Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]([N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:52]([O:59][C:60]([N:62]1[CH2:67][CH2:66][N:65]([C:68](=[O:75])[CH:69](O)[CH2:70][CH:71]([CH3:73])[CH3:72])[CH2:64][CH2:63]1)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C1COCC1.C(Cl)Cl.O>[CH2:52]([O:59][C:60]([N:62]1[CH2:63][CH2:64][N:65]([C:68](=[O:75])[CH:69]([O:16][C:15](=[O:17])[CH2:14][N:12]([C:10](=[O:11])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:18])[CH3:13])[CH2:70][CH:71]([CH3:72])[CH3:73])[CH2:66][CH2:67]1)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CN(CC(=O)O)C(=O)CN(C)C(=O)OC(C)(C)C
Reactant: CC(C)CC(O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CC(OC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 40.9 %

Procedure:
To {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid (427 mg, 1.57 mmol) in 2 mL of THF was added sequentially HBTU (624 mg, 1.2 mmol), diisopropyl ethylamine (860 μL, 4.71 mmol) at room temperature. After 5 min, 4-(2-hydroxy-4-methyl-pentanoyl)-piperazine-1-carboxylic acid benzyl ester (403 mg 1.2 mmol) in 2 mL of THF was added to the reaction mixture, and the solution was heated at 65° C. for 12 h. The reaction mixture was cooled and diluted with 20 mL of CH2Cl2 and 10 mL of water. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give an oil. The residue was subjected to purification by normal phase LC using 30-100% EtOAc-hexanes to give 4-[2-(2-{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetoxy)-4-methyl-pentanoyl]-piperazine-1-carboxylic acid benzyl ester (283 mg, 41% yield). LC/MS: m/z 577 (M+H)+ at 3.43 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.COS(C1C=CC(C)=CC=1)(=O)=O.C1(N=C=NCCN2CCOCC2)CCCCC1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:69]([O:81][C:82](=[O:85])[CH2:83][NH2:84])[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80]>ClCCl>[CH2:69]([O:81][C:82]([CH2:83][NH:84][C:8]([C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])=[O:85])[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80]
Reactant: O=C(O)c1ncccc1O
Reactant: CCCCCCCCCCCCOC(=O)CN
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOC(=O)CNC(=O)c1ncccc1O
Temperature: 20 °C
Reaction time: 50 h

Procedure:
7 g (50 mmol) of 3-hydroxypyridine-2-carboxylic acid were suspended in 800 ml of anhydrous dichloromethane and treated with 7.5 g (55 mmol) of 1-hydroxy-1H-benzotriazole, 19.2 ml (150 mmol) of N-ethylmorpholine, 21.2 g (50 mmol) of N-cyclohexyl-N'-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate (CMC) and 20.8 g (50 mmol) of glycine 1-dodecyl ester tosylate and the mixture was stirred at 20° C. for 50 h.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(O)[CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[CH:4][CH:3]=1.S([O-])(O)(=O)=O.[K+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnnc1CC(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cn1nnnc1C=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 195 °C
Yield: 102.9 %

Procedure:
A mixture of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (4.2 g, 12.7 mmoles) [prepared in Step A] and potassium hydrogen sulfate was heated at 195° C. for 0.5 hour. After cooling, the mixture was dissolved in chloroform and washed with water. The organic layer was dried and evaporated in vacuo. The residue was triturated with diethyl ether to give 3.9 g of the title compound; m.p.=169°-171° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[C:9]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]1)=[O:6].[CH2:26]([C:30]1[CH:35]=[CH:34][C:33]([CH:36](Br)[C:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=2)=[CH:32][CH:31]=1)[CH:27]([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C.Cl>ClCCl>[CH2:43]([C:40]1[CH:41]=[CH:42][C:37]([CH:36]([NH:1][C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=3)[C:9]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8]2)=[O:6])[C:33]2[CH:34]=[CH:35][C:30]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=2)=[CH:38][CH:39]=1)[CH:44]([CH3:46])[CH3:45]
Reactant: Nc1cccc(C(=O)n2cc(CCCC(=O)O)c3cc(Cl)ccc32)c1
Reactant: CC(C)Cc1ccc(C(Br)c2ccc(CC(C)C)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)n3cc(CCCC(=O)O)c4cc(Cl)ccc43)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A mixture of 4-[1-(3-aminobenzoyl)-5-chloroindol-3-yl]butyric acid (700 mg), bis(4-isobutylphenyl)methyl bromide (705 mg) and diisopropylethylamine (620 mg) in dichloromethane (20 ml) was stirred at 20° C. for 1 hour, and then bis(4-isobutylphenyl)methyl bromide (150 mg) and diisopropylethylamine (70 mg) were added. After stirred at 20° C. for 3 hours, the reaction mixture was poured into iced 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (20 g) eluting with a mixture of hexane and ethyl acetate (10:1 to 1:1) to give 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-5-chloroindol-3-yl]butyric acid (803 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([F:13])[CH:7]=1.C(OC)(=O)C.S([O-])([O-])=O.[Na+].[Na+].[Cl-].[Na+]>C(Cl)Cl.C(O)(=O)C.O>[CH3:3][O:4][C:5](=[O:14])[C:6]1[CH:7]=[C:8]([F:13])[C:9]([OH:12])=[C:10]([Br:1])[CH:11]=1
Reactant: BrBr
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: O=S([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)c(O)c(Br)c1
Reaction time: 0.5 h

Procedure:
During 30 min, 5.64 g (35.27 mmol) of bromine were added to a solution of 5.00 g (29.39 mmol) of 3-fluoro-4-hydroxy-benzoic acid methyl ester in 30 ml of DCM and 30 ml of acetic acid at 0° C. After stirring overnight, 200 ml of methyl acetate were added. The resulting solution was extracted with a solution of 7.56 g (60 mmol) of sodium sulfite in 50 ml of water, a saturated sodium chloride solution and water. The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting white solid (7.2 g) was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[C:4](=[O:12])[N:3]1[C:13]1[CH2:14][O:15][C:16](=[O:18])[CH:17]=1.F[C:20](F)(F)S(OC1COC(=O)C=1C)(=O)=O>>[CH3:1][CH:2]1[CH2:6][C:5]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[C:4](=[O:12])[N:3]1[C:13]1[CH2:14][O:15][C:16](=[O:18])[C:17]=1[CH3:20]
Reactant: CC1CC2(CCNCC2)C(=O)N1C1=CC(=O)OC1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Product: CC1=C(N2C(=O)C3(CCNCC3)CC2C)COC1=O

Procedure:
The title compound was prepared in two steps in an analogous fashion to that described for 3-methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (I-22), except starting from 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (I-9). LC-MS (IE, m/z): 265 (M+1)+.
Reaction SMILES: O=[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=3)[C:19]#[N:20])[CH:14]=2)[C:4]2([CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH2:3]1.C[Si]([N:28]=[C:29]=[N:30][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:19]([C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[C:4]2([CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:3][C:2]3=[N:30][C:29]#[N:28])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC32CCOCC2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC2(CCOCC2)c2ccc(-c3cccc(C#N)c3)cc21
Reaction time: 1 h

Procedure:
To a solution of 3-(3-oxo-2,2′,3,3′,5′,6′-hexahydrospiro[indene-1,4′-pyran]-5-yl)benzonitrile (42 mg, 0.139 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.28 mL, 0.28 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.1 mL, 0.427 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (15 g), and stirred for 30 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give the desired product as white solid, which was used for next step without further purification. MS ESI+ve m/z 328 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2cnc(Nc3cccc4c3CC(=O)CC4)o2)c1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: Cc1cccc(-c2cnc(Nc3cccc4c3CC(O)CC4)o2)c1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 15C for the product of Example 1I. 1H NMR (DMSO-d6) δ 9.08 (s, 1H), 7.58 (d, 1H, J=7.3 Hz), 7.26-7.39 (m, 4H), 7.04-7.12 (m, 2H), 6.83 (d, 1H, J=7.2 Hz), 4.81 (d, 1H, J=4.1 Hz), 3.93 (m, 1H), 2.73-2.97 (m, 4H), 2.33 (s, 3H), 1.86 (m, 1H), 1.61 (m, 1H); MS (ESI+) m/z 321 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21](I)[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cu][C:31]#[N:32]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([C:31]#[N:32])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reaction time: 1 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (10 mL) was added copper(I) iodide (180 mg, 0.094 mmol), tetrakis(triphenyphosphine)palladium(0) (5.4 mg, 0.047 mmol) and copper(I) cyanide (420 mg, 4.7 mmol) sequentially at room temperature. After heating the reaction mixture at reflux overnight, additional copper(I) cyanide (420 mg, 4.7 mmol), copper(I) iodide (107 mg, 0.56 mmol) and tetrakis(triphenyphosphine)palladium(0) (325 mg, 0.28 mmol) were added and the reflux was continued for 1 hour. The reaction mixture turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was then diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 410 mg of the title compound as a crude yellow solid.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([CH2:12][Br:13])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(C#N)oc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1nc2ccc(CBr)cc2o1

Procedure:
To a stirred solution of 2-cyano-6-methylbenzoxazole (2.0 g, 12.66 mmol) in carbon tetrachloride (50 ml) at room temperature are added successively N-bromosuccinimide (2.37 g, 13.3 mmol) and benzoyl peroxide (30.7 mg, 0.13 mmol). The solution is irradiated with a sun-lamp for 2 hours and concentrated. The residue is dissolved in 500 ml of ether and the solution filtered. The filtrate is concentrated and subjected to HPLC (2% ethyl acetate in hexane) to afford 2-cyano-6-bromomethylbenzoxazole which is used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:19])=[N:4][C:5]2[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1>Cl>[NH2:16][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]2[N:11]=[C:2]([OH:1])[C:3]([OH:19])=[N:4][C:5]=2[CH:6]=1
Reactant: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2ccccc12
Agent: Cl
Product: Nc1cc2nc(O)c(O)nc2c2ccccc12
Reaction time: 2 h
Yield: 79.2 %

Procedure:
A solution of stannous chloride dihydrate (3.7 g, 16 mmol) in 10 ml of conc. hydrochloric acid was added dropwise to a stirred suspension of 2,3-dihydroxy-6-nitrobenzo(f)quinoxaline (1.3 g, 5 mmol) in 8 ml of conc. hydrochloric acid. Then the mixture was stirred at 60°-70° C. on an oil bath for 2 h. After cooling on ice, the precipitate was collected, dissolved in boiling water (1 l), filtered while hot, and neutralized to pH 6 with solid sodium hydrogen carbonate. The yellow product was isolated and recrystallized from DMF/water, washed with water, ethanol and ether and finally dried at 110° C. to give 0.90 g (63%) of pure title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5]>C1COCC1.CC1C=CC([Mg]Br)=NC=1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:9]3[CH:14]=[CH:15][C:6]([CH3:4])=[CH:7][N:8]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: Cc1ccc([Mg]Br)nc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)nc1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 1.96 mL 0.25M 5-methyl-2-pyridylmagnesium bromide. Yield: 33 mg of a white solid. LC-MSD, m/z for C22H16BrN3O2 [M+H]+=434.0, 436.0; HPLC retention time: 2.0 min.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f19) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[C:6]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Br:28][C:29]1[C:30](B(O)O)=[N:31][CH:32]=[CH:33][CH:34]=1.BrC1C=NC=C(Br)C=1>>[Br:28][C:29]1[CH:34]=[C:33]([C:8]2[CH:7]=[C:6]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:22][CH:23]=3)[CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)[CH:32]=[N:31][CH:30]=1
Reactant: OB(O)c1ncccc1Br
Reactant: O=S(=O)(Oc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CC2)n1)C(F)(F)F
Agent: Brc1cncc(Br)c1
Product: FC(F)(F)c1ccc(-c2cc(-c3cncc(Br)c3)nc(C3CC3)c2)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.34) (2.0 g, 4.86 mmol) and commercially available 3-bromo-pyridine-boronic acid [CAS-No. 452972-09-07] (alternatively prepared from commercially available 3,5-dibromopyridine according to Tetrahedron 2002, 58(17), 3323 or Synthesis 2003, (7), 1035) (1.079 g, 5.34 mmol) according to the general procedure IVb. Obtained as a white solid (1.55 g, 76%). MS (ISP) 419.1 [(M+H)+] and 421.0 [(M+2+H)+].
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.O1CCCC1.Cl[C:24]1[C:33]2[C:28](=[C:29]([O:38][CH3:39])[C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>CC(O)C>[CH2:9]([O:8][C:6]([CH2:5][CH2:4][CH2:3][NH:2][C:24]1[C:33]2[C:28](=[C:29]([O:38][CH3:39])[C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1)=[O:7])[CH3:10]
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCCNc1ncnc2c(OC)c(OC)c(OC)cc12
Yield: 70.1 %

Procedure:
1.0 g of ethyl 4-aminobutyrate hydrochloride (6.0 mmol), 2 ml of triethylamine, 10 ml of tetrahydrofuran and 10 ml of 2-propanol are added to 0.50 g (2.0 mmol) of 4-chloro-6,7,8-trimethoxyquinazoline, followed by heating under reflux one whole day and night. The reaction liquid is distilled under reduced pressure to remove the solvent. The obtained residue is purified by silica gel column chromatography (ethyl acetate) and then recrystallized from ethyl acetate/hexane. Thus, 0.49 g (yield 72%) of a white crystal is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[CH3:17]I.[Cl-].[NH4+]>CN(C=O)C>[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:15][CH3:17])([CH3:14])[CH3:13])=[CH:8][CH:7]=1
Reactant: CI
Reactant: COC(=O)c1ccc(C(C)(C)O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C)(C)OC)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.8 %

Procedure:
439 mg of sodium hydride (60% in mineral oil) were suspended in 10 ml DMF and a solution of 1.64 g of 4-(1-hydroxy-1-methyl-ethyl)-benzoic acid methyl ester (8.4 mmol) in 10 ml DMF was added at 0° C. The mixture was allowed to warm to rt and was stirred for 1 h at this temperature before 0.79 ml of methyl iodide (12.7 mmol) were added. After 17 h additional 338 mg of sodium hydride (60% in mineral oil) and 0.53 ml methyl iodide (8.4 mmol) were added and stirring was continued for 20 h. Then saturated ammonium chloride solution was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried with magnesium sulfate, filtered and the solvent was evaporated. Chromatographic purification (silica gel; c-hexane/EtOAc 9:1 to 4:1) of the remaining residue yielded 661 mg (38%) of 4-(1-methoxy-1-methyl-ethyl)-benzoic acid methyl ester as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ 1.54 (s, 6H), 3.09 (s, 3H), 3.92 (s, 3H), 7.48 (d, J=9 Hz, 1H), 8.02 (d, J=9 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH2:25])=[N:21]2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH:25][CH:10]3[CH2:11][CH2:12][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:8][CH2:9]3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: Nc1ncn(Cc2ccc(F)cc2)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4ccc(F)cc4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(4-fluoro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid.
Reaction SMILES: C([Cl:4])(=O)C.[F:5][C:6]1[CH:7]=[CH:8][C:9]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[C@@H:21]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[CH2:20]3)[C:16]3[C:15]4[CH:36]=[CH:37][CH:38]=[CH:39][C:14]=4[S:13][C:12]=3[NH:11][C:10]=2[CH:40]=1>C(O)C.C(#N)C.O>[ClH:4].[ClH:4].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[C@@H:21]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[CH2:20]3)[C:16]3[C:15]4[CH:36]=[CH:37][CH:38]=[CH:39][C:14]=4[S:13][C:12]=3[NH:11][C:10]=2[CH:40]=1
Reactant: CC(=O)Cl
Agent: COc1ccc(CC[C@H]2CN(C3=Nc4ccc(F)cc4Nc4sc5ccccc5c43)CCN2C)cc1
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add a solution of acetyl chloride (0.144 mL, 2.02 mmol) in absolute ethanol to a solution of (S)-9-fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene (0.174 g, 0.348 mmol) in absolute ethanol and stir briefly at ambient temperature. Concentrate solution under reduced pressure to give an orange solid. Reconstitute the solid in acetonitrile: water (1:1), freeze-dry the solution in a dry-ice/acetone bath, and lyophilize overnight to give the title compound (0.208 g) as a yellow solid: mass spectrum (APCI+, m/e): 501 (M+1–2HCl); exact mass spectrum (ES+, m/e, C29H29FN4OS.2HCl): calc. 501.2124 (M+1–2HCl), found 501.2130.
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([N:10]2[CH:22]=[CH:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:3]=1[CH:4]=[O:5].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([N:10]3[CH:22]=[CH:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[C:3]=2[CH:4]=[O:5])=[CH:30]1
Reactant: O=Cc1c(Br)cncc1-n1ccn2c3c(cc2c1=O)CCCC3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2cncc(-n3ccn4c5c(cc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 46.8 %

Procedure:
A sealed tube was charged with 126a (100 mg, 0.27 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 101l (125 mg, 0.27 mmol), PdCl2(dppf) (18 mg, 0.02 mmol), K3PO4 (30 mg), and NaOAc (20 mg) in CH3CN (5 mL) and H2O (1 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h, and then cooled to room temperature. It was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography eluting with 10:1 of DCM/MeOH to afford 126b (80 mg, 48%) as a yellow solid. MS: [M+H]+ 633.