Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([NH2:11])=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C.C(Cl)(Cl)Cl.C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:4]([NH2:11])[N:3]=1
Reactant: Nc1[nH]c(Cl)nc2ncnc1-2
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Nc1nc(Cl)nc2c1ncn2CC1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a suspension of 2-chloro-1H-purin-6-amine (1.57 g) and potassium carbonate (2.57 g) in DMF (55 mL) was added 4-(bromomethyl)tetrahydro-2H-pyran (2.0 g) in one portion. The mixture was stirred at 90° C. overnight. The reaction mixture was taken up in chloroform/isopropanol (3:1, 100 mL) and was extracted with water (100 mL). The organics were separated and the aqueous was extracted with chloroform/isopropanol (3:1, 2×50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give the title compound as an off-white solid (1.30 g, 52%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][CH:9]=[CH:8][C:7]=1[C:26]1[CH:31]=[C:30]([NH:32][C:33]2[CH:44]=[C:36]3[CH2:37][N:38]([C:41](=[O:43])[CH3:42])[CH2:39][CH2:40][N:35]3[N:34]=2)[C:29](=[O:45])[N:28]([CH3:46])[CH:27]=1)(=O)C.[OH-].[Li+].C1COCC1.CC(O)C>CO.CCOCC.O.CCOC(C)=O>[C:41]([N:38]1[CH2:39][CH2:40][N:35]2[N:34]=[C:33]([NH:32][C:30]3[C:29](=[O:45])[N:28]([CH3:46])[CH:27]=[C:26]([C:7]4[C:6]([CH2:5][OH:4])=[C:11]([N:12]5[CH2:24][CH2:23][N:15]6[C:16]7[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=7[CH:22]=[C:14]6[C:13]5=[O:25])[CH:10]=[CH:9][CH:8]=4)[CH:31]=3)[CH:44]=[C:36]2[CH2:37]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(C)=O)C4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N1CCn2nc(Nc3cc(-c4cccc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A 25 mL round bottom flask with a magnetic stirrer was charged with 2-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 108e (69 mg, 0.11 mmol), lithium hydroxide (8 mg, 0.3 mmol), THF (1 mL), i-PrOH (1 mL) and water (2 mL). The mixture stirred at rt for 2 h. After this time, EtOAc (3 mL) and water (3 mL) were added. The separated aqueous layer was extracted with EtOAc (2×5 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography eluting with a gradient of CH2Cl2-75:18:7 CH2Cl2:Et2O:MeOH to afford a 63% yield (40 mg) of 2-(3-(5-(5-acetyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 108. MS (ESI+) m/z 582.3 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=[O:13])[N:10]([CH:14]([C:20](OCC)=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])(=[O:35])=[O:34])=[CH:29][C:28]=1[Cl:48]>C1(C)C(C)=CC=CC=1>[Cl:48][C:28]1[CH:29]=[C:30]([S:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])(=[O:35])=[O:34])[CH:31]=[CH:32][C:27]=1[NH:26][C:20](=[O:21])[CH:14]([N:10]1[C:11](=[O:13])[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(C(=O)OCC)N1C(=O)CN(Cc2ccccc2)C1=O
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(N)c(Cl)c1
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(NC(=O)C(C(=O)OCC)N2C(=O)CN(Cc3ccccc3)C2=O)c(Cl)c1
Temperature: 70 °C

Procedure:
Diethyl 2-(3-benzyl-2,5-dioxo-1,3-diazolidin-1-yl)-malonate (19.3 g, 55.5 mmol) and (4-amino-3-chloro-phenyl)dodecylsulphone (20.0 g,56.0 mmol) were added to xylene (100 ml) and refluxed under Dean and Stark conditions for 80 hr, occasionally removing a small amount of distillate and replenishing the solvent as necessary. The reaction was followed by TLC (1:2 ethyl acetate:60-80° C. petroleum ether), the Rf of the product being between that of the two starting materials. The xylene was removed on the rotary evaporator and the residual yellowish oil stirred with 60-80° C. petroleum ether (100 ml), allowed to settle and decanted from the oil. This removed some front-running impurities. On standing the oil solidified to a crystalline mass which was crystallized from toluene and petrol to give a white solid, 17.0 g, 46%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]([CH3:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[CH2:11]([O:13][C:14]([C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1)=[O:15])[CH3:12]>CN(C=O)C>[CH2:11]([O:13][C:14]([C:16]1[N:17]=[N:18][C:19]([O:3][C:4]2[C:5]([CH3:10])=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:20][CH:21]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1ccc(Cl)nn1
Reactant: Cc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2cccnc2C)nn1
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
Sodium hydride (0.21 g of an 80% dispersion in oil, 7.0 mmol) was added to a solution of 3-hydroxy-2-methylpyridine (0.88 g, 8.0 mmol) in DMF (15 ml). After 1.5 h at r.t. a solution of 6-chloropyridazine-3-carboxylic acid ethyl ester (Chem. Pharm. Bull. 1994, 42(2), 371) (1.0 g, 5.4 mmol) in DMF (10 ml) was added and the mixture was stirred for a further 1.5 h. The DMF was removed in vacuo and the residue partitioned between dil. aq. NaOH (50 ml) and CH2Cl2 (100 ml). After drying (Na2SO4) the organics were evaporated to give the title compound as an off-white solid (1.09 g, 78%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:13]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)=[CH:12][N:11](S(C3C=CC=CC=3)(=O)=O)[C:8]2=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>CCO.CCOC(C)=O.[Cl-].[Na+].O>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:13]([C:14]3[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cnc2c(c1)c(-c1cnn(C)c1)cn2S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Cc1cnc2[nH]cc(-c3cnn(C)c3)c2c1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 97.3 %

Procedure:
To crude azaindole 62 (118 mg) in EtOH (6 mL) was added 10% NaOH (1 mL) and the mixture was stirred in an oil bath (90° C.) for 4.5 h. The mixture was then cooled to r.t., diluted with AcOEt and saturated brine and partitioned. The aqueous layer was extracted with AcOEt (3×). The combined organic solutions were dried (MgSO4), filtered and concentrated. The residual yellow oil was partially purified by means of PTLC employing AcOEt as eluent to afford a semi-pure azaindole 63 (74 mg). A fraction (14 mg) of this material was further purified by means of preparative LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give the desired azaindole 63 (5.6 mg, 25%); 1H NMR (400 MHz; CDCl3) δ 0.92 (s, 3H), 0.94 (s, 3H), 1.90 (m, 1H), 2.59 (d, J=7.2 Hz, 2H), 3.98 (s, 3H), 7.36 (d, J=2.1 Hz, 1H), 7.60 (s, 1H), 7.74 (d, J=0.6 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 9.62 (br s, 1H); MS (CI) m/z 255 (MH+).
Reaction SMILES: C1C2C(COC(N[C@@H](CSC[C@H](O)CO)C(OC(C)(C)C)=O)=O)C3C(=CC=CC=3)C=2C=CC=1.C(Cl)(=O)CCCCCCCCC.[C:46]([O:59][CH2:60][C@@H:61]([O:91][C:92](=[O:104])[CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101]CC)[CH2:62][S:63][CH2:64][C@H:65]([NH:73][C:74]([O:76][CH2:77][CH:78]1[C:90]2[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=2[C:84]2[C:79]1=[CH:80][CH:81]=[CH:82][CH:83]=2)=[O:75])[C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])(=[O:58])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]CC>>[C:46]([O:59][CH2:60][C@@H:61]([O:91][C:92](=[O:104])[CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH3:101])[CH2:62][S:63][CH2:64][C@H:65]([NH:73][C:74]([O:76][CH2:77][CH:78]1[C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][C:84]=2[C:85]2[C:90]1=[CH:89][CH:88]=[CH:87][CH:86]=2)=[O:75])[C:66]([O:68][C:69]([CH3:70])([CH3:72])[CH3:71])=[O:67])(=[O:58])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Agent: CC(C)(C)OC(=O)[C@H](CSC[C@H](O)CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCCCCCCCCC(=O)Cl
Product: CCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCC

Procedure:
The product was prepared from (R)-tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-((R)-2,3-dihydroxypropylthio)propanoate (10, 1 eq) and decanoyl chloride (3.7 eq) by following the procedure described for compound 11.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(ethoxycarbonylmethyl)piperidine (0.0222 mol) and 2-chloro-5-nitropyridine (0.0222 mol) in DMSO (40 ml) was stirred in the presence of Na2CO3 during 2 hours. The reaction mixture was cooled to room temperature and poured into an ice/water mixture. The resulting precipitate was filtered and washed with water. The reaction product was purified by recrystallisation from a mixture of ethyl acetate and hexane, yielding (5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester (intermediate 1, mp. 99-101° C.).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([Cl:10])=[CH:4][CH:3]=1.[F-].[Cs+].[CH3:13][O:14][C:15]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:16]=1[CH2:17][N:18]1[C@@H:22](/[CH:23]=[C:24](\[C:38]2[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=2)/[Sn](CCCC)(CCCC)CCCC)[CH2:21][CH2:20][C:19]1=[O:47].O>CN(C)C=O.[Cu](I)I.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.C(OCC)(=O)C>[Cl:10][C:5]1[CH:4]=[CH:3][C:2](/[C:24](/[C:38]2[CH:39]=[CH:40][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:42][CH:43]=2)=[CH:23]/[C@@H:22]2[N:18]([CH2:17][C:16]3[CH:48]=[CH:49][C:50]([O:52][CH3:53])=[CH:51][C:15]=3[O:14][CH3:13])[C:19](=[O:47])[CH2:20][CH2:21]2)=[N:7][C:6]=1[O:8][CH3:9]
Reactant: COc1nc(Br)ccc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/[C@H]1CCC(=O)N1Cc1ccc(OC)cc1OC)c1ccc(C(C)C)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)C)cc2)c2ccc(Cl)c(OC)n2)c(OC)c1
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
6-bromo-3-chloro-2-methoxypyridine (361 mg), cesium fluoride (246 mg), copper iodide (170 mg) and tetrakis(triphenylphosphine)palladium(0) (92 mg) were added to a solution of (5R)-1-(2,4-dimethoxybenzyl)-5-[(E)-2-[4-(propan-2-yl)phenyl]-2-(tributylstannyl)ethenyl]pyrrolidin-2-one obtained in Reference Example 4-27 (543 mg) in N,N-dimethylformamide (6 mL), and the mixture was stirred at 65° C. for 1.5 hours. Water and ethyl acetate were added to the reaction solution. After filtration through celite, the organic layer was washed with brine. The organic layer dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→0:1) to give (5R)-5-{(E)-2-(5-chloro-6-methoxypyridin-2-yl)-2-[4-(propan-2-yl)phenyl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a yellow oil (268 mg).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7]C(N)=[CH:4][C:3]=1[CH3:9].C([O-])(O)=O.[Na+].IC.[CH3:17][N:18]([CH:20]=O)[CH3:19]>C(OCC)(=O)C.O>[I:1][C:2]1[CH:8]=[CH:7][C:20]([N:18]([CH3:19])[CH3:17])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1I
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: Cc1cc(N(C)C)ccc1I

Procedure:
To a solution of 4-iodo-3-methylaniline (commercially available) (1 eq), NaHCO3 (2.5 eq), and iodomethane (2.5 eq), in DMF ((0.2M) was stirred at ambient temperature overnight. The reaction mixture was then diluted with ethyl acetate and water. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane and 4-iodo-N,N,3-trimethylaniline was isolated as a yellow solid.
Reaction SMILES: C(OC([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[C:13]([F:30])([F:29])[CH2:12]1)=O)C1C=CC=CC=1>CO.O1CCCC1.[C].[Pd]>[F:30][C:13]1([F:29])[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:15]2)[NH:11][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: FC1(F)CNC12CCCN(c1ncnc3[nH]ccc13)C2
Reaction time: 21 h
Yield: 81.4 %

Procedure:
To a solution of an optically-active compound of 3,3-difluoro-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diaza-spiro[3.5]nonane-1-carboxylic acid benzyl ester (12.0 g) in methanol/tetrahydrofuran (120 ml/120 ml) was added 10% palladium carbon (2.4 g), and the mixture was hydrogenated at room temperature under 4 atmospheres for 21 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was slurry-purified by a mixed solvent of n-hexane/ethyl acetate (2/1) to give the titled compound (6.6 g).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:16]2[CH:12]([O:13][C:14]([CH3:18])([CH3:17])[O:15]2)[O:11][C:10]1([CH2:38][OH:39])[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:8][CH:9]1[CH:16]2[CH:12]([O:13][C:14]([CH3:17])([CH3:18])[O:15]2)[O:11][C:10]1([C:19]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:38]=[O:39])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC2OC(CO)(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(OCc3ccccc3)C2O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(C)OC2OC(C=O)(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(OCc3ccccc3)C2O1
Yield: 96 %

Procedure:
To a flask was added [6-Benzyloxy-5-(tert-butyl-diphenyl-silanyloxymethyl)-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]dioxol-5-yl]-methanol, methylene chloride, and Dess-Martin periodinane. The reaction was stirred, extracted, and the solvent was evaporated to provide the titled aldehyde in 96% yield.
Reaction SMILES: CON(C)[C:4](=[O:22])/[CH:5]=[C:6](/[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1)\[CH3:7].[C:24]1([CH3:32])[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1.CCOCC.[NH4+].[Cl-]>C1COCC1.O>[C:24]1([CH3:32])[CH:29]=[CH:28][C:27]([C:4](=[O:22])/[CH:5]=[C:6](/[C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:12][CH:13]=2)\[CH3:7])=[CH:26][CH:25]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)/C=C(\C)c1ccc(OCCCC(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C/C(=C\C(=O)c1ccc(C)cc1)c1ccc(OCCCC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 76 %

Procedure:
To a solution of Intermediate 11C (1.62 g, 4.89 mmol) in anhydrous THF (25 mL) at −78° C. was added dropwise 0.5 M p-tolylmagnesium bromide in ether (25 mL, 12.5 mmol). The reaction was stirred at −78° C. for 40 min, then gradually warmed to rt. The reaction was poured into 1:1 sat'd aq NH4Cl and water (60 mL). The mixture was extracted with EtOAc. The organic layer was washed with sat'd aq NaCl, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluted with EtOAc in hexanes) to provide Intermediate 11D (1.34 g, 76%) as a light brown solid. LCMS Anal. Calc'd for C21H21F3O2 362.39, found [M+H] 363.2. 1H NMR (500 MHz, CDCl3) δ 2.01-2.11 (m, 2H), 2.29-2.37 (m, 2H), 2.42 (s, 3H), 2.58 (s, 3H), 4.07 (t, J=6.05 Hz, 2H), 6.92 (d, J=8.80 Hz, 2H), 7.14 (s, 1H), 7.23-7.34 (m, J=8.25 Hz, 2H), 7.55 (d, J=8.80 Hz, 2H), 7.90 (d, J=8.25 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18]S(O)(=O)=O.CO>>[CH3:18][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: CS(=O)(=O)O
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Solvent: CO
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Yield: 948.5 %

Procedure:
As in Example 2, a melt of 10 g (0.0455 mol) of 3,5-diphenylpyrazole and 0.44 g (0.0045 mol) of methanesulfonic acid was introduced and reacted over the course of 4 hours with 175 g (5.46 mol) of gaseous methanol (vaporized at 160° C.). 10 g (92%) of 1-methyl-3,5-diphenylpyrazole were obtained, boiling point 190° C./3 mbar, with a content of 98% (GC).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:31])[C:23]=4[O:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:41][CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[O:28])=[C:24]([F:31])[C:23]=4[O:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc(C(=O)O)c1F
Reactant: CN1CCC(N)CC1
Product: COc1c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)ccc(C(=O)NC2CCN(C)CC2)c1F

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-3-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the General procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.66 (m, 7H) 1.75 (m, 4H) 1.82-2.04 (m, 4H) 2.15 (m, 3H) 2.66-2.81 (m, 2H) 3.16 (s, 1H) 3.70 (m, 1H) 3.90 (s, 3H) 4.05 (t, J=13.8 Hz, 2H) 4.77 (m, 1H) 7.24 (t, J=8.1 Hz, 1H) 7.96-8.13 (m, 2H) 8.26 (s, 1H) 8.35 (s, 1H). [M+H] calc'd for C27H34F3N7O3, 562. found 562.
Reaction SMILES: ClC1C(OC)=NN=NC=1OC.[NH2:12][C:13]1[NH:14][C:15](=[O:33])[C:16]2[CH:21]([CH2:22][CH2:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[CH2:20][NH:19][C:17]=2[N:18]=1.CN1CCOCC1.Cl.[CH2:42]([O:44][C:45](=[O:55])[C@H:46]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH2:47])[CH3:43]>CN(C)C=O>[CH2:42]([O:44][C:45](=[O:55])[C@H:46]([CH2:48][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[NH:47][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][CH2:22][CH:21]2[C:16]3[C:15](=[O:33])[NH:14][C:13]([NH2:12])=[N:18][C:17]=3[NH:19][CH2:20]2)=[CH:25][CH:26]=1)[CH3:43]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: Nc1nc2c(c(=O)[nH]1)C(CCc1ccc(C(=O)O)cc1)CN2
Agent: COc1nnnc(OC)c1Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(N)[nH]c(=O)c32)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
1.12 Grams (6.36 mmol) of chlorodimethoxytriazine was added to a solution of 1.91 grams (6.36 mmol) of 4-(2-[2-amino-4,5,6,7-tetrahydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoic acid and 0.63 grams (6.3 mmol) of N-methylmorpholine (NMM) in 20 ml of dimethylformamide (DMF) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Next, an additional 0.3 grams (2.97 mmol) of NMM and 0.22 grams (1.25 mmol) of chlorodimethoxytriazine was added to the solution and the mixture stirred for an additional 30 min. Then, 0.64 grams (6.3 mmol) of NMM and 1.52 grams (6.3 mmol) of diethyl-L-glutamate hydrochloride was added to the mixture. After stirring overnight at room temperature, the resulting suspension was mixed with 30 grams of silica gel and dried under vacuum. The residue was added to a column of 70 grams silica gel and eluted with 500 ml of CH2Cl2 -EtOH 90:10 followed by CH2Cl2 -EtOH 80:20. 1.62 Grams (52%) of purified N-[4-[2-(2-amino-4,5,6,7-tetrahydro-4-oxo 3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester was obtained as a colorless powder. Selected data: 1H NMR (DMSO-d6) δ 9.55 (s, 1H), 8.60 (d, J=7.4 Hz, 1H), 7.73 (d, J=8.3 Hz, 2H) 7.27 (d, J=8.3 Hz, 2H), 6.28 (s, 1H), 6.20 (s, 2H), 4.38 (m, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.40 (m, 1H), 3.02 (m, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.39 (t, J=7.5 Hz, 2H), 2.00 (m, 3H), 1.54 (m, 1H), 1.13 (t, J =7.1 Hz, 3H), 1.11 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH2:12][C:13]1=[O:18])(=[O:21])[CH3:20]
Reactant: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)Cc2cc(C(=O)c3ccccc3)ccc21

Procedure:
Prepared from 5-benzoyl-2-indolinone and acetic anhydride