Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([CH2:16][F:17])[NH:14][C:13](=[O:15])[CH2:12][O:11][CH2:10]2)[C:5]([Cl:8])=[N:6][CH:7]=1.[C:18](=[NH:31])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)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]>[C:18](=[N:31][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16][F:17])[NH:14][C:13](=[O:15])[CH2:12][O:11][CH2:10]2)[C:5]([Cl:8])=[N:6][CH:7]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=C1COCC(CF)(c2cc(Br)cnc2Cl)N1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C1COCC(CF)(c2cc(N=C(c3ccccc3)c3ccccc3)cnc2Cl)N1
Temperature: 100 °C

Procedure:
To a solution of 5-(5-bromo-2-chloro-pyridin-3-yl)-5-fluoromethyl-morpholin-3-one (199 mg, 0.615 mmol), benzophenone imine (86 mg, 0.473) and Cs2CO3 (620 mg, 1.89 mmol) in toluene (4.6 ml) and dioxane (4.6 ml) was added Pd2(dba)3 (22 mg, 0.024 mmol) and Xantphos (41 mg, 0.071 mmol) and the mixture was purged with nitrogen, the reaction mixture was heated to 100° C. for 4 h. After cooling to 0° C. water was added and the mixture was extracted with EtOAc, the combined organic layers were washed with water, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:4) to provide the title compound as yellowish foam.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO>[C:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]#[CH:13])[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1nccc(C#C[Si](C)(C)C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccnc(NC(C)(C)C)n1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A solution of 2-tert-butylamino-4-[trimethylsilylethynyl]pyrimidine (from Example 2) in CH3OH (150 mL) was treated with a solution of KOH (30 mg) in CH3OH (5 mL). After 30 min, additional KOH (30 mg) in CH3OH (5 mL) was added. After a further 30 min, the mixture was concentrated and the residue was diluted with hexanes and loaded directly onto a short pad of SiO2. The product was eluted with 10% EtOAc in hexanes to provide the crude product as a light brown oil (18.6 g, 90% for 2 steps), which was used without further purification. TLC: Rf=0.29. IR: 3294 (m), 2965 (m), 2114 (w), 1571 (s). 1H NMR: 8.23 (d, J=5.0 Hz, 1H), 6.60 (d, J=5.0 Hz, 1H), 5.20 (s, 1H), 3.15 (s, 1H), 1.43 (s, 9H). 13C NMR: 161.97, 157.99, 149.87, 112.63, 81.71, 78.72, 51.06, 28.80.
Reaction SMILES: [NH3:1].Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[N:6]=[CH:5][N:4]=1>O1CCOCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH2:1])[CH:8]=1
Reactant: N
Reactant: COc1ccccc1-c1cc(Cl)ncn1
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(N)ncn1
Temperature: 110 °C

Procedure:
25% ammonia solution (10 ml) was added to a solution of 4-chloro-6-(2-methoxy-phenyl)-pyrimidine (2 g, 9.06 mmol) in 1,4-dioxane (10 ml) and the mixture was heated in a sealed tube at 110° C. for 8 hours with continuous stirring. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine as a white solid. Yield: 1.6 g, 87.9%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])[NH:17][NH2:18]>C(O)C>[C:21]([O:20][C:16]([NH:17][NH:18][C@@H:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]1[OH:14])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Yield: 65.6 %

Procedure:
6-Cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (8.0 g) and tert-butyl carbazate (6.3 g) were dissolved in 40 ml of ethanol and the solution was heated under reflux for 28 hours. The resulting ethanol was distilled off and the residue was recrystallized from 80 ml of hexane and 8 ml of ethanol to yield 8.7 g of trans-4-(2-tert-butoxycarbonyl- hydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol as white crystals, m.p. 136°-138° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2I)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Sn]([C:37]1[CH2:41][CH2:40][CH2:39][CH:38]=1)(CCCC)CCCC)CCC>CN(C=O)C.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>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([O:21][CH3:22])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:37]2[CH2:41][CH2:40][CH2:39][CH:38]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCC1
Reactant: COc1ccc2c(cc(I)n2S(=O)(=O)c2ccccc2)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc2c(cc(C3=CCCC3)n2S(=O)(=O)c2ccccc2)c1OC
Temperature: 90 °C
Yield: 65 %

Procedure:
To 539 mg (1.22 mmol) the iodo intermediate from step 2 in 5 mL dry DMF was added 43 mg (0.061 mmol, 5 mol %) of PdCl2(PPh3)2, followed by 870 mg (2.44 mmol, 2 eq) tributylstannylcyclopentene. The reaction was heated to 90° C. for 4 h, concentrated, dissolved in EtOAc and filtered through celite. The EtOAc layer was washed with H2O, aqueous NaCl solution, dried (MgSO4), and concentrated. The product was purified by silica gel chromatography (5-15% EtOAc/hexane) to yield 302 mgs of 1-benzenesulfonyl-2-cyclopent-1-enyl-4,5-dimethoxy-1H-indole (65%).
Reaction SMILES: O[N:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][C:10]#[N:11].C1(S(Cl)(=O)=[O:19])C=CC=CC=1.[OH-].[Na+]>CC(C)=O.O>[O:19]=[C:3]1[NH:2][CH:4]([CH2:9][C:10]#[N:11])[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#CCC1CCCCC1=NO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: N#CCC1CCCCC(=O)N1

Procedure:
The product of Example 150 is reacted with benzenesulfonyl chloride and sodium hydroxide in acetone/water by the method of Example 67 to generate the title compound.
Reaction SMILES: [Cl:1][C:2]12[C:9](=O)[CH2:8][CH:7]1[CH:6]=[CH:5][CH2:4][CH2:3]2.Cl.[NH2:12][OH:13].O>N1C=CC=CC=1>[Cl:1][C:2]12[C:9](=[N:12][OH:13])[CH2:8][CH:7]1[CH:6]=[CH:5][CH2:4][CH2:3]2
Reactant: O=C1CC2C=CCCC12Cl
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: ON=C1CC2C=CCCC12Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.2 g of 6-chlorobicyclo[4.2.0]oct-2-en-7-one, prepared as shown in Preparation 7, and 3.4 g. of hydroxylamine hydrochloride in 30 ml of pyridine was stirred at 0° C. for 1 hour, then stirred overnight at room temperature. The mixture was poured into water and extracted with methylene chloride. The extract was washed with 0.5N hydrochloric acid followed by brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residual pyridine removed under high vacuum. The residue was dissolved in diethyl ether, filtered and solvent removed from the filtrate under reduced pressure, to give 6-chlorobicyclo[4.2.0]oct-2-en-7-one oxime, the compound of formula (6A) where Y is hydrogen, 5.4 g.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28](=[O:36])[CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[S:26])=[CH:20][C:19]=4[F:37])=[C:11]3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>>[NH:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28](=[O:36])[CH2:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[S:26])=[CH:20][C:19]=3[F:37])=[C:11]2[CH:10]=[N:9]1
Reactant: COc1ccc(Cn2ncc3c(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3[nH]ncc23)c(F)c1
Temperature: 65 °C

Procedure:
A stirred mixture of 1-(4-(1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea (0.630 g, 1.16 mmol) and 2,2,2-trifluoroacetic acid (TFA) (1.79 mL, 23.3 mmol) was heated to 65° C. for 3 hours under N2. The mixture was concentrated in vacuo using toluene (3×5 mL) to azeotrope residual TFA. The residue was partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL). The phases were separated, and the organic phase washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was partially purified by preparative TLC eluting with EtOAc. The crude was then triturated with DCM (5 mL) and chilled to −10° C. to obtain the product as a white powder. The solid was suspended in abs EtOH (2×2 mL) and concentrated in vacuo to remove residual DCM. The white powder (61 mg, 12%) was then dried at 60° C. under high vacuum for 1 hour. LRMS (APCI+): 100% purity, 220 nm, m/z 422 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 13.79 (s, 1H), 12.49 (s, 1H), 11.84 (s, 1H), 8.39 (d, J=5.5 Hz, 1H), 7.99 (d, J=12.1 Hz, 1H), 7.79 (s, 1H), 7.54 (m, 2H), 7.35 (m, 4H), 7.29 (m, 1H), 6.51 (d, J=5.5 Hz, 1H), 3.84 (s, 2H); 19F NMR (376 MHz, DMSO-d6) δ −129.2 (m).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[NH:24][C:23]5C=[CH:26][CH:27]=[C:28](CO)[C:22]=5[N:21]=4)=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:3][N:2]=1.[CH3:31][CH2:32][N:33]([CH:37]([CH3:39])C)[CH:34]([CH3:36])C.CS(Cl)(=O)=O.N1CCCC1>C1COCC1>[N:33]1([CH2:32][C:31]2[C:23]3[N:24]=[C:20]([C:19]4[C:13]5[C:14](=[N:15][CH:16]=[C:11]([C:4]6[C:5]7[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=7)[CH:1]=[N:2][CH:3]=6)[CH:12]=5)[NH:17][N:18]=4)[NH:21][C:22]=3[CH:28]=[CH:27][CH:26]=2)[CH2:34][CH2:36][CH2:39][CH2:37]1
Reactant: OCc1cccc2[nH]c(-c3n[nH]c4ncc(-c5cncc6ccccc56)cc34)nc12
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: c1ccc2c(-c3cnc4[nH]nc(-c5nc6c(CN7CCCC7)cccc6[nH]5)c4c3)cncc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A suspension of Compound 3 (30 mg, 0.08 mmol) and DIPEA (28 μl, 0.36 mmol) in dry THF (1 mL) was cooled to 0° C. Methanesulfonyl chloride (18 μl, 0.23 mmol) was added dropwise and the mixture was stirred at 0° C. for 3 hours. Pyrrolidine (32 μl 0.39 mmol) was added and the suspension was gradually warmed to room temperature and stirred for 2 hours. The reaction was quenched with water (0.1 mL) and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography to give Compound 7 (13 mg, 38%) as a yellow powder. 1H NMR (300 MHz MeOD) δ 9.36 (s, 1H), 9.10 (d, 1H, J=2.1 Hz), 8.78 (d, 1H, J=2.1 Hz), 8.55 (s, 1H), 8.27 (d, 1H, J=7.8 Hz), 7.95 (m, 1H), 7.83 (m, 2H), 7.72 (dd, 1H, J=1.8, 7.2 Hz), 7.39 (m, 2H), 4.75 (s, 2H), 3.38 (b, 4H), 2.01 (b, 4H); MS (ESI) m/z: 446 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N:16]([O-:18])=[O:17].[Na+].CC1(C)P(C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)C(C)(C)CC2(OCCO2)C1.COCCOCCN(CCOCCOC)CCOCCOC>C(O)(C)(C)C.O1CCCC1.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]>[N+:16]([C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([O-:18])=[O:17]
Reactant: O=N[O-]
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Pd]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: COc1ccc(OC)c(P2C(C)(C)CC3(CC2(C)C)OCCO3)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with 4-chlorobenzophenone (100 mg, 0.462 mmol, 1 equivalent), sodium nitrite (63.7 mg, 0.923 mmol, 2 equivalents), tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (0.005 or 0.0025 equivalents) and 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane (0.012 or 0.006 equivalents, respectively). The solids were slurried in t-butyl alcohol (0.84 mL) before adding tris[2-(2-methoxyethoxyl)ethyl]amine (TDA-1) (7.4 μL, 0.023 mmol, 0.05 equivalents). The vial was sealed with a crimp top and placed in a heating block at 130° C. After indicated reaction time, the vial was cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with tetrahydrofuran (2 mL) and filtered through a pad of diatomaceous earth into a tared 125-mL Erlenmeyer flask. The vial was rinsed with tetrahydrofuran (5×1 mL) before the filter cake was washed with tetrahydrofuran (5 mL). A wt % analysis was performed on the filtrate and an assay yield was measured.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=1)[O:10][C:9](=[O:17])[CH:8]=[C:7]2[CH3:18])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[OH:17][CH2:9][CH:8]=[C:7]([C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]=1[OH:10])[CH3:18]
Reactant: Cc1cc(=O)oc2c(C(C)C)cc(C(C)C)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(=CCO)c1cc(C(C)C)cc(C(C)C)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6,8-diisopropyl-4-methylchromen-2-one Intermediate 11, 2.6 g, 10.7 mmol) in Et2O (100 mL) at 0° C. was added LiAlH4 portionwise (405 mg, 10.7 mmol). The reaction was stirred at 0° C. for 1 h, quenched by careful addition of ice, and acidified with 1M HCl. The mixture was then extracted with EtOAc. The organic layer was separated, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (20% EtOAc-hexanes) to yield the title compound as a nearly colorless syrup (1.82 g, 70%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10][CH:11]=1
Reactant: COC(=O)c1cc(C(=O)OC)c(C#CCCO)cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C(=O)OC)c(CCCCO)cn1
Reaction time: 4 h

Procedure:
200 mg of dimethyl 5-(4-hydroxy-1-butinyl)-pyridine-2,4-dicarboxylate (from Example 7) are dissolved in 25 ml of methanol and, after addition of the palladium catalyst (10% strength on charcoal) are hydrogenated. The reaction has ended after 4 hours (thin layer control). The catalyst is filtered off and the solution is concentrated in vacuo. The colorless oil is chromatographed on silica gel.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:17][C:18](=[O:20])[CH3:19])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.9 %

Procedure:
Triethylamine (2.8 mL) was dropped to the solution of 1-(4-bromophenyl)ethanamine (2.0 g, 10.0 mmol), and acetic anhydride (1.53 g, 15.0 mmol) in dichloromethane (30 mL) at room temperature. Then the mixture was stirred at room temperature for 12 hours. The mixture was washed with sodium hydroxide solution (40 mL, 0.5M) and water (40 mL). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:5) to give N-(1-(4-bromophenyl)ethyl)acetamide (2.2 g, 91%) as a white solid. 1H NMR (300 MHz, d6-DMSO): δ 8.27 (d, J=4.8 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 1H), 4.94 (m, 1H), 2.12 (s, 3H), 1.45 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:7](C(O)=O)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].[N:20]1C=CC=CC=1.C(O)(C)(C)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:7]([NH2:20])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: c1ccncc1
Reactant: Cc1ccnc(C(=O)O)c1Oc1cc(Cl)cc(Br)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: Cc1ccnc(N)c1Oc1cc(Cl)cc(Br)c1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 3-(3-bromo-5-chlorophenoxy)-4-methylpyridine-2-carboxylic acid (2 g, 5.84 mmol) in THF (12 mL) was added TEA (1.627 mL, 11.68 mmol), pyridine (944 ul, 11.68 mmol), t-butanol (2.79 mL, 29.2 mmol) and diphenylphosphoryl azide (1.89 mL, 8.76 mmol). The resulting mixture was heated to 65° C. for 35 minutes, after which the mixture was diluted with CH2Cl2 (2×100 mL) and washed with water (100 mL). The combined organic extracts were concentrated in vacuo, and the resulting residue was dissolved in TFA (20 mL) and allowed to stand for 15 minutes. After this time, the solvent was removed in vacuo and the residue was partitioned between saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (100 mL). The organic extract was concentrated on the rotary evaporator and the residue was purified using a RediSep column (330 g) eluting with a gradient of 0-30% EtOAc/CH2Cl2 to give the title compound. LRMS (M+1)=314.9.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](Cl)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[S-:17][C:18]#[N:19].[K+].C(OCC)C>CC(C)=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([N:19]=[C:18]=[S:17])[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: N#C[S-]
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C(NC(N=C=S)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 6 h
Yield: 0.1 %

Procedure:
A solution of Example 41B (1.91 g, 6.31 mmol) in acetone (30 mL) at ambient temperature was treated with potassium thiocyanate (1.38 g, 14.1 mmol). The mixture was stirred for 6 hours and solids were removed by filtration. The filtrate was concentrated to provide a yellow residue. The residue was treated with diethyl ether, and the suspension was sonicated and filtered. Concentration of the residue and purification by recrystallization (25% ethyl acetate/hexanes) provided 1.85 mg of the desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].N1C=CN=C1>CN(C)C=O>[C:21]([Si:25]([CH3:28])([CH3:27])[O:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:12][CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=Cc1cc(Cl)ccc1Oc1ccc(OCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Oc2ccc(Cl)cc2C=O)cc1
Yield: 90.5 %

Procedure:
In a manner similar to the method described in Example 60b, 5-chloro-2-[4-(2-hydroxy-ethoxy)-phenoxy]-benzaldehyde (1.68 g, 5.7 mmol) was reacted with tert-butyldimethylchlorosilane (1.3 g, 8.6 mmol) and imidazole in N,N-dimethylformamide to give 2-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenoxy}-5-chloro-benzaldehyde as a white solid (Yield 2.1 g, 90%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][NH:23][C:22]1=[O:26]>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][NH:23][C:22]3=[O:26])[N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cnc(S(C)(=O)=O)nc1-c1ccc(Br)s1
Reactant: NCCN1CCNC1=O
Solvent: Cc1ccccc1
Product: Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(Br)s1
Temperature: 120 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
4-(5-Bromothiophen-2-yl)-5-methyl-2-(methylsulfonyl)pyrimidine (2 g, 6 mmol) in toluene (10 mL) was treated with 1-(2-aminoethyl)imidazolidin-2-one (1.489 g, 10.2 mmol) and the reaction stirred at 120° C. overnight. The volatiles were removed in vacuo and the residue purified by flash chromatography using a gradient of 2 to 10% methanol in dichloromethane to obtain a light yellow solid (1.8 g). MS (M+H)+ 383.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][N:14]=1)[C:11](=[O:15])[N:10]([CH3:16])[C:9]1[CH:17]=[C:18]([O:21][CH2:22][C@@H:23]([NH:28]C(=O)OC(C)(C)C)[CH2:24][CH:25]([CH3:27])[CH3:26])[CH:19]=[CH:20][C:8]2=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7]3[C:12](=[CH:13][N:14]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=3)[C:11](=[O:15])[N:10]([CH3:16])[C:9]=2[CH:17]=1
Reactant: CC(=O)Nc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)ccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 6.7 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-((2-acetamido-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (140 mg, 0.059 mmol) in CH2Cl2 (15 mL) at 0° C. was added TFA (1.2 mL, 15.58 mmol) and the reaction mixture was stirred at RT for 40 min. After the completion of reaction, the volatile organics were evaporated under reduced pressure and the residue was purified by preparative HPLC (0.1% TFA in water/Acetonitrile) to yield (S)—N-(8-((2-amino-4-methylpentyl)oxy)-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-2-yl)acetamide (2 mg, 3.93 μmol, 6.6% yield) as a mono TFA salt. LC/MS (ESI) m/e 383.2 [(M+H)+, calcd for C21H22N4O3 383.2]; LC/MS retention time (method C): tR=1.80 min; HPLC retention time (method A): tR=5.14 min; HPLC retention time (method B): tR=5.62 min; 1H NMR (400 MHz, CD3OD) δ 9.28 (s, 1H), 8.93 (s, 1H), 8.35 (d, J=8.80 Hz, 1H), 7.17 (s, 1H), 7.15 (d, J=2.00 Hz, 1H), 4.46 (d, J=8.80 Hz, 1H), 4.28 (dd, J=6.40, 10.80 Hz, 1H), 3.76-3.79 (m, 4H), 2.29 (s, 3H), 1.65-1.88 (m, 3H), 1.08 (d, J=4.40 Hz, 3H), 1.07 (d, J=4.40 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6](=[CH:9]N(C)C)[C:7]#[N:8])=O.C(#N)C=C.Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[C:28]([NH2:30])=[NH:29].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[C:4]1[C:6]([C:7]#[N:8])=[CH:9][N:30]=[C:28]([C:27]2[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:25]([O:24][CH3:23])[CH:26]=2)[N:29]=1
Reactant: COc1cc(OC)cc(C(=N)N)c1
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C=CC#N
Product: COc1cc(OC)cc(-c2ncc(C#N)c(-c3ccc(Cl)cc3Cl)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
To a stirred solution of Step 2 acrylonitrile (1.5 g, 5.6 mmol) and 3,5-dimethoxybenzamidine hydrochloride (1.2 g, 5.6 mmol) in MeOH (30 mL) was added NaOMe (25% in MeOH, 2.56 mL, 11.2 mmol). The reaction was heated to reflux for 5 hr. Additional NaOMe (25% in MeOH, 2.56 mL, 11.2 mmol) was added and was kept for 16 hr. The reaction was cooled to ambient temperature and quenched by addition of H2O (50 mL). The reaction was filtered and the solid was washed with MeOH (40 mL) to give 4-(2,4-dichlorophenyl)-2-(3,5-dimethoxyphenyl)pyrimidine-5-carbonitrile (960 mg, 38.4%) as a white solid.