Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[C:92]([F:94])[CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C:78]([NH2:80])=[O:79])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:94][C:92]1[CH:91]=[C:49]([CH:48]=[C:47]([F:46])[CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C:78]([NH2:80])=[O:79])[CH2:75][CH2:76]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)cc(F)c6)c5)c4c3)cn2)CC1
Yield: 36.3 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(4-(5-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperazin-1-yl) acetamide (100 mg, 0.146 mmol) was hydrolyzed with lithium hydroxide (31 mg, 0.733 mmol) in THF/methanol/water (2/2/1 mL) to yield 28 mg (36.3% yield) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.53-8.48 (m, 3H), 8.259-8.257 (d, 1H), 8.15-8.05 (dd, 1H), 7.988-7.986 (d, 1H), 7.72 (s, 1H), 7.19-7.10 (d, 1H), 6.90-6.82 (m, 3H), 5.43 (s, 2H), 4.05-3.90 (m, 6H), 3.51-3.49 (t, 4H). MS: m/z=529.2 (M+1), HPLC: 98.61% in method A.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][C:9]([CH3:11])=[CH:8][C:6]=2[N:7]=1.[S:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][NH:16][CH2:15][CH2:14]1>>[S:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:16]([C:2]2[N:3]=[C:4]([NH:3][CH2:4][CH2:5][CH2:6][NH2:7])[C:5]3[S:10][C:9]([CH3:11])=[CH:8][C:6]=3[N:7]=2)[CH2:15][CH2:14]1
Reactant: Cc1cc2nc(Cl)nc(Cl)c2s1
Reactant: c1ccc2c(c1)CNCCS2
Product: Cc1cc2nc(N3CCSc4ccccc4C3)nc(NCCCN)c2s1

Procedure:
The title compound was prepared in analogy to Example 1-1 in Scheme 1 by using 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine and propane-1,3-diamne, followed by reaction with 2,3,4,5-tetrahydro-1,4-benzothiazepine. MS obsd. (ESI+) [(M+H)+] 386, 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.61-7.71 (m, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.15-7.23 (m, 1H), 7.08-7.15 (m, 1H), 6.80 (s, 1H), 5.00 (s, 2H), 4.41 (br. s., 2H), 3.75 (d, J=4.0 Hz, 2H), 2.89-2.98 (m, 4H), 2.53 (s, 3H), 1.84 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:11])[C:8]([NH2:10])=[O:9])=[CH:3][CH:2]=1.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1>O1CCCC1.O1CCOCC1>[NH2:10][C:8](=[O:9])[C@@H:7]([NH:11][CH2:13][CH2:12][CH2:18][S:15]([OH:17])(=[O:16])=[O:14])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=S1(=O)CCCO1
Reactant: NC(=O)C(N)c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC(=O)[C@@H](NCCCS(=O)(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
To a solution of D-Phenylglycine amide (850 mg, 7.5 mmol) in tetrahydrofuran (10 mL) and 1,4-dioxane (4 mL) was added 1,3-propanesultone (818 mg, 6.8 mmol). The solution stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in 50% water/EtOH mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (50 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (720 mg, 34%). 1H NMR (D2O, 500 MHz) δ ppm 7.38 (m, 5H), 4.92, (s, 1H), 3.00 (m, 1H), 2.90 (m, 1H), 2.78 (m, 2H), 1.97 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.14, 130.95, 130.24, 129.94, 128.74, 63.40, 47.99, 44.92, 21.27. [α]D=+106° (c=0.0016 in water), ES-MS 273 (M+1).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][CH:25]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=2)=[CH:28][CH:29]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 30.1 %

Procedure:
A solution of 3,5-dibromo-1-methyl-2-pyridone (267 mg, 1.0 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (568 mg, 1.0 mmol) in DMF (7 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3 ×). bis(triphenylphosphine)palladium dichloride (80 mg, 0.11 mmol) was added and the mixture was heated to 90° C. for 3 hr as the mixture turned dark. TLC indicated that the reaction was not complete and an additional 40 mg portion of the catalyst was added and heating continued for 4 hr. The mixture was allowed to cool and was diluted with dichloromethane (40 mL) and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was dissolved in ethyl acetate (30 mL). The solution was washed with water (1×10 mL), 5% potassium fluoride (2×10 mL) and brine (1×5 mL) and was dried (MgSO4). The residue obtained upon concentration was chromatographed over 45 g of silica gel eluting with 3:7 ethyl acetate:hexane to give 4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxyl)carbonyl]-L-phenylalanine methyl ester (140 mg, 30%). FAB MS: 465 (M+H (1 Br)).
Reaction SMILES: [C:1]1(=[O:15])[N:5]([CH2:6][CH2:7][CH2:8][OH:9])[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]12.[CH:16](O)=[O:17]>>[CH:16]([O:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:10])[C:3]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:2]2[C:1]1=[O:15])=[O:17]
Reactant: O=CO
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Product: O=COCCCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 3-(phthalimido)-propanol (20.5 g) and formic acid (33 ml) was refluxed overnight and evaporated in vacuo to leave a yellow oil which crystallized from absolute ethanol to give colourless crystals with m.p. 68°-70° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5](C(OC)=O)=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+].C1(P([N:30]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)([O-])O.[Na+]>CO.CN(C)C=O.O1CCOCC1.C(O)(C)(C)C.C(N(CC)CC)C>[CH:1]1([C:4]2[C:5]([NH2:30])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ncccc1C1CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nc1ncccc1C1CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
360 mg of the methyl 3-cyclopropylpyridine-2-carboxylate [121-4] was dissolved in 4 mL of methanol, then 4 mL of 1N aqueous solution of sodium hydroxide was added thereto, and stirred at 50° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the thus obtained residue was subjected to azeotrope twice with toluene to obtain a white solid. The obtained solid was dissolved in a mixture solvent of 4 mL of N,N-dimethylformamide and 3 mL of 1,4-dioxane, then 736 μL of triethylamine and 569 μL of diphenylphosphoryl azide were added under an ice-cold condition, and stirred at room temperature for 1 hour. Thereafter, 1.5 mL of t-butanol was added to the reaction mixture, and was stirred overnight at 80° C. After cooling the reaction mixture back to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by silica gel column chromatography, to obtain 41.2 mg of 3-cyclopropylpyridine-2-amine [121-5] as a light brown oily product.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[N:16]=[C:15](O)[CH:14]=[C:13]([CH3:18])[N:12]=2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:15]1[CH:14]=[C:13]([CH3:18])[N:12]=[C:11](/[CH:10]=[CH:9]/[C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:19])[CH3:1])=[CH:4][CH:5]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(C=Cc2ccc(N(C)C)cc2)n1
Product: Cc1cc(Cl)nc(/C=C/c2ccc(N(C)C)cc2)n1
Yield: 17.8 %

Procedure:
In analogy to example 12c), by heating 2-[2-(4-dimethylamino-phenyl)-vinyl]-6-methyl-pyrimidin-4-ol (2 g, 7.8 mmol) in POCl3 (14.3 ml, 157 mmol) at 130° C. for 4.5 h there was obtained (E)-4-chloro-2-[2-(4-dimethylamino-phenyl)-vinyl]-6-methyl-pyrimidine (0.38 g, 18.5%) as a dark oil. EI mass spectrum, m/e: 273 (M calculated for C15H16ClN3: 273).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=CI)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[Cl-].[NH4+].CC[O:27]CC>CCCCCC.CN(P(N(C)C)N(C)C)C>[Si:1]([O:8][C:9]12[CH2:10][CH:15]([CH2:14][CH2:13]1)[CH2:16][C:17]2=[O:27])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCCCCC(C=CI)O[Si](C)(C)C(C)(C)C
Reactant: CCOCC
Agent: CN(C)P(N(C)C)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC12CCC(CC1=O)C2
Reaction time: 0.5 h

Procedure:
3-t-Butyldimethylsilyloxy-1-iodo-1-octene (6.07 g) in dry light petroleum (b.p. 60°-80°, 50 ml) was cooled, under nitrogen, to -70°, 2.1 M n-butyllithium in hexane solution (8.0 ml) was added and the solution was stirred 1/2 hour at -70°. A solution of cuprous n-propyl acetylide (2.15 g) in ether (25 ml) and hexamethylphosphorus triamide (6.04 ml) was added to this solution which was stirred for a further 15 minutes at -70°. 3-endo-t-Butyldimethylsilyloxytricyclo[3,2,0,02,7 ]heptan-6-one (3.7 g) in dry ether (ca. 50 ml) was then added to the orange solution which was stored at -70° for 11/2 hours, and warmed to -30°. The cold reaction mixture was poured into saturated ammonium chloride solution (40 ml) and shaken. The organic layer was removed and the aqueous layer was extracted once with ether (20 ml). The combined organic solutions were then shaken with ice-cold 2% sulphuric acid (ca. 200 ml) and the mixture filtered through hyflo to remove precipitated copper salts. The organic layer was removed, washed once with 8% sodium bicarbonate solution and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica in light petroleum containing increasing amounts of ethyl acetate. Light petroleum eluted unreacted octene side chain and impure product was eluted with ethyl acetate/ light petroleum (5:95) as a pale yellow oil (5.26 g). Short path distillation afforded pure title compound as a pale yellow oil (3.29 g) b.p. ca. 180°-200°/0.15 mm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[CH3:18])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[C:10]([CH3:18])[CH:11]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-c1cccc(C#N)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)ccc1-c1cccc(C#N)c1
Temperature: 70 °C
Yield: 68.5 %

Procedure:
1-(3-Cyanophenyl)-2-methyl-4-nitrobenzene (3.0 gm, 12.61 mmol) and tin(II) chloride dihydrate were suspended in ethanol (30 mL) and heated to 70° C. for 30 mins. After being cooled, the mixture was poured onto ice, and neutralised by the addition of sodium bicarbonate. The mixture was then extracted with dichloromethane (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give 4-amino-1-(3-cyanophenyl)-2-methylbenzene (1.8 gm, 69%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]N(C=O)C.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a 500 ml flask under nitrogen atmosphere was charged 3-fluoro-4-nitro benzoic acid (10 g, 0.054 mol, 1 eq) and 250 ml of Toluene followed by DMF (210 ul, 3.7 mmol, 0.05 eq) and was heated to 70° C. At 40° C. thionyl chloride (8.0 ml, 0.11 mol, 2.0 eq) was added and the reaction was allowed to stir at 70° C. for 16 hours. The reaction was removed from the heat and placed in an ambient temperature bath. 100 ml of anhydrous methanol was added and then concentrated on rotary evaporator under reduced pressure, and bath temp of 45° C. The final volume was reduced to ˜70 ml and slowly add hexane 100 ml with stiring to yield a light yellow solid, yield 97%. 1H NMR (Solvent CDCl3), Singlet, 3 H, 3.99 ppm, Doublet of Doublets, 2H, 7.95 ppm, Triplet, 1H, 8.15 ppm. Thin Layer Chromatography elution 5% methanol/dichloromethane, Rf=0.9.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[OH:28])[CH:23]=O>>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])[CH:25]=[CH:26][C:27]=1[OH:28]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: O=C(C=Cc1ccc(O)c(Br)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(3-Bromo-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 3-bromo-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is crystallized from ethanol.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24]C=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.CC1C(N)=C(C)[O:49][N:48]=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[C:21]([CH3:22])=[N:48][O:49][C:25]=4[CH3:24])[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Cc1noc(C)c1N
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Cc1noc(C)c1Nc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,5-dimethyl-4-isoxazolamine were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dimethylisoxazol-4-yl)-2,4-pyrimidinediamine. LCMS: ret. time: 18.89 min.; purity: 98%; MS (m/e): 358 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]([CH3:20])[C:8]([NH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:9].[NH2:21][C:22]1[C:27]([NH:28]C(=O)OCC2C=CC=CC=2)=[CH:26][CH:25]=[C:24]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:23]=1>>[NH2:28][C:27]1[C:22]([NH:21][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])[CH3:20])=[CH:19][CH:18]=2)=[N:23][C:24]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:25][CH:26]=1
Reactant: Nc1nc(-c2ccccc2)ccc1NC(=O)OCc1ccccc1
Reactant: CC(C(=O)Nc1ccc(C(=O)O)cc1)N1CCCC1=O
Product: CC(C(=O)Nc1ccc(C(=O)Nc2nc(-c3ccccc3)ccc2N)cc1)N1CCCC1=O

Procedure:
Similar procedure from Example 2 was followed to obtain benzyl 2-(4-(2-(2-oxopyrrolidin-1-yl)propanamido)benzamido)-6-phenylpyridin-3-ylcarbamate using 4-(2-(2-oxopyrrolidin-1-yl)propanamido)benzoic acid and benzyl 2-amino-6-phenylpyridin-3-ylcarbamate. The Cbz group was then deprotected under standard hydrogenation conditions to give the title compound. C25H25N5O3 444.0 (M+1). 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H); 10.25 (s, 1H); 8.01 (d, J=8.8 Hz, 2H); 7.92 (d, J=8.8 Hz, 2H); 7.71 (d, J=8.4 Hz, 2H); 7.65 (d, J=8.4 Hz, 1H); 7.38-7.35 (m, 2H); 7.27-7.22 (m, 2H); 5.11 (s, 2H); 4.70 (q, J=7.2 Hz, 1H); 3.55 (m, 1H); 3.44 (m, 1H); 2.26-2.23 (m, 2H); 1.97-1.91 (m, 2H); 1.36 (d, J=7.2 Hz, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][C:15]=1[F:27].[CH2:28]1[O:31][C@@H:29]1[CH3:30]>C1COCC1>[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[C:16]([CH2:28][C@H:29]([OH:31])[CH3:30])[C:15]=1[F:27]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1
Reactant: C[C@@H]1CO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[C@@H](O)Cc1c(C(=O)NC(C)(C)C)ccc(Br)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (11.7 mL, 82.0 mmol) in THF (200 mL) was treated with n-butyllithium (33 mL, 82 mmol) at 0° C. The solution was stirred for 30 min before being cooled to −78° C. Next, a solution of 4-bromo-N-tert-butyl-3-fluorobenzamide (9.0 g, 33 mmol) in THF (100 mL) was added. The solution was then warmed to −40° C. and maintained there for 1 h. Next, (R)-(+)-propylene oxide (6.9 mL, 98 mmol) was added and the solution warmed to 0° C. After 1 h, the ice bath was removed and the solution was allowed to warm to rt. LC/MS indicated desired product present. The solution was quenched with MeOH, diluted with brine (200 mL), and extracted with EtOAc (300 mL). The organic layer was removed, dried over MgSO4, filtered and concentrated. The crude material was purified using a 340 g Biotage SNAP (0-60% Hexanes: EtOAc) cartridge to yield the title compound. LC-MS: m/z 332.08 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17]C)[N:3]=1.C(Cl)Cl.B(Br)(Br)Br>O>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([OH:17])=[C:10]([C:4]2[C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=2)[CH:15]=1
Reactant: COc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)c1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)c1Cl
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A 250 mL 2-neck flask fitted with a rubber septum, temperature probe, and addition funnel was charged with 2,4,5-trichloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidine (5.97 g, 18.54 mmol) and CH2Cl2 (90 mL) and kept under a N2 atmosphere. BBr3 (1 M in CH2Cl2; 37.1 mL, 37.1 mmol, 2 equiv.) was added slowly via addition funnel so that the temperature never exceeded 25° C. After 1 h, water (90 mL) was added and the mixture was stirred for approximately 30 min. The organic layer was washed with satd. aq. NaHCO3, dried, and concentrated to give a yellow powder (5.6 g, 98%). MS (ESI+): mass calcd. for C10H5Cl4N2O, 308.9; m/z found, 308.9 [M+H]+. 1H NMR (CDCl3): 9.76 (s, 1H), 8.00 (d, J=2.6 Hz, 1H), 7.39 (dd, J=8.9, 2.6 Hz, 1H), 7.03 (d, J=8.9 Hz, 1H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[C:15](=[O:17])[N:14]4[C:18]([CH3:21])=[N:19][N:20]=[C:13]4[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:11]=3[N:10]=[C:9]2[C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)=CC=1>FC(F)(F)C(O)=O>[CH3:21][C:18]1[N:14]2[C:15](=[O:17])[C:16]3[NH:8][C:9]([C:27]4[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=4)=[N:10][C:11]=3[N:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:13]2=[N:20][N:19]=1
Reactant: CCCCCn1c2nc(-c3cnn(C)c3)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Solvent: O=C(O)C(F)(F)F
Product: CCCCCn1c2nc(-c3cnn(C)c3)[nH]c2c(=O)n2c(C)nnc12

Procedure:
6-(4-Methoxybenzyl)-3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (50 mg, 0.10 mmol) in trifluoroacetic acid (5 mL) was stirred at 60° C. overnight. The mixture was concentrated, and the residue was purified by preparative LC-MS to give final product. 1HNMR (300 MHz, CD3OD): δ 8.23 (d, J=4.9 Hz, 1H), 8.05 (d, J=4.9 Hz, 1H), 4.45 (t, J=7.0 Hz, 2H), 3.98 (s, 3H), 2.46 (s, 3H), 1.93 (m, 2H), 1.41 (m, 4H), 0.92 (m, 3H). LCMS calculated for C16H21N8O(M+H): 341.2; found 341.2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=2)=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].[Br-].[CH:20]1([Zn+])[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCOCC1.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>[CH:20]1([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:9]=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=3)=[CH:4][C:3]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(-c2cncc(C)c2)cnc1Cl
Reactant: [Zn+]C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cncc(C)c2)cnc1C1CCCC1
Temperature: 90 °C

Procedure:
To a solution of methyl 6-chloro-5′-methyl-3,3′-bipyridine-5-carboxylate (6-1, 0.15 g, 0.57 mmol, 1.0 equiv, prepared in an analogous fashion to Examples 2 and 8) in dioxane (2.9 mL) at 25° C. was added cyclopentylzinc bromide (3.43 mL, 1.71 mmol, 3.0 equiv, 0.5 M in THF) and tetrakis(triphenylphosphine)palladium(0) (0.099 g, 0.086 mmol, 0.15 equiv). The reaction mixture was heated for 3 h at 90° C. The reaction mixture was cooled partitioned between water (10 mL) and EtOAc (30 mL), washed with water (3×30 mL) and brine (1×30 mL), and the organic phase was dried over magnesium sulfate. The residue was purified via normal phase chromatography (5 to 100% EtOAc in hexanes, silica) to afford the desired product (6-2) as an oil after concentration. ESI+MS [M+H]+ C18H20N2O2 calc'd 297.2, found 297.1
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH:37]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(Cl)Cl>[N:37]1([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1
Reactant: C1CNCCNC1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)c1ccccc1
Solvent: ClCCl
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnn5ccc(CN6CCCNCC6)c45)ccc32)c1
Temperature: 135 °C
Yield: 82.1 %

Procedure:
A mixture of (5-benzenesulfinylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (50 mg, 0.101 mmole) and homopiperazine (300 mg, 30 equiv) in a sealed tube was heated at 135° C. overnight. The reaction mixture was taken up in DCM, washed with water, and dried (Na2SO4). Removal of the solvent followed by radial chromatography (2 mm silica gel plate eluted with DCM containing 5% MeOH) afforded the title compound as a foam (39 mg, 82%). 1H NMR (CDCl3) δ 1.85 (m, 2H), 2.96 (m, 8H), 3.91 (s, 2H), 5.58 (s, 2H), 6.50 (d, 1H, J=3 Hz), 6.8-7.6 (m, 7H), 7.89 (s, 1H), 8.05 (d, 1H, J=1 Hz), 8.11 (d, 1H, J=2 Hz); MS: 471 (M+H)+; HPLC Ret Time: 1.09 min (YMC Xterra ODS S7, 3.0×50 mm column, 2 min gradient, 5 mL/min).