-237° C. (softens 233° C.). MS (m/z) 321/323 ([M+H]+). HPLC indicates a major component (99.6%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].[CH2:24]([NH2:26])[CH3:25]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:26][CH2:24][CH3:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(N2CCN(C)CC2)c([N+](=O)[O-])c1Cl
Reactant: CCN
Solvent: CCN(CC)CC
Product: CCNc1c(C(=O)OCC)c(C)nc(N2CCN(C)CC2)c1[N+](=O)[O-]
Yield: 73 %

Procedure:
32.7 g. of 4-chloro-2-methyl-5-nitro-6-[(N-methyl)-piperazino]pyridine-3-carboxylic acid ethyl ester (0.1 mol.) and 12 g. of triethylamine are treated with stirring in 100 ml. of alcohol at reflux temperature with 6 g. of ethylamine for 1 hour. After this time, the solution is evaporated and dissolved in 100 ml. of ether. The precipitated triethylamine hydrochloride is filtered off and the filtrate cooled to -30°. 4-Ethylamino-2-methyl-5-nitro-6-[(N-methyl)piperazino]-pyridine-3-carboxylic acid ethyl ester precipitates, yield 73%, m.p. 59°-61° (methanol).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[C:27]([NH2:30])(=[O:29])[CH3:28]>>[C:27]([NH:30][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1)(=[O:29])[CH3:28]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Reactant: CC(N)=O
Product: CC(=O)Nc1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and acetamide were reacted to give 121bp. 1H NMR (400 MHz, CDCl3) δ 6.84-7.31 (m, 6 H), 6.76 (s, 1 H), 5.05 (s, 2 H), 3.40 (s, 3 H), 2.16 (s, 3 H). LCMS (ESI) m/z: 414.9
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:16])=[C:10]([OH:15])[C:11]([CH3:14])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[C:17]([Si](OC1C(F)=CC=CC=1CC)(C)C)(C)(C)C>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:16])=[C:10]([OH:15])[C:11]([CH2:14][CH3:17])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cnc(N)cn2)c(F)c1O
Reactant: CCc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Product: CCc1ccc(-c2cnc(N)cn2)c(F)c1O

Procedure:
The title compound was prepared in an analogous way to 3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol in Steps B-D of Intermediate J using tert-butyl(2-ethyl-6-fluorophenoxy)dimethylsilane. 1H NMR (500 MHz, CD3OD) δ 8.26 (dd, J=2.3, 1.5, 1H), 8.02 (d, J=1.5, 1H), 7.12 (dd, J=8.0, 7.3, 1H), 6.99-6.93 (m, 1H), 2.68 (q, J=7.5, 2H), 1.21 (t, J=7.5, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:18][C:19]1[S:20][CH:21]=[C:22]([Sn](CC)(CC)CC)[N:23]=1>>[CH3:18][C:19]1[S:20][CH:21]=[C:22]([C:2]2[CH:3]=[C:4]3[CH2:10][C@:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)[N:23]=1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Reactant: CC[Sn](CC)(CC)c1csc(C)n1
Product: Cc1nc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)cs1

Procedure:
Prepared by a method analogous to that described for the preparation of Example 1 from (2′R)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] and 2-methyl-4-triethylstannyl-thiazole. The title compound was obtained as a colourless solid; m/e 314 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([C:56]3[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=3)[CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:62]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([C:56]7[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=7)[CH2:54][CH2:55]6)=[O:49])=[CH:44][C:43]=5[CH3:62])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: Cc1cc(C(=O)N2CCN(c3cccnc3)CC2)ccc1Br
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(c5cccnc5)CC4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and (4-bromo-3-methyl-phenyl)-(4-pyridin-3-yl-piperazin-1-yl)-methanone (70 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-(4-pyridin-3-yl-piperazin-1-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-311) as a yellow powder (41 mg, 55%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([CH3:28])([CH3:27])[C:25]#[N:26])[CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[CH:38][C:5]=2[N:4]=1)[CH3:2].[OH:39]S(O)(=O)=O.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([CH3:28])([CH3:27])[C:25]([NH2:26])=[O:39])[CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[CH:38][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCN(C(C)(C)C#N)CC3)n(C)c2n1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3CCN(C(C)(C)C(N)=O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-{4-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-1-yl}-2-methylpropionitrile (300 mg, 0.58 mmol) was added slowly to conc. H2SO4 (3.5 mL). The resulting mixture was allowed to stir at r.t. for 3 h then poured onto ice and basified with K2CO3. The resulting mixture was extracted with DCM and the combined organic phases dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 703 (177 mg, 57%). LCMS (method I): RT 2.45 min, [M+H]+ 532.3. 1H NMR (DMSO, 400 MHz): δ 8.01-7.97 (1 H, m), 7.63-7.62 (1 H, m), 7.23-7.22 (3 H, m), 6.93 (1 H, d, J=3.36 Hz), 4.26 (4 H, brd s), 3.79-3.74 (7 H, m), 3.26 (2 H, q, J=7.42 Hz), 3.07-2.97 (1 H, m), 2.88 (2 H, d, J=10.76 Hz), 2.32-2.21 (2 H, m), 1.93-1.91 (4 H, m), 1.33 (3 H, t, J=7.44 Hz), 1.12 (6 H, s)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:16]=4[N:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:52](O)[CH2:53][OH:54]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:54][CH2:53][CH2:52][O:23][C:22]([C:19]1[CH:20]=[CH:21][C:16]2[N:15]=[C:14]([C:25](=[O:36])[NH:26][CH:27]3[CH2:28][CH2:29][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:31][CH2:32]3)[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]=2[CH:18]=1)=[O:24]
Reactant: OCCO
Reactant: CC(C)N1CCC(NC(=O)c2nc3ccc(C(=O)O)cc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2nc3ccc(C(=O)OCCO)cc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.08 mmol) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid were dissolved in 10 mL CH2Cl2. Subsequently 3 mg DMAP, 23 mg (0.11 mmol) DCC and 46 μl (0.83 mmol) ethylene glycol were added. The resulting mixture was stirred at room temperature for 16 h and then concentrated under removed pressure. The remaining residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) to give pure 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid 2-hydroxy-ethyl ester as a white amorphous solid. The corresponding dihydrochloride was obtained by treatment with a 0.1 M HCl-solution and following lyophilization.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:9]3[C:14]([C:15]=2[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[NH2:25][OH:26].[OH-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:9]3[C:14]([C:15]=2/[C:16](=[N:25]/[OH:26])/[NH2:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1c(-c2ccc(Cl)s2)n(-c2ccc(O)cc2)c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N/C(=N\O)c1c(-c2ccc(Cl)s2)n(-c2ccc(O)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 18 h

Procedure:
The compound 2-(5-chlorothiophen-2-yl)-1-(4-hydroxyphenyl)-1H-indole-3-carbonitrile (Example 86) was dissolved in DMSO (0.25 mL) and hydroxylamine (0.25 mL, 100 eq) was added from a 2M stock solution of hydroxylamine*hydrochloride neutralized with sodium hydroxide (pH=7.01 as measured with pH-meter). The mixture was stirred at 60° C. for 18 hours. The cooled mixture was diluted with brine and extracted with EtOAc and subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC. ES/MS m/z: 386.3 (M+H), 384.2 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.89 (m, 1H), 7.21-7.13 (m, 4H), 7.04 (m, 1H), 7.00-6.97 (m, 3H) and 6.91 (d, 1H, J=4.0 Hz).