Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([OH:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[OH:16].[CH3:17][N:18]=[C:19]=[O:20]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:14][O:13][C:12]1[C:3]([O:2][CH3:1])=[C:4]([O:16][C:19](=[O:20])[NH:18][CH3:17])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]=1[O:15][C:19](=[O:20])[NH:18][CH3:17]
Reactant: COc1c(OC)c(O)c2ccccc2c1O
Reactant: CN=C=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CNC(=O)Oc1c(OC)c(OC)c(OC(=O)NC)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.00 g of 2,3-dimethoxy-1,4-dihydroxynaphthalene, prepared as shown in Preparation 5, in 50 ml of tetrahydrofuran was added 0.670 g of methyl isocyanate followed by 0.12 g of 4-dimethylaminopyridine. The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue chromotographed on silica gel, eluting with methylene chloride, giving 2,3-dimethoxy-1,4-di(methylcarbamoyloxy)naphthalene, m.p. 228°-229° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[N:18]1([C:22]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[N:18]1([C:22]([C:24]2[N:25]=[CH:26][C:27]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([OH:7])=[O:6])=[CH:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Temperature: 160 °C
Yield: 58 %

Procedure:
Methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (875 mg, 3.68 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (1.06 g, 4.41 mmol), caesium carbonate (3.59 g, 11.03 mmol), and bromotris(triphenylphosphine)copper (0.69 g, 0.735 mmol) were added together in DMA (16 mL) and heated in a microwave reactor at 160° C. for 9 hours. The mixture was taken up in water (25 mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was acidified with 1N hydrochloric acid (30 mL) and extracted with ethyl acetate (5×30 mL). The combined organic extract was washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and evaporated to give a brown solid which was triturated with diethyl ether to give the desired compound as a beige solid (820 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Using General Procedure F; 6-ethynyl-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 13, 190.0 mg, 0.96 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 245.0 mg, 0.96 mmol) in triethyl amine (8 mL) was treated with copper(I)iodide (46 mg, 0.24 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)palladium(II) (168 mg, 0.24 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (10-20% EtOAc-hexanes) afforded 250.0 mg (75%) of the title compound as a pale-yellow solid.
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]Br)#[N:2].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>O>[C:1]([C:3]([C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)#[N:2]
Reactant: c1c[nH]cn1
Reactant: CCCCC(C#N)(CBr)c1ccc(Sc2ccccc2)cc1
Solvent: O
Product: CCCCC(C#N)(Cn1ccnc1)c1ccc(Sc2ccccc2)cc1
Reaction time: 4 h
Yield: 82 %

Procedure:
A mixture of 10 g (0.027 mole) of 2-cyano-2-(4-phenylthiophenyl)hexyl bromide and 8 g (0.13 mole) of imidazole is heated with stirring at 160° for four hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are washed with water and dried over Na2SO4. The drying agent is filtered and to the filtrate is bubbled dry hydrogen chloride gas until solution is strongly acidic. The hydrochloride salt is washed with ether and back neutralized with dilute ammonium hydroxide solution to give 8 g of pure product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[CH3:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.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>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:34]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: COCCOCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COCCOCCn1cc(-c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)cn1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 50 mg, 0.160 mmol), 1-[2-(2-methoxy-ethoxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 233.1, 47 mg, 0.160 mmol), Pd(PPh3)2Cl2 (6 mg, 0.008 mmol) and 2 M K2CO3 (216 μL, 0.432 mmol) in DME (1 mL) was stirred at 95° C. for 1 h. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified twice by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 19:1)=100:0→0:100) to afford the title compound as a foam (tR 3.56 min (conditions 3), MH+=447.1, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.42 (s, 1H); 8.33 (d, 1H); 8.08 (m, 2H); 8.01 (d, 1H); 7.76 (d, 1H); 7.61 (s, 1H); 7.52 (d, 1H); 7.46 (dd, 1H); 4.55 (s, 2H); 4.31 (t, 2H); 3.79 (t, 2H); 3.50 (m, 2H); 3.36 (m, 2H); 3.15 (s, 3H)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([OH:16])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:46][C:47]([F:54])([F:53])[CH:48]([CH3:52])[CH2:49][CH2:50]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:50][CH2:49][CH:48]([C:47]([F:54])([F:53])[F:46])[CH3:52])=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2O)cc1
Reactant: CC(CCO)C(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,4-difluorophenyl)-4-hydroxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (189 mg, 0.5 mmol), Ph3P (262 mg, 1 mmol) and 3-trifluoromethyl-1-butanol (66 mg, 0.5 mmol) in THF (25 mL) was added dropwise a solution of DIAD (0.2 mL, 1 mmol) in THF (5 mL) and the resulting mixture was stirred at room temperature for 8 hours. The mixture was concentrated in vacuo and the residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product, (yield: 180 mg 71%). mp 126-128° C. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (d, J=7 Hz, 3H), 1.55 (m, 1H), 1.97 (m, 1H), 2.30 (m, 1H), 3.29 (s, 3H), 4.46 (m, 2H), 7.52 (m, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.90 (d, J=9 Hz, 2H), 8.08 (d, J=9 Hz, 2H), 8.22 (s, 1H). MS (APCI+) m/z 503 (M+H)+; (APCI−) m/z 537 (M+Cl)−. Anal. calc. for C22H19F5N2O4S: C, 52.59; H, 3.81; N, 5.57. Found: C, 52.70; H, 3.73; N, 5.63.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:19])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2Br)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:1]1([C@H:7]([O:9][C:10](=[O:19])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:24]2[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: C[C@@H](OC(=O)Nc1ccccc1Br)c1ccccc1
Product: C[C@@H](OC(=O)Nc1ccccc1-c1ccc(O)cc1)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 2, using the following starting materials: (2-bromo-phenyl)-carbamic acid (R)-1-phenyl-ethyl ester and 4-hydroxyphenylboronic acid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:13].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[CH3:12][C:8]1([CH3:11])[CH2:7][C:6]2[CH:5]=[CH:4][C:3]([CH3:13])=[C:2]([N:1]=[C:15]=[O:17])[C:10]=2[O:9]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc2c(c1N)OC(C)(C)C2
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1N=C=O)OC(C)(C)C2
Temperature: 80 °C

Procedure:
A 400 mg amount of 7-amino -2,2,6-trimethyl-2,3-dihydrobenzofuran was dissolved in 10 ml of carbon tetrachloride, and 246 mg of triphosgene was added thereto. The reaction solution was heated to 80° C., and 229 mg of triethylamine was slowly added thereto with stirring. Further, the mixture was heated under reflux for 1.5 hr. The reaction mixture was filtered through Celite to remove insolubles. The solvent was removed by evaporation to provide 461 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].O>C(N(CC)CC)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.[Cu]I>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:15]#[C:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#Cc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
4 g (20 mmol) of ortho-bromonitrobenzene, 842 mg (1.2 mmol) of bis(triphenyl-phosphine)palladium(II) chloride and 230 mg (1.2 mmol) of copper(I) iodide were, under argon, initially charged in 40 ml of triethylamine. At room temperature, 2.95 g (30 mmol) of trimethylsilylacetylene were then added dropwise over a period of 10 min, and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into 50 ml of water and extracted three times with in each case 50 ml of diethyl ether, and the extracts were dried over sodium sulphate and concentrated. Column-chromatographic purification on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 3:1) gave 4.2 g (96% of theory) of trimethyl-(2-nitrophenyl-ethynyl)silane [log P (pH 2.3)=4.12].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12](Cl)=[O:13].[OH-].[NH4+:16].CCCCCC>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([NH2:16])=[O:13]
Reactant: [NH4+]
Reactant: O=C(Cl)/C=C1\CCc2c(F)cccc21
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCC
Product: NC(=O)/C=C1\CCc2c(F)cccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
An ice cold solution of (E)-2-(4-fluoro-1-indanylidene)acetyl chloride (2.11 g, 0.01 mol) in dichloromethane (65 mL) was treated with a 30% aqueous solution of ammonium hydroxide (2.63 ml, 0.02 mol), and the mixture was stirred for 18 h. Hexane was added to the mixture, and the solids were collected by filtration to give 1.63 g of crude product. Recrystallization from acetonitrile:water mixtures gave 1.11 g (58%) of (E)-2-(4-fluoro-1-indanylidene)-acetamide as a white solid; m.p., 198-200° C.
Reaction SMILES: [CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCNCC4)cc3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCN(C5CCN(C)CC5)CC4)cc3)c2n1
Reaction time: 0.33 h
Yield: 43.5 %

Procedure:
A solution of Compound 157 (0.250 g, 0.69 mmol) in 1,2-dichloroethane was added with 1-methyl-4-piperidone (0.128 mL, 1.04 mmol) followed by stirring for 20 minutes. The mixture was added with sodium triacetoxyborohydride (0.439 g, 2.07 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=19:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 160 (0.139 g, 0.30 mmol, 44%).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[CH2:16]1[CH2:20]OC[CH2:17]1>>[CH:16]([C:3]1[C:4]2[NH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[S:12][C:13]=2[CH:14]=[CH:15][CH:2]=1)([CH3:20])[CH3:17]
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Reactant: C1CCOC1
Product: CC(C)c1cccc2c1Nc1ccccc1S2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of 2-chlorophenothiazine (4.67 g, 20 mmol) in anhydrous THF (40 mL) i-propyllithium (0.7 m solution in pentane, 100 mL, 70 mmol) was added at −75° C. (1 h). The reaction mixture had been stirred (2 h), ice-water was added slowly (30 min.) and after that the stirring was continued for 30 min. The organic layer was separated and combined with ether extracts of the aqueous phase. The combined organic phase was washed with water, dried (Na2SO4) and concentrated to give the crude product (52% yield). Compound was purified by flash chromatography (solvent system: hexane-ethyl acetate).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.Cl[CH2:32][C:33]1[C:38]([C:39]#[N:40])=[CH:37][CH:36]=[CH:35][N:34]=1>O>[C:39]([C:38]1[C:33]([CH2:32][N:4]2[C:5](=[O:16])[C:6]3[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:17])=[N:34][CH:35]=[CH:36][CH:37]=1)#[N:40]
Reactant: N#Cc1cccnc1CCl
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1ncccc1C#N)c(=O)n2C
Temperature: 70 °C
Reaction time: 19 h

Procedure:
202 g (0.68 mol) of 3-methyl-7-(2-butin-1-yl)-8-bromoxanthine, 188.5 g (1.36 mol) of anhydrous potassium carbonate and 1.68 liters of N-methyl-2-pyrrolidone are initially charged in the reactor and heated to 70° C. Subsequently, 119 g (0.75 mol) of 2-chloromethyl-3-cyanopyridine in 240 ml of N-methyl-2-pyrrolidine (NMP) are added dropwise. The reactor contents are stirred at 70° C. for 19 hours. After the reaction has ended, 2.8 liters of water are added to the reaction mixture and it is cooled to 25° C. The product is filtered off, washed with 2 liters of water and dried at 70° C. in a drying cabinet under inertization.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]1=[O:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]([C:30]2([C:33]3[CH:43]=[CH:42][C:36]4[O:37][C:38]([F:41])([F:40])[O:39][C:35]=4[CH:34]=3)[CH2:32][CH2:31]2)=[O:29])[CH:24]=[CH:23][C:22]=1[CH3:44]>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.C([O-])([O-])=O.[Na+].[Na+]>[F:41][C:38]1([F:40])[O:37][C:36]2[CH:42]=[CH:43][C:33]([C:30]3([C:28]([NH:27][C:25]4[CH:24]=[CH:23][C:22]([CH3:44])=[C:21]([C:7]5[CH:8]=[CH:9][N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:19])[CH:6]=5)[N:26]=4)=[O:29])[CH2:32][CH2:31]3)=[CH:34][C:35]=2[O:39]1
Reactant: CC1(C)OB(c2ccn(CCO)c(=O)c2)OC1(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: [Na+]
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccn(CCO)c(=O)c1
Temperature: 120 °C

Procedure:
1-(2-Hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (0.14 mmol) was added to a microwave vial containing N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (51 mg, 0.14 mmol) and Pd(PPh3)4 (8.0 mg, 0.0070 mmol). Saturated aqueous Na2CO3 (70 μL) was added and the reaction vial was flushed with N2 (g) and sealed. The reaction was heated in the microwave at 120° C. for 20 minutes before being filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 469.1. found 470.5 (M+1)+. Retention time 1.58 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.63 (d, J=6.9 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.34 (dd, J=1.7, 8.3 Hz, 1H), 6.39 (d, J=1.8 Hz, 1H), 6.26 (dd, J=1.9, 6.9 Hz, 1H), 3.96 (t, J=5.4 Hz, 2H), 3.63 (t, J=5.5 Hz, 2H), 2.26 (s, 3H), 1.52-1.50 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: N1(O[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)C2C=CC=CC=2N=N1.[NH2:20][C:21]1[CH:26]=[CH:25][O:24][CH2:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:19])=[CH:17][CH:16]=1
Reactant: Nc1ccc(C(=O)On2nnc3ccccc32)cc1
Reactant: NC1=CCOC=C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
To a mixture of 1.1441 g (4.5 mmole) of 4-amino-benzoic acid benzotriazol-1-yl ester and 8 mL of dry dimethylformamide was added 0.6575 g (6.5 mmole) of 4-amino-pyran followed by 0.4554 g (0.45 mmole) of triethylamine. The mixture stirred at room temperature for 90 minutes. Volatiles were removed under reduced pressure and the residue taken up in ethyl acetate, and the organic layer washed once with 100 mL of 0.5 M sodium carbonate, twice with 75 mL water, and then 75 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.5378 g 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide, which was used without further purification.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]#[N:13])(=[O:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OCC)C>[C:1]([O:4][C:5]1[CH:10]=[C:9]([CH2:11][Br:14])[CH:8]=[CH:7][C:6]=1[C:12]#[N:13])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1cc(C)ccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(CBr)ccc1C#N
Temperature: 25 °C
Yield: 29.7 %

Procedure:
To a solution of (2-cyano-5-methyl-phenyl) acetate (0.72 g, 4.11 mmol) in CCl4 (10 mL) was added recrystallized N-bromosuccinimide (0.767 g, 4.31 mmol) followed by benzoyl peroxide (56 mg, 0.23 mmol). The resultant mixture was heated to reflux for 2.5 hours then cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (6:1 hexanes-EtOAc) provided 0.31 g (30%) of (5-bromomethyl-2-cyano-phenyl) acetate as a colorless oil. 1H NMR (CDCl3) δ2.40 (s, 3H), 4.45 (s, 2H), 7.33 (s, 1H), 7.35 (d, 1H, J=9 Hz), 7.65 (d, 1H, J=9 Hz).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.Br[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:37]5[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccncc1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(Nc4ccncc4)ccc32)n1)c1ccccc1
Temperature: 100 °C
Yield: 8.1 %

Procedure:
2-[(S)-1-phenylethylamino]-4-[5-aminobenzimidazol-1-yl]pyrimidine (49.8 mg) was dissolved in DMF (2 mL). Diisopropylethylamine (79 μL) and 4-bromopyridine hydrochloride (43.2 mg) were added, and the mixture left heating overnight at 100° C. After 17 h added more diisopropylethylamine (79 μL) and 4-bromopyridine hydrochloride (40.2 mg) and continued heating at 100° C. for another 24 h. The volatiles were removed in vacuo and the residue purified on silica gel (2-5%(2M NH3 in MeOH)/CH2Cl2) to yield 5.0 mg of impure product that was purified by HPLC (Zorbax Rx-SIL, 60:40 hexanes:ethanol) to yield 3.0 mg of the title compound. Mass spectrum (ESI) 408.4 (M+1).