Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Cl:18][C:19]1[C:20]([C:25](Cl)=[O:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:10])/[CH:3]=[C:4](/[C:25](=[O:26])[C:20]1[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C(Cl)c1ncccc1Cl
Reactant: CCOC(=O)/C=C/N(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1Cl
Temperature: 83 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
To a light yellow solution of (E)-ethyl 3-(dimethylamino)acrylate (1.72 g, 12.0 mmol) in toluene (20 mL) was added triethylamine (1.21 g, 1.67 mL, 12.0 mmol) at room temperature. To this, a solution of 3-chloropicolinoyl chloride (34) (1.76 g, 10 mmol) in toluene (5 mL, heated to dissolve) was added. Then, the resulting dark brown solution was heated to 83° C. and stirred for 12 h at this temperature. During this period, it turned to a dark brown solution. Then, the heating was stopped and the dark brown mixture was filtered off and the solids were washed with ethyl acetate. The brown ethyl acetate solution was washed with water which was diluted with 1.0N HCl. The acidic aqueous layer was extracted one more time with ethyl acetate and the combined organic layer was washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave only 1.6 g of crude brown mixture. Then, the acidic aqueous layer was extracted with dichloromethane (2×100 mL) and then the aqueous layer was neutralized with a saturated sodium bicarbonate solution and then extracted one more time with dichloromethane. The combined dichloromethane extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave another 1.2 g of dark drown oil which was combined with the first brown residue and the mixture was purified using an ISCO (120 g) column, eluting with ethyl acetate in hexanes (0 to 100%) and then 10% methanol in dichloromethane. The pure fractions were combined and the solvent was removed under vacuum to obtain (Z)-ethyl 3-(dimethylamino)-2-(3-chloropicolinoyl)acrylate (35) (1.16 g, 41% yield) as a dark brown oil.
Reaction SMILES: [CH:1]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[N+:20]([C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:24]=1[CH2:25]Cl)([O-:22])=[O:21].CN(C)C=O>C1C=CC=CC=1>[C:8]([C:1]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH2:25][C:24]1[C:27]([CH3:31])=[CH:28][CH:29]=[CH:30][C:23]=1[N+:20]([O-:22])=[O:21])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cc1cccc([N+](=O)[O-])c1CCl
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)CC(Cc1c(C)cccc1[N+](=O)[O-])(C(=O)OCC)C(=O)OCC

Procedure:
The title compound was prepared by the same procedure as described in example 1 for 1a (R2 = R3 = H), using triethyl 1,1,2-ethanetricarboxylate (9.85 g; 0.04 mole), NaH (1.6 g; 0.04 mole) and 2-nitro-6-methylbenzyl chloride (7.4 g; 0.04 mole) in 20 ml. 10% dimethylformamide (DMF) in benzene. The crude product so obtained was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[F:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([F:14])[CH:23]=2)[CH:19]=[CH:20]1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2ccn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (34.5 g) in dimethylformamide (250 ml) was added 6-fluoroindole (34.5 g) and potassium carbonate (20.4 g). The mixture was heated at 90° C. for 6 hours and then left to stir for 16 hours at room temperature. The reaction was diluted with water (1000 ml) and extracted with hexane (1000 ml). The organic fraction was separated and evaporated to dryness to give the title compound as a colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:33])=[C:11]([C:15]3[C:27]4[C:26]5[C:21](=[CH:22][C:23]([CH:28]=O)=[CH:24][CH:25]=5)[NH:20][C:19]=4[C:18]([C:30]([NH2:32])=[O:31])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:33])=[C:11]([C:15]3[C:27]4[C:26]5[C:21](=[CH:22][C:23]([CH2:28][N:36]6[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]6)=[CH:24][CH:25]=5)[NH:20][C:19]=4[C:18]([C:30]([NH2:32])=[O:31])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:34][CH:35]=1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C=O)ccc3c12
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(CN4CCCCC4)ccc3c12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 40.9 %

Procedure:
Step 2 A suspension of 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-formyl-9H-carbazole-1-carboxamide (30 mg, 0.064 mmol) in THF (3 mL) was treated with piperidine (16.46 mg, 0.193 mmol) and sodium triacetoxyborohydride (34.1 mg, 0.161 mmol). The mixture was stirred at rt for 3.5 h, the was treated again with additional piperidine (16.5 mg, 0.193 mmol) and sodium triacetoxyborohydride (20 mg). After stirring overnight, the mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was purified by preparative HPLC to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(piperidin-1-ylmethyl)-9H-carbazole-1-carboxamide (14 mg, 39%). 1H NMR (400 MHz, methanol-d4) δ 8.06 (2H, dd, J=8.7, 5.4 Hz), 7.98 (1H, d, J=7.8 Hz), 7.63 (1H, s), 7.52 (1H, d, J=7.3 Hz), 7.44 (1H, t, J=7.8 Hz), 7.18-7.31 (3H, m), 7.07 (2H, d, J=7.5 Hz), 6.96-7.02 (1H, m), 3.96 (2H, s), 2.72-2.88 (4H, m), 1.99 (3H, s), 1.63-1.75 (4H, m), 1.48-1.60 (2H, m). Mass spectrum m/z 535.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O.[CH3:15][N:16](C)C=O>>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:15]#[N:16])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CN(C)C=O
Solvent: O
Product: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]

Procedure:
1-Chloro-2,6-dinitrobenzene (40.4 grams) is dissolved in anhydrous dimethylformamide (200 ml.). Cuprous cyanide (72 grams) is added and the stirred reaction mixture is heated to reflux for 6 hours. The dark brown reaction mixture is cooled and poured into water (1.5 l.) with stirring. The tan precipitate is collected by filtration and then extracted three times with hot ethanol (300 ml.). Removal of two-thirds of the solvent from combined ethanol extracts under reduced pressure gives a tan precipitate. The precipitate is collected by filtration and recrystallized from ethanol to give a tan product (7.2 grams) melting at 143°-146.5°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[CH3:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccc(Cl)nc1
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 17, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 56% yield; NMR Spectrum: (DMSOd6): 2.21 (s, 3H), 3.50-3.53 (m, 4H), 3.69-3.73 (m, 4H), 7.08 (d, 1H), 7.25 (d, 2H), 7.56 (d, 1H), 7.69 (d, 1H), 7.82 (s, 1H), 8.26 (d, 1H), 8.37 (d, 1H), 8.96 (d, 1H); Mass Spectrum M+H+ 452 and 454.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:14]=2)[NH:9][N:8]=1)=[O:5].[O:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:6][C:4](=[O:5])[C:3]1[CH:25]=[CH:26][C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[CH:28][C:2]=1[NH:1][CH:39]1[CH2:40][CH2:41][O:36][CH2:37][CH2:38]1
Reactant: O=C1CCOCC1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of 2-amino-N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide (1.9 g, 3.98 mmol) in dichloromethane (80 mL) were added tetrahydro-pyran-4-one (0.55 mL, 5.98 mmol), trifluoroacetic acid (4 mL) and tetramethylammonium triacetoxyborohydride (1.57 g, 5.98 mmol). The mixture was stirred at room temperature overnight, and then more tetramethylammonium triacetoxyborohydride (1.57 g) was added. After stirring for additional 3 hours at room temperature the mixture was diluted with dichloromethane, washed with 2N sodium hydroxide and brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/methanol/NH3 5N in MeOH 96:4:0.5 as the eluant, affording 1.61 g of the title compound (72% yield).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9][C:10]([O:13][CH2:14][CH:15]([OH:18])[CH:16]=[CH2:17])=[CH:11][CH:12]=1)(=O)=O.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(C(C)C)CC)(C)C>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.CN(C)C=O>[CH2:19]([C:8]1[C:7]([C:29]#[C:28][C:30]2([OH:38])[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[CH:12][CH:11]=[C:10]([O:13][CH2:14][CH:15]([OH:18])[CH:16]=[CH2:17])[N:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=CC(O)COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)n1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(O)COc1ccc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 22.9 %

Procedure:
A mixture of 46.5 mg of 2-benzyl-6-(2-hydroxy-3-butenyl)oxy-3-pyridyl trifluoromethane sulfonate, 22.7 mg of 3-ethynyl-3-quinuclidinol, 6.6 mg of tetrakis(triphenylphosphine)palladium(0), 0.1 mg of cuprous iodide, 60.1 μl of diisopropylethylamine and 1 ml of N,N-dimethylformamide was stirred at 80° C. for 3 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 5% methanol/ethyl acetate, to give 10.7 mg of the target compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][C@H:4]([N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[CH:14]([CH:21]=[CH2:22])[O:13][C:11]=2[CH:12]=1>CO.[Pd]>[CH2:21]([CH:14]1[C:15]2=[CH:16][N:17]=[CH:18][CH:19]=[C:20]2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][C@@H:4]([N:23]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:33])[CH2:3][CH:2]([CH3:34])[CH3:1])=[CH:12][C:11]=2[O:13]1)[CH3:22]
Reactant: C=CC1Oc2cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc2-c2ccncc21
Agent: [Pd]
Solvent: CO
Product: CCC1Oc2cc(OC[C@H](CC(C)C)N3C(=O)c4ccccc4C3=O)ccc2-c2ccncc21
Yield: 33.5 %

Procedure:
To a stirred solution of 2-((2S)-4-methyl-1-((5-vinyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)pentan-2-yl)isoindoline-1,3-dione (0.3 g, 0.660 mmol) in methanol (15 mL) was added 10% palladium on carbon (0.070 g, 0.660 mmol). The resultant mixture was stirred at room temperature under a hydrogen atmosphere (1 atm) for 12 h. The reaction mixture was then filtered through celite and concentrated under reduced pressure to yield crude 2-((5)-1-(5-ethyl-5H-chromeno[3,4-c]pyridin-8-yloxy)-4-methylpentan-2-yl)isoindoline-1,3-dione (0.28 g, 0.221 mmol, 33% crude yield); LCMS (ESI) m/e 457.2 [(M+H)+, calcd for C28H29N2O4 457.2]; LC/MS retention time (Method C): tR=2.32 min.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:51][O:52][C:53]([C:55]1[C:63]2[N:62]=[C:61]([NH2:64])[NH:60][C:59]=2[CH:58]=[CH:57][CH:56]=1)=[O:54]>CN(C=O)C>[CH3:51][O:52][C:53]([C:55]1[C:63]2[N:62]=[C:61]([NH:64][C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:14]=3)=[O:17])[NH:60][C:59]=2[CH:58]=[CH:57][CH:56]=1)=[O:54]
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: O=C(O)c1cccc(C#Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2[nH]c(NC(=O)c3cccc(C#Cc4ccccc4)n3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.3 %

Procedure:
To a solution of 4.4 g (20 mmol) of 6-phenylethynyl-pyridine-2-carboxylic acid in DMF (30 mL) was added 7.6 g (20 mmol) of HBTU and DIEA (4 mL). The resulted mixture was stirred at room temperature for 10 min, then 4 g (21 mmol) of 2-amino-1H-benzoimidazole-4-carboxylic acid methyl ester (Intermediate A) was added, and stirred at room temperature for 1 h. After usual workup as described in general procedure A, 7 g (88%) of 2-[(6-phenylethynyl-pyridine-2-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester was obtained after column chromatography purification eluting with DCM/EtOAc. LCMS: 397 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 8.20 (dd, 1H), 8.13 (dd, 1H), 7.96 (d, 1H), 7.81 (d, 1H), 7.74 (d, 1H), 7.60 (m, 2H), 7.50 (m, 3H), 7.31 (t, 1H), 3.95 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[CH:10]N(C)C.[C:22]([CH2:24][C:25]([NH2:27])=[O:26])#[N:23].CO.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:27][C:25](=[O:26])[C:24]([C:22]#[N:23])=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Temperature: 95 °C

Procedure:
To the product of step B was added 2-cyanoacetamide (1.912 g, 22.74 mmol), methanol (1.84 mL, 45.5 mmol) and DMF (50 mL). This solution was cannulated into a slurry of NaH (2.067 g, 51.7 mmol, 60% dispersion in mineral oil, washed with hexane) and DMF (24 mL) and then heated to 95° C. for 2.5 hours. The reaction was cooled and then concentrated in vacuo. The residue was diluted with ethyl acetate and then washed with 10% aq. NaHSO4 and water. The organic portion was dried (Na2SO4) and concentrated before suspending the solid in hot ethanol. After cooling, the solid was filtered and washed with ethanol and then hexane. This afforded product. MS (electrospray) m/e 341.1 MH+ (Rt=3.1 min LC/MS).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:14]([C:20]5[CH:25]=[CH:24][C:23]([C:26]6([NH:34]C(=O)OC(C)(C)C)[CH2:29][C:28]7([O:33][CH2:32][CH2:31][O:30]7)[CH2:27]6)=[CH:22][CH:21]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:19]3[C:10]([C:11]4[CH:12]=[C:13]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:14]([C:20]5[CH:21]=[CH:22][C:23]([C:26]6([NH2:34])[CH2:29][C:28]7([O:33][CH2:32][CH2:31][O:30]7)[CH2:27]6)=[CH:24][CH:25]=5)=[N:15][C:16]=4[CH:17]=[CH:18]3)=[N:9][N:8]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(NC(=O)OC(C)(C)C)CC7(C6)OCCO7)cc5)nc4ccn23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(N)CC7(C6)OCCO7)cc5)nc4ccn23)c1

Procedure:
To a solution of tert-butyl (2-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-5,8-dioxaspiro[3.4]oct-2-yl) (1-11) in DCM (50 mL) was added TFA (50 mL) at rt under N2 for 2 hours. The reaction was quenched with 1N NaOH (650 mL), poured into saturated sodium bicarbonate, extracted with chloroform, dried over sodium sulfate, filtered and concentrated. The crude residue was recrystallized from methanol to give 2-{4-[3-(1-methyl-1/1-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-5,8-dioxaspiro[3.4]octan-2-amine (1-12) as a white solid. HRMS (M+H)+: observed=530.2315, calculated=530.2299.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([C:10]([N:12]1[CH2:20][CH2:19][CH2:18][C@H:13]1[C:14]([O:16]C)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([C:10]([N:12]1[CH2:20][CH2:19][CH2:18][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 86.3 %

Procedure:
Boc-D-Phe-Pro-OMe (8.3 g) was dissolved in dioxane/water=6/4 v/v (150 ml) and treated with 2M sodium hydroxide solution (16.5 ml) portionwise over 1 h at room temperature, keeping the pH at 12.5. 2M hydrogen chloride solution was added to the reaction mixture until pH 3.0 and the water layer was extracted with ethyl acetate. The combined organic phases were washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to yield Boc-D-Phe-Pro-OH (6.9 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[N:15]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:12][C:14]2[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[N:15]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CC(N)c1cccc([N+](=O)[O-])c1
Product: CC(Nc1nc(Cl)cc(Cl)n1)c1cccc([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 1-(3-nitrophenyl)ethylamine and 2,4,6-trichloropyrimidine according to the procedure described in EXAMPLE 306, Step A.
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH2:14][S:15]([O:18][CH2:19][CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH2:14][S:15]([O:18][CH2:19][CH3:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CCOS(=O)(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOS(=O)(=O)CCc1ccc(O)cc1

Procedure:
To a solution of ethyl 4-benzyloxyphenethyl sulfonate (1.43 g) in ethyl acetate (25 ml) is added 10% palladium on carbon (0.25 g) and the mixture shaken under 30 psi of hydrogen for 3 hours. The mixture is filtered and concentrated in vacuo to give ethyl 4-hydroxyphenethyl sulfonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Fc1ccccc1C1CCCN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccccc2F)cc1

Procedure:
The title compound, white solid, m.p. 143° C. and MS: m/e=320.3 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(2-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:23]1[CH2:24][CH:25]=[C:26]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:27][CH2:28]1
Reactant: Fc1cccnc1Nc1ccc(Oc2nccnc2Cl)cc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1cccnc1Nc1ccc(Oc2nccnc2C2=CCOCC2)cc1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added N-(4-(3-chloropyrazin-2-yloxy)phenyl)-3-fluoropyridin-2-amine (0.2824 g, 0.892 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.281 g, 1.337 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.050 g, 0.071 mmol), and sodium carbonate (0.473 g, 4.46 mmol) in DME (2.378 mL) and Water (0.594 mL). The reaction mixture was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 100° C. for 20 min (60 watts, Powermax feature on, ramp time 5 min). The crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-3-fluoropyridin-2-amine. MS (ESI, pos. ion) m/z: 365.0 (M+1). IC50 (uM) 0.0.0217.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].F[C:20]1[C:21]([CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:20]2[C:21]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH2:31]3)=[N:22][CH:23]=[CH:24][N:25]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: COC(=O)N1CCC(c2nccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)N1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 80 °C

Procedure:
The mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (112 mg, 0.468 mmol), methyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate (56 mg, 0.23 mmol), and cesium carbonate (153 mg, 0.468 mmol) in DMSO (0.8 mL) was heated at 80° C. for 20 h. The reaction mixture was partitioned between Teac and brine. The aqueous layer was back extracted with Teac (3×) and the combined organic layer was dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% Teac in hexane, to provide methyl 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate as white solid. MS (ESI, pos. ion) m/z: 458.1 (M+1). IC50 (uM) +++++.