Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]2[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:10][CH:9]=[N:8][N:7]2[C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1.O[C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[O:15]1[CH2:16][CH2:17][N:12]([C:11]2[C:6]3[N:7]([C:18]([C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]5)=[N:23][CH:24]=4)=[C:4]([CH2:3][CH2:2][O:1][C:39]4[CH:40]=[N:41][C:42]5[C:47]([CH:48]=4)=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:5]=3)[N:8]=[CH:9][CH:10]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CCO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Reactant: Oc1cnc2ccccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CCOc4cnc5ccccc5c4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound 28f (97.3 mg, 0.191 mmol), 3-hydroxyquinoline (38.8 mg, 0.267 mmol), and PPh3 (70.1 mg, 0.267 mmol) were placed in an 8 mL vial equipped with a stir bar. DCM (2 mL) was added and the mixture was stirred at rt for 5 min. 40% Diethyl azodicarboxylate in toluene (0.104 mL, 0.229 mmol) was added dropwise and then the resulting solution was stirred at rt for 30 min. The crude reaction was chromatographed on a 12 g SiO2 pre-packed column and eluted with 0-80% ACN/DCM to afford compound 28g. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.59 (d, J=2.9 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 7.95-8.05 (m, 2H), 7.84 (dd, J=8.8, 2.2 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.45-7.59 (m, 2H), 7.37 (d, J=2.7 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.07 (d, J=5.6 Hz, 1H), 4.51 (t, J=6.7 Hz, 2H), 3.87-4.00 (m, 8H), 3.52-3.65 (m, 8H), 3.38 (t, J=6.7 Hz, 2H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H40N8O4: 637.3 (M+H). Found: 637.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.CO.[CH3:29][Si](C=[N+]=[N-])(C)C>C(OCC)(=O)C>[CH3:29][O:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC)c2[nH]1
Temperature: 4 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To an ice-cooled and stirred solution of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.08 g) in ethyl acetate (30 mL)-methanol (8 mL) was added 2M trimethylsilyldiazomethane (diethyl ether solution, 2.8 mL), and the mixture was stirred at 4° C. for 2 h, followed by an addition of 2M trimethylsilyldiazomethane (diethyl ether solution, 2.8 mL). After stirred at 4° C. for 1 h, the reaction mixture was quenched with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium hydrogen carbonate and brine, dried (MgSO4), filtered, and concentrated to give a light yellow oil, which was crystallized from ethyl acetate-hexane to give the title compound (933 mg, 83%) as pale yellow crystals. mp 161-162° C.
Reaction SMILES: [CH3:1][N:2]([C:20]1[C:21]2[CH:28]=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([OH:19])[CH2:14]2)(=[O:12])=[O:11])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:38](Cl)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:38]([O:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:13]([S:10]([CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:8][CH2:7]2)(=[O:12])=[O:11])[CH2:14]1)(=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]
Reactant: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](O)C2)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncnc2[nH]ccc12)[C@H]1CC[C@H](CS(=O)(=O)N2CCC[C@@H](OC(=O)C(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-(R)-1-((4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methylsulfonyl)piperidin-3-ol (0.400 g, 0.98 mmol), DMF (10 mL), and DIEA (0.25 mL, 1.4 mmol) was treated with pivaloyl chloride (0.10 mL, 0.81 mmol) and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the resulting residue chromatographed over SiO2 using 0→5% MeOH in CH2Cl2. The desired product fractions were pooled and concentrated to afford the title compound (0.182 g, 38%). MS for C24H37N5O4S (ESI) (MH)+ m/z=492.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([NH:12][C:13](=O)[CH2:14][Cl:15])=[C:4]([F:17])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>ClCCCl>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]#[CH:11])=[CH:6][C:5]([N:12]=[C:13]([Cl:38])[CH2:14][Cl:15])=[C:4]([F:17])[CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C#CCOc1cc(NC(=O)CCl)c(F)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: C#CCOc1cc(N=C(Cl)CCl)c(F)cc1Cl
Reaction time: 2 h

Procedure:
First, 2.00 g of N-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2-chloroacetamide, 4.50 g of triphenylphosphine and 5 ml of carbon tetrachloride were dissolved in 45 ml of 1,2-dichloroethane, and then the reflux under heat was continued for 2 hr. After letting the solution stand to cool the same, the solvent was distilled out under reduced pressure, and then the residue was refined by silica gel column chromatography (effluent: ethyl acetate/n-hexane (v/v)=6/4) to obtain 1.43 g of N-(4-chloro-2-fluoro-5-propargyloxyphenyl)-2-chloroacetimidoylchloride. The boiling point was 144°-146° C./0.4 mm Hg.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Cl)=[CH:17][CH:16]=1>C1COCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:4]([C:6]2[S:10][C:9]([CH3:11])=[N:8][C:7]=2[CH3:12])=[O:5])=[CH:17][CH:16]=1
Reactant: Cl[Mg]c1ccc(Cl)cc1
Reactant: CON(C)C(=O)c1sc(C)nc1C
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a flask containing N-methoxy-N,2,4-trimethylthiazole-5-carboxamide (510 mg, 2.55 mmol, Intermediate 17: step a) was added THF (18 mL) and the solution was cooled to 0° C. To this solution was added (4-chlorophenyl)magnesium chloride (1 M in diethylether, 3.3 mL, 3.3 mmol). A homogeneous yellow mixture resulted and was allowed to warm to room temperature over 15 minutes. After 2 hours, the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (100% DCM increasing to 10% EtOAc-DCM) provided the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:31])=[C:4]([N:20]2[C:28](=[O:29])[CH:27]3[CH:22]([CH2:23][CH2:24][CH2:25][CH2:26]3)[C:21]2=[O:30])[CH:5]=[C:6]([CH3:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[Cl:18]>C(OCC)(=O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:6]([CH3:19])=[CH:5][C:4]([N:20]3[C:21](=[O:30])[CH:22]4[CH:27]([CH2:26][CH2:25][CH2:24][CH2:23]4)[C:28]3=[O:29])=[C:3]([CH3:31])[C:2]=2[Br:1])=[C:10]([Cl:18])[CH:11]=1
Reactant: Cc1cc(N2C(=O)C3CCCCC3C2=O)c(C)c(Br)c1Oc1ccc([N+](=O)[O-])cc1Cl
Solvent: CCOC(C)=O
Product: Cc1cc(N2C(=O)C3CCCCC3C2=O)c(C)c(Br)c1Oc1ccc(N)cc1Cl
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
Into a Parr bottle was charged 8-[3-bromo-4-(2-chloro-4-nitrophenoxy)-2,5-dimethylphenyl]-8-azabicyclo[4.3.0]-nonan-7,9-dione (3.45 grams, 6.79 mmol) prepared in Part D and ethyl acetate (100 milliliters). The reaction mixture was purged with nitrogen, 5% platinum on carbon (480 milligrams) was added and the mixture was hydrogenated for 1.5 hours at 40-50 psi hydrogen and room temperature on a rocking Parr hydrogenator. Filtration through celite and concentration under reduced pressure afforded the desired product (2.73 grams, 5.71 mmol, 84%). H'-NMR (CDCl3) 6.93 (br s, 1H), 6.80 (d, J=2 Hz, 1H), 6.33 (m, 2H), 3.45 (br s, 2H), 3.06 (br m, 2H) 2.4-1.2 (m, 14H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:31](=[CH:32][CH:33]=2)[C:15]2[NH:16][C:17]([C@@H:19]4[CH2:23][CH2:22][CH2:21][N:20]4[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:18][C:14]=2[CH2:13][CH2:12]3)O1.Br[C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH:42]=[C:41]([C:46]1[NH:50][C:49]([C@@H:51]3[CH2:55][CH2:54][CH2:53][N:52]3[C:56](=[O:66])[C@@H:57]([NH:61][C:62](=[O:65])[O:63][CH3:64])[CH:58]([CH3:60])[CH3:59])=[N:48][CH:47]=1)[CH:40]=[CH:39]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:64][O:63][C:62]([NH:61][C@@H:57]([CH:58]([CH3:60])[CH3:59])[C:56]([N:52]1[CH2:53][CH2:54][CH2:55][C@H:51]1[C:49]1[NH:50][C:46]([C:41]2[CH:42]=[C:43]3[C:38](=[CH:39][CH:40]=2)[CH:37]=[C:36]([C:9]2[CH:10]=[C:11]4[C:31](=[CH:32][CH:33]=2)[C:15]2[NH:16][C:17]([C@@H:19]5[CH2:23][CH2:22][CH2:21][N:20]5[C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])=[N:18][C:14]=2[CH2:13][CH2:12]4)[CH:45]=[CH:44]3)=[CH:47][N:48]=1)=[O:66])=[O:65]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c([nH]1)-c1ccc(B3OC(C)(C)C(C)(C)O3)cc1CC2
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]c4-5)ccc3c2)[nH]1)C(C)C
Temperature: 85 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
(S)-tert-butyl 2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (574 mg, 1.23 mmol), methyl (S)-1-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (616 mg, 1.23 mmol), Pd(PPh3)4 (142 mg, 0.123 mmol), and K2CO3 (2M in H2O, 1.2 mL, 2.4 mmol) were combined in DME. The reaction mixture was degassed with bubbling N2 for 10 min, then heated to 85° C. After 16 h, the reaction mixture was cooled to RT and concentrated. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford the title compound (516 mg, 55%).
Reaction SMILES: S([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][NH:21][C:22]([C@@H:24]3[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.CCOC(C)=O>[C:22]1([C@@H:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]2)[N:19]2[C:14]3[CH:13]=[CH:12][NH:11][C:15]=3[N:16]=[CH:17][C:18]2=[N:20][N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NNC(=O)[C@@H]4CC[C@H](NC(=O)OC(C)(C)C)C4)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
To a solution of tert-butyl (1S,3R)-3-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (4.73 g, 9.19 mmol) in 1,4-dioxane (50 mL) was added TEA (5.10 mL, 36.8 mmol) and SOCl2 (1.34 mL, 18.4 mmol). The reaction mixture was heated at about 80° C. After about 1.5 h, saturated aqueous Na2CO3 (100 mL) was added and heating was resumed at about 80° C. for about 6 h. The reaction mixture was cooled to ambient temperature for about 3 days and then heated at about 80° C. for about 16 h. Water and EtOAc (100 mL each) were added and the layers were separated. The aqueous layer was then extracted with additional EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude solid was triturated with petroleum ether (b.p. 30-60° C.; 30 mL) and collected by vacuum filtration, while washing with additional petroleum ether (b.p. 30-60° C.; 20 mL), to give tert-butyl (1S,3R)-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylcarbamate as a light brown solid (2.86 g, 86%): LC/MS (Table 2, Method a) Rt=1.75 min; MS m/z: 343 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[OH-].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O.C(OCC)(=O)C>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: CCOC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 3,6-dibromocarbazole (325.0 mg, 1.0 mmol, 1 equiv) in anhydrous N,N-dimethylformamide (5 mL) was added crushed KOH (67.3 mg, 1.2 mmol, 1.2 equiv). The mixture was stirred for 30 minutes. Ethyl bromoacetate (277.2 μL, 2.5 mmol, 2.5 equiv) was added into the mixture and it was stirred at room temperature overnight. The reaction crude was diluted with ethyl acetate (30 mL) and washed with 1M HCl and water. The organic layer was dried with MgSO4 and the concentrated to afford 396.3 mg white solid as product (96.4%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH3:9].[Cl:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH3:9])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: CNc1cnccc1I
Product: CNc1cnccc1-c1cccnc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine and 2-chloropyridin-3-ylboronic acid after a reaction time of 5 hours at 90° C. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (82%). MS (EI): m/z=219 [M]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:25]2[C:26]([N:45]([CH3:50])[S:46]([CH3:49])(=[O:48])=[O:47])=[CH:27][C:28]3[O:32][C:31]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[C:30]([C:40]([NH:42][CH3:43])=[O:41])[C:29]=3[CH:44]=2)=[N:13][C:14]=1[C:15]1[NH:16][C:17]2[C:22]([CH:23]=1)=[C:21]([F:24])[CH:20]=[CH:19][CH:18]=2)C1C=CC=CC=1>CO.[Pd]>[F:24][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[CH:23]=[C:15]([C:14]1[N:13]=[C:12]([C:25]3[C:26]([N:45]([CH3:50])[S:46]([CH3:49])(=[O:48])=[O:47])=[CH:27][C:28]4[O:32][C:31]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)=[C:30]([C:40]([NH:42][CH3:43])=[O:41])[C:29]=4[CH:44]=3)[CH:11]=[CH:10][C:9]=1[OH:8])[NH:16]2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A mixture of 5-(5-(benzyloxy)-6-(4-fluoro-1H-indol-2-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (120 mg, 0.173 mmol) and Pd/C (20 mg) in methanol (10 mL) was stirred under H2 atmosphere at room temperature for 1 hour. The mixture was then filtered through Celite and concentrated to provide 5-(6-(4-fluoro-1H-indol-2-yl)-5-hydroxypyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (60 mg, yield: 57.7%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.95˜8.00 (m, 4H), 7.80 (s, 1H), 7.37 (t, J=8.8 Hz, 2H), 7.22˜7.30 (m, 4H), 6.64˜6.69 (m, 1H), 3.23 (s, 3H), 2.94 (s, 3H), 2.90 (s, 3H). MS (M+H)+: 603.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([F:21])[CH:3]=1.C([Li])CCC.[B:27](OC)([O:30]C)[O:28]C.FC1C(F)=CC=CC=1B(O)O>C1COCC1>[F:21][C:4]1[CH:3]=[C:2]([B:27]([OH:30])[OH:28])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCOc1ccc(Br)cc1F
Reactant: COB(OC)OC
Agent: OB(O)c1cccc(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(B(O)O)cc1F

Procedure:
Quantities: compound 13 (10.00 g, 0.039 mol) in anhydrous THF (150 ml), n-butyllithium (17 ml, 2.5M in hexane, 0.0425 mol), trimethyl borate (8.12 g, 0.078 mol) in anhydrous THF (50 ml). The experimental procedure was as described for the preparation of compound 2.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].[NH2:13][OH:14].O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.O>CO.O>[Cl:1][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([CH3:12])[C:3]=1/[C:4](=[N:13]/[OH:14])/[NH2:5]
Reactant: NO
Reactant: Cc1nc(Cl)c(C#N)c(C)c1Cl
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Solvent: CO
Product: Cc1nc(Cl)c(/C(N)=N/O)c(C)c1Cl
Temperature: 75 °C

Procedure:
A suspension of 2,5-Dichloro-4,6-dimethyl-nicotinonitrile (45.0 kg) and 50% hydroxylamine (59.2 kg) in the presence of catalytic amount of 1,10-phenanthroline monohydrate (0.680 kg) in methanol/water (214 kg/362 kg) is heated to 70-80° C. The mixture is agitated at 70-80° C. Water (353 kg) is added slowly into the resulting solution while the temperature is maintained at >79° C. The solution is cooled to 75° C. with stirring resulting in crystallization of (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide. The suspension is further cooled to 20° C., the solid is filtered off and the wet cake is washed with water (160 kg). (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide is dried under vacuum at max. 60° C. until residual water level is max 0.15% (KF).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=2)=[CH:14][CH:13]=1>>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:9])[NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=3)=[CH:16][CH:17]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3c[nH]c(=O)cn3)cc2)cc1

Procedure:
Using a procedure similar to that of Example 17 p-tolyl isocyanate is reacted with 5-(4-aminophenyl)-2(1H)-pyrazinone (or its hydrobromide salt) to give 5-[4-(3-p-tolylureido)phenyl]-2(1H)-pyrazinone.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[N:5]=[C:4]([NH:23][C:24]2[CH:29]=[C:28]([CH3:30])[C:27]([CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[CH:26][C:25]=2[O:38][CH:39]([CH3:41])[CH3:40])[N:3]=1.[NH2:42][NH2:43]>C(O)(C)C>[CH:39]([O:38][C:25]1[CH:26]=[C:27]([CH:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]2)[C:28]([CH3:30])=[CH:29][C:24]=1[NH:23][C:4]1[N:3]=[C:2]2[NH:42][N:43]=[C:8]([NH2:9])[C:7]2=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[N:5]=1)([CH3:41])[CH3:40]
Reactant: Cc1cc(Nc2nc(Cl)c(C#N)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(C)CC1
Reactant: NN
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3ccccc3S(=O)(=O)C(C)C)c3c(N)n[nH]c3n2)c(OC(C)C)cc1C1CCN(C)CC1
Temperature: 120 °C

Procedure:
To a solution of 4-chloro-2-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenylamino)-6-(2-(isopropylsulfonyl)phenylamino)pyrimidine-5-carbonitrile (0.1 mmol) in 5 mL of isopropanol, was added hydrazine anhydrous (0.3 mmol). The solution was heated at 120° C. for 3 hours. Product was obtained after work-up and prep-HPLC. MS (ES+): 593.29 (M+1)+. 1H NMR (MeOD, 400 MHz) δ 8.01-8.03 (d, 1H), 7.83-7.86 (m, 1H), 7.31-7.43 (m, 3H), 6.91(s, 1H), 4.56-4.59 (m. 1H), 3.64-3.68 (m, 2H), 3.19-3.24 (m, 3H), 2.93(s, 3H), 2.25 (s, 3H), 2.02-2.07 (m, 4H), 1.17-1.32 (m, 12H); MS (ES+): 593.18 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[C:5]#N.C(O)=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:12])[C:9]=1[O:10][CH3:11])[CH:5]=[O:14]
Reactant: COc1c(F)cc(C#N)cc1F
Reactant: O=CO
Product: COc1c(F)cc(C=O)cc1F

Procedure:
3,5-Difluoro-4-methoxybenzonitrile (0.237 mol), Raney alloy (40 g) and 90% formic acid (400 ml) were reacted substantially as described in Example 7A above to obtain 22.9 g (56%) of a white, low melting solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:22]\[O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)/[C:13]([NH:15][C:16]2C=CN(C)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:29][C:30]1N=C(N)[S:32][N:31]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:22]\[O:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)/[C:13]([NH:15][C:16]2[S:32][N:31]=[C:30]([CH3:29])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: Cc1nsc(N)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nsc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reaction time: 2 h
Yield: 50 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic (prepared as in Example 1, 96 mg, 0.28 mmol), 3-methyl-[1,2,4]thiadiazol-5-ylamine (32 mg, 0.28 mmol) and N,N-diisopropylethylamine (145 μL, 0.83 mmol) were combined in acetonitrile (1.25 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(3-methyl-[1,2,4]thiadiazol-5-yl)-acetamide (62 mg, 50%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H19ClN4O4S2 [M+] 442.05, found 443 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.67 (m, 4 H, 2×CH2), 1.90 (m, 4 H, 2×CH2), 2.60 (s, 3 H, ArCH3), 3.32 (s, 3 H, SO2CH3), 4.95 (m, 1 H, OCH), 7.60 (dd, Jo=8.3, Jm=1.6 Hz, 1 H, Ar), 7.70 (d, Jm=1.6 Hz, 1 H, Ar), 8.22 (d, Jo=8.3 Hz, 1 H, Ar), 10.35 (s, 1 H, NH).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:9][C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 84.2 %

Procedure:
2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (200 mg, 0.8 mmol) was treated with 2,4-difluorobenzene-1-sulfonyl chloride (220 μl, 1.6 mmol) according to the method of Preparation 15b to give 287 mg (66% yield) of the title compound as an oil. Purity 78%.