Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](I)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:12]([CH:14]1[NH:18][C:17](=[O:19])[C:16]([CH3:21])([CH3:20])[C:15]1=[O:22])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:18]2[CH:14]([CH2:12][CH3:13])[C:15](=[O:22])[C:16]([CH3:21])([CH3:20])[C:17]2=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC1NC(=O)C(C)(C)C1=O
Reactant: Cc1c(I)ccc(C#N)c1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1C
Yield: 27.2 %

Procedure:
A solution of 2-chloro-4-iodo-3-methylbenzonitrile (983 mg), 5-ethyl-3,3-dimethylpyrrolidine-2,4-dione (550 mg), cesium carbonate (1.73 g), tris(dibenzylideneacetone)dipalladium(0) (325 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (615 mg) in dioxane was reacted in a microwave reactor at 120° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from THF/hexane to give the title compound as a colorless solid (yield: 294 mg, 27%).
Reaction SMILES: CC[O:3][C:4]([C@@H:6](O)[CH3:7])=O.[C:9]([OH:14])(=[O:13])[C@H:10]([CH3:12])[OH:11].C(O)(=O)C(C)O>>[CH3:12][C@@H:10]1[O:11][C:4](=[O:3])[C@H:6]([CH3:7])[O:14][C:9]1=[O:13]
Reactant: CCOC(=O)[C@H](C)O
Reactant: C[C@H](O)C(=O)O
Agent: CC(O)C(=O)O
Product: C[C@@H]1OC(=O)[C@H](C)OC1=O

Procedure:
The reaction was performed in the same manner as in Example 1 to produce lactide, except that a mixture containing L-ethyl lactate with L-lactic acid and an oligomer of lactic acid which were 10% by weight with respect to L-ethyl lactate.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl>O>[CH:8](=[C:7]1[NH:1][C:2](=[S:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CNC(=S)N1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1NC(=S)NC1=Cc1ccccc1

Procedure:
A flask equipped with a magnetic stirrer, nitrogen pressure, and reflux condenser was charged with thiohydantoin (24.9 g, 0.215 mol), benzaldehyde (22.8 g, 0.215 mol), triethylamine (43 g, 0.43 mol), and water (250 mL). Slight warming and vigorous stirring brought everything into solution. The mixture was stirred overnight and then transferred to an Erlenmeyer flask equipped with a magnetic stirrer. The pH was brought to ca. 3 with 3 M hydrochloric acid, and the mixture was stirred for 3 hr. The resulting solid was collected and washed with water and 2×50 mL of diethyl ether. The product weighed 97.6 g (97%). No other components were found in an HPLC trace at 260 and 350 nm. NMR (d6-DMSO) δ 7.2-7.8 (m, 5H), 6.4 (s, 1H), 3.5 (bs, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([C@H:7]([OH:10])[CH:8]=[CH2:9])[O:5][C:4](=[O:11])[C@@H:3]1[O:12][CH3:13].C([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[CH:16]1(/[CH:9]=[CH:8]/[C@H:7]([C@@H:6]2[O:5][C:4](=[O:11])[C@H:3]([O:12][CH3:13])[C@@H:2]2[OH:1])[OH:10])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=C[C@@H](O)[C@@H]1OC(=O)[C@H](OC)[C@@H]1O
Reactant: C=CC1CCCC1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Temperature: 60 °C

Procedure:
100 mg (0.53 mmol) of 18, 4 ml of CH2Cl2, 726 μl (5.3 mmol) of vinylcyclopentane and then 90.2 mg (106 μmol) of second-generation Grubbs catalyst are introduced into a 5 ml vial. The solution is microwave-heated at 60° C. for 10 min. The solvent is subsequently evaporated to dryness under reduced pressure and the residue is then purified on a Biotage 12-M silica column (eluent: 40/60 Hept/EtOAc). The product 19 (76.3 mg, Rf=0.35 under the elution conditions used) is obtained in the form of a brown solid.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][P:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23])([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])[O:4][CH3:5].B.[OH-].[Na+].OO.S(=O)(O)[O-:30].[Na+]>C(OCC)(=O)C>[CH3:5][O:4][P:3]([CH2:7][P:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:30])([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])[O:2][CH3:1]
Reactant: C=CCCCCCCCCCP(=O)(CP(=O)(OC)OC)OCC
Reactant: O=S([O-])O
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCCCCCCCCO)CP(=O)(OC)OC
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
((10-undecenyl)-ethoxyphosphinyl) methylphosphonic acid dimethyl ester (30 g, 81.4 mmol) was added slowly to the borane solution. The reaction mixture was stirred at −10° C. for 15 minutes and then warmed to ambient temperature and stirred for 2 hours. The solution was again cooled to −10° C. and 1N NaOH (81.4 mL, 81.4 mmol) was added dropwise in a manner that controlled the frothing. This addition was followed by the addition of a 30 wt % hydrogen peroxide solution (28.6 g). This mixture was then heated to 50° C. for 2 hours and then allowed to cool to ambient temperature. The excess peroxide was then reduced by the addition of aqueous sodium bisulfite (22 g in 120 mL water). The volatiles were removed by rotary evaporation to give a viscous liquid. The liquid was dissolved in ethyl acetate (800 mL) and then extracted twice with water (500 mL). The water layer was collected and extracted with ethyl acetate (600 mL). The organic extracts were combined and dried over sodium sulfate. The solvent was then removed by rotary evaporation revealing a viscous liquid. The liquid was placed under high vacuum to remove remaining volatiles providing the desired product (28.5 g, 90% yield). 1H NMR (400 MHz CDCl3): δ 4.0 (m, 2H), 3.7 (m, 6H), 3.5 (t, 2H), 2.3 (m, 2H), 1.8 (m, 2H), 1.5 (m, 4H), 1.2 (m, 18H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:14]2=[O:23])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:14]2=[O:23]
Reactant: COC(=O)c1cc(OCc2ccccc2)c2c(c1)C(=O)N(CC(C)C)CC2
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(O)c2c(c1)C(=O)N(CC(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of methyl 5-(benzyloxy)-2-isobutyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (1 g, 2.72 mmol) in MeOH (10 mL) was added catalyst amount of 10% Pd on C. This mixture was stirred under H2 balloon at room temperature for 3 hr. The solids were filtered through a bed of Celite. Removal of the solvent gave the product (750 mg, 98%) as light yellow solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97 (d, 6 H) 1.98-2.16 (m, 1 H) 3.05 (t, J=6.59 Hz, 2 H) 3.38-3.50 (m, 2 H) 3.57 (t, J=6.69 Hz, 2 H) 3.82-3.93 (m, 3 H) 7.50 (s, 1 H) 7.74 (d, J=1.51 Hz, 1 H) 8.30 (d, J=1.32 Hz, 1 H); MS (ESI, pos): 278.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.Cl([O-])(=O)(=O)=O.[Li+].[N:25]1([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:28]1[CH2:29][CH2:30][N:25]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[CH2:26][CH2:27]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: C[C@@H](N1CCN(c2nccs2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 77.3 %

Procedure:
To a mixture of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane IV (502 mg, 2 mmol) and lithium perchlorate (320 mg, 3 mmol) in acetonitrile (10 ml), 2-(piperazin-1-yl)thiazole (X)(507 mg, 3 mmol) was added. The resulting mixture was heated under reflux for 48 h. The reaction mixture was cooled, concentrated under reduced pressure. The residue was disolved in chloroform, washed with water, brine, dried (Na2SO4) and concentrated. The resulting product was purified on a column of silica gel using ethyl acetate and hexane (4:1) as eluent to give the title compound as colorless solid (650 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1.[NH3:12].CO>C1COCC1>[CH3:1][C:2]1[C:6]([S:7]([NH2:12])(=[O:9])=[O:8])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: Cc1noc(C)c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
3,5-Dimethylisoxazole-4-sulfonyl chloride (4.3 g; 21.8 mmol; 1 eq) is dissolved in THF (10 mL), ammonia in MeOH (55 mL; 2 M; 109 mmol; 5 eq) is added and the reaction is stirred for 1 h at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is taken up in 100 mL of EtOAc. The organic phase is washed with a saturated aqueous solution of NH4Cl (100 mL) then dried over MgSO4. The solvent is removed under reduced pressure, affording 2.6 g (67%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.59 (s, 2H), 2.56 (s, 3H), 2.34 (s, 3H). HPLC (max plot) 96.5%; Rt 1.22 min.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[H][H]>C(O)C.[Pd]>[F:19][C:2]([F:1])([F:18])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:16][CH:17]=1
Reactant: [O-][n+]1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)Oc1ccc(Oc2ccncc2)cc1
Yield: 100.5 %

Procedure:
After 4-[4-(Trifluoromethoxy)phenoxy]pyridine-N-oxide (130.0 g) was dissolved in ethanol (500 mL) and (50% wet) 5 w/w % palladium on carbon (6.5 g) was added. The resulting mixture was stirred under 3 atms of atmosphere of hydrogen at 27-49° C. for 6.5 hr. The reaction mixture was filtered to remove the catalyst followed by concentration in vacuo to give a quantitative yield (122.9 g) of pale yellow oily crude product. Purification by flash column chromatography (600 g of Silica Gel 60, spherical, ethyl acetate) afforded the pure target compound product as a colorless oil (86.74 g, 70.91% yield).
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(O)=O)C4)=CC=2)=CC=1.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:44](=[O:70])[NH:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[CH2:55]3)=[CH:48][CH:47]=1>>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:44](=[O:70])[NH:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[CH2:55]3)=[CH:48][CH:47]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)ccc2C1=O
Yield: 89 %

Procedure:
The compound of example 237 was prepared analogous to compound of example 225 by hydrolysis of compound of example 236.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10](Br)([F:12])[F:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:26]=[C:25]([N:27]2[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[N:28]2)[CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:12])([F:11])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[N:26]=[C:25]([N:27]3[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[N:28]3)[CH:24]=[CH:23][CH:22]=2)=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1C(F)(F)Br
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OC(F)(F)c3ccc(Br)cc3C=O)n2)c1C(F)(F)F

Procedure:
By analogy to Example 300 Step A, reaction of the title compound from Example 302 Step C with the title compound from Example 1 Step B provided the title compound: LCMS m/z 592.5 [M−F]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][Cl:33]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:29][CH2:30][CH2:31][CH2:32][Cl:33])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCl

Procedure:
Using 5 g of of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 131), 120 ml of methylisobutylketone, 3.5 g of potassium carbonate, and 2.9 ml of 1-bromo-4-chlorobutane, a reaction similar to that conducted in Example 106 was carried out. As a result, 5.79 g of N-(trans-4-methylcyclohexyl)-4-(4-chlorobutoxy ) - 3 -methoxycinnamamide ( a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [C:1]1([OH:21])[C:2]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[CH:3][CH:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.CS(O[CH:27]([CH3:29])[CH3:28])(=O)=O>[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C(Cl)(Cl)(Cl)Cl>[CH:27]([C:3]1[CH:4]=[C:5]2[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)=[C:1]([OH:21])[C:2]=1[C:11]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=1)([CH3:29])[CH3:28]
Reactant: Oc1c(-c2ccc3c(c2)CCCC3)ccc2c1CCCC2
Reactant: CC(C)OS(C)(=O)=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc2c(c(O)c1-c1ccc3c(c1)CCCC3)CCCC2
Reaction time: 18 h
Yield: 78 %

Procedure:
A mixture of 5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol (2 g, 6.8 mmol), isopropyl methanesulfonate (5.5 mmol), scandium triflate (0.34 g, 5 mol %), and carbon tetrachloride (10 ml) was brought to reflux under argon. After 18 hours, GC indicated 65% conversion to give 78% desired product. Additional isopropyl methanesulfonate (3.1 mmol) was added, and the reaction mixture was refluxed for another 8 hours. GC showed 86% conversion, and 76% selectivity to 3-isopropyl-5,5′,6,6′,7,7′,8,8′-octahydro-2,2′-binaphthol. The mixture was diluted with ether (20 ml) and 10% HCl (20 ml). The layers were separated, and the aqueous layer was extracted with ether (3×20 ml). The ether layers were combined, dried (MgSO4), and concentrated. The crude product was purified by column chromatography (SiO2, 2% ethyl acetate/hexanes) to yield 1.1 g white solid (48%). MP: 100–102° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].[C:13]1([C:19]2[O:20][CH:21]=[C:22](B3OC(C)(C)C(C)(C)O3)[N:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[C:13]1([C:19]2[O:20][CH:21]=[C:22]([C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([O:3][CH2:1][CH3:2])=[O:12])[N:23]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1(C)OB(c2coc(-c3ccccc3)n2)OC1(C)C
Reactant: CCOC(=O)c1cccnc1Cl
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cccnc1-c1coc(-c2ccccc2)n1
Temperature: 65 °C
Yield: 42 %

Procedure:
[1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (22 mg, 0.032 mmol) was added to a mixture of ethyl-2-chloronicotinate (120 mg, 0.647 mmol) and 2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (220 mg, 0.811 mmol) in dioxane (5 mL). After the addition of K2CO3 (402 mg, 2.910 mmol) the reaction mixture was heated at 65° C. for 4 h and then allowed to cool to room temperature. Water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water and dried (MgSO4). Purification of the thus obtained raw product by flash column chromatography (dichloromethane/EtOAc, gradient 5-10% EtOAc) provided the title compound (80 mg, 42%); ESI-MS [M+H+]=295.1.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C:28]4[CH2:29][C:30]([CH3:37])([CH3:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH:33]=4)[CH:13]=[C:14]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.[Pd]>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([CH:28]4[CH2:33][C:32]([CH3:35])([CH3:34])[NH:31][C:30]([CH3:37])([CH3:36])[CH2:29]4)[CH:13]=[C:14]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.06 g, 0.119 mmol) in EtOH (10 mL), 10% Pd/C in catalytic amount was added and stirred it at room temperature under hydrogen pressure (bladder pressure) for 3-5 hr. On completion of reaction, reaction mass filter it through celite bed, then filtrate was concentrated under reduce pressure. The residue was washed with acetonitrile followed by ether to provide the desired product (75% yield). LCMS: 505.30 (M+1)+; HPLC: 99.69% (@ 254 nm) (Rt; 5.517); 1H NMR (CD3OD-d6, 400 MHz) δ 11.54 (bs, 1H), 8.76 (t, 1H, J=4.8 Hz), 8.26 (s, 1H), 7.51 (s, 1H), 5.89 (s, 1H), 5.38-5.36 (m, 1H), 4.36 (d, 2H, J=4.8 Hz), 2.21 (s, 3H), 2.12 (s, 3H), 2.12 (m, 3H), 2.01-1.98 (m, 2H), 1.96-1.89 (m, 2H), 1.75-1.71 (m, 4H), 1.52 (m, 2H), 1.27 (s, 6H), 1.12 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:25]=3[NH2:32])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:43][S:44]([CH2:47][CH2:48][CH2:49][C:50](Cl)=[O:51])(=[O:46])=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:25]=3[NH:32][C:50](=[O:51])[CH2:49][CH2:48][CH2:47][S:44]([CH3:43])(=[O:46])=[O:45])[CH:21]=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH:14]=1)=[NH:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)CCCC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(Cl)cc2N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(Cl)cc2NC(=O)CCCS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
{[4-(2′-Amino-4′-chloro-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (120 mg, 0.22 mmol, Example 135, e) and Et3N (0.91 μL, 0.65 mmol) were dissolved into DCM (4 mL). To this was added (4-Methanesulfonyl-butyryl chloride (0.144 M, 3.1 mL, 0.44 mmol, Example 209: a) and the reaction was stirred at RT overnight. The solvents were removed in vacuo followed by purification by flash column chromatography (20% EtOAc/hexanes) that yielded the title compound as an orange solid (124 mg, 81%). ESI-MS (m/z): Calcd. for C29H34ClN3O7S4: 700.1 (M+1) found: 700.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[CH:7][C:6]([C:13]#[N:14])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=1.Br[CH2:25][CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCCO)C>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[NH:15][C:5]1[C:4]2[CH:3]=[C:2]3[NH:1][CH2:25][CH2:26][O:12][C:11]3=[CH:10][C:9]=2[N:8]=[CH:7][C:6]=1[C:13]#[N:14]
Reactant: BrCCBr
Reactant: N#Cc1cnc2cc(O)c(N)cc2c1Nc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCCO
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc(F)c(Cl)c1)NCCO3
Temperature: 135 °C
Yield: 45.1 %

Procedure:
An amount of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-hydroxy-quinoline-3-carbonitrile (4 g, 12.2 mmol) was stirred in 2-ethoxyethanol (480 mL), and to this were added 1,2-dibromoethane (22.9 g, 12.2 mmol), and potassium carbonate (10.1 g, 73 mmol), and the mixture was heated at 135° C. for 0.5 hours. After cooling to room temperature, the mixture was filtered over a thin silica pad and evaporated to an oil. To this was added ethyl acetate and saturated brine solution, and the layers were separated. The organic layer was dried on sodium sulfate and evaporated to a brown oil. Purification was carried out by flash chromatography (70% ethyl acetate in hexane) to yield a yellow solid (1.95 g, 45% yield), m.p. 244-245° C.; 1H NMR (DMSO-d6) δ 9.32 (s, 1H), 8.29 (s, 1H), 7.36 (m, 2H), 7.19 (s, 1H), 7.12 (m, 2H), 6.59 (s, 1H), 4.27 (m, 2H), 3.37 (m, 2H); HRMS (EI) m/z 355.07512 (M+1). Analysis for C18H12ClFN4.O0.1H2O.0.4CH3CO2C2H5: Found: C, 59.59; H, 3.66; N, 14.69. Calcd: C, 59.97; H, 3.93; N, 14.29.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@H:13]([CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:14]([NH2:16])=[O:15].CCN(C(C)C)C(C)C.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:14]([NH2:16])=[O:15])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: NC(=O)[C@H](N)Cc1cccs1
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ncc(N[C@H](Cc2cccs2)C(N)=O)nc1Cl
Yield: 76.4 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (137 mg, 0.787 mmol), (R)-2-amino-3-(thiophen-2-yl)propanamide hydrochloride (163 mg, 0.789 mmol) and DIEA (0.350 mL, 2.01 mmol) in DMF (4 mL) was stirred at room temperature for 4 h. Water and EtOAc were added. Organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-(thiophen-2-yl)propanamide (185 mg).
Reaction SMILES: Cl[C:2]([O:4][C:5]([CH2:8][CH3:9])([CH3:7])[CH3:6])=[O:3].[OH:10][N:11]=[C:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.O>C1C=CC=CC=1>[C:5]([O:4][C:2]([O:10][N:11]=[C:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:3])([CH2:8][CH3:9])([CH3:7])[CH3:6]
Reactant: CCC(C)(C)OC(=O)Cl
Reactant: CCOC(=O)C(C#N)=NO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)=NOC(=O)OC(C)(C)CC
Yield: 39.8 %

Procedure:
A solution of t-amyl chloroformate (0.05 mol) in an ether-toluene mixture (30 ml) is cooled to -10°C, and a solution of ethyl 2-hydroxyimino-2-cyanoacetate (7.2 g) and triethylamine (7.0 ml) in dry benzene (50 ml) is dropwise added thereto. The resulting mixture is allowed to stand at room temperature over night. The reaction mixture is admixed with water and filtered. The organic layer is separated, washed with water, dried and concentrated to give ethyl 2-t-amyloxycarbonyloxyimino-2-cyanoacetate (5.1 g) as an oil.