Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[C:8]3[CH2:24][C:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:9]3=[CH:10][C:11]=2[N:12]=1>C(Cl)(Cl)Cl.CO.[O-2].[Mn+4].[O-2]>[O:23]=[C:15]1[NH:16][C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:14]21[CH2:13][C:9]1=[CH:10][C:11]3[N:12]=[C:3]([CH:2]=[O:1])[CH:4]=[N:5][C:6]=3[CH:7]=[C:8]1[CH2:24]2
Reactant: O=C1Nc2ncccc2C12Cc1cc3ncc(CO)nc3cc1C2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=Cc1cnc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21

Procedure:
A mixture of (±)-2-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoxaline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (35 mg, 0.11 mmol) and manganese (IV) oxide (158 mg, 1.82 mmol) in CHCl3 (5 mL) and MeOH (0.1 mL) was heated at reflux for 18 h. The cooled mixture was filtered through a pad of Celite, washing with CH2Cl2 and MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=358 (M+1+CH3CN).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[Cl:23][CH2:24][CH2:25][NH2:26].CN1CCOCC1>CN(C=O)C>[Cl:23][CH2:24][CH2:25][NH:26][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCCCl
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(N(C)c2nc(NCCCl)nc3ccccc23)cc1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.671 g (2.0 mmol), 2-chloro-ethylamine hydrochloride 0.58 g (5.0 mmol) and N-methylmorpholine 1.0 mL in DMF 1.0 mL was stirred under microwave irradiation at 130° C. for 20 minutes. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO2, EtOAc 0˜100% in hexanes) to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.44-7.46 (m, 1H), 7.34-7.38 (m, 1H), 7.08-7.11 (m, 2H), 6.85-6.91 (m, 3H), 6.65-6.70 (m, 1H), 3.92-3.94 (m, 2H), 3.82-3.84 (m, 2H), 3.82 (s, 3H), 3.50 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=2)=[N:18]1.[CH3:30][C:31]([CH3:35])([CH3:34])[C:32]#[CH:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(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>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:16])[C:3]=1[N:17]1[C:21](=[O:22])[NH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26]([C:33]#[C:32][C:31]([CH3:35])([CH3:34])[CH3:30])=[CH:25][CH:24]=2)=[N:18]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1F
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C#Cc1ccc(-c2nn(-c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c(=O)[nH]2)cc1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 48.5 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-68, 0.050 g, 0.094 mmol) in DMSO (3.0 mL), 3,3-dimethylbut-1-yne (0.011 g, 0.142 mmol), TBAF (0.074 g, 0.283 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.022 mmol) were added and the reaction mass was stirred at 80° C. for 5-6 h. After completion of the reaction, the reaction mass was quenched with water and extracted with DCM and concentrated. The obtained crude product was purified with column chromatography on silica gel column and 2.0% EA:DCM as mobile phase to afford 0.022 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 1.09 (s, 9H), 1.25 (s, 9H), 4.31 (br s, 2H), 7.35-7.51 (m, 4H), 7.80 (d, J=8.3 Hz, 2H), 8.18-8.20 (m, 1H); MS (m/z): 481.14 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][O-:26].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([O:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Reactant: CN(C)CC[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1

Procedure:
To 100 mg of 4-(3-bromo-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 3 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 3 hours, the reaction was diluted with water and the product extracted five times with chloroform. The crude product was purified by flash chromatography with 1% triethyl amine and 10% methanol/chloroform followed by recrystallized from chloroform/ether to give 100 mg of 4-(3-bromo-phenylamino)-6-(2-dimethylamino-ethoxy)-[1.7]naphthyridine-3-carbonitrile as a yellow solid: melting point 138-139° C.; mass spectrum (m/e): M+H 411.9, 413.9.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([O:19][CH3:20])[N:10]=1)C1C=CC=CC=1>CO.CC(O)=O.[OH-].[Pd+2].[OH-]>[CH3:20][O:19][C:11]1[N:10]=[C:9]([NH2:8])[CH:14]=[CH:13][C:12]=1[C:15]([F:18])([F:16])[F:17]
Reactant: COc1nc(N(Cc2ccccc2)Cc2ccccc2)ccc1C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1nc(N)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of N,N-dibenzyl-6-methoxy-5-(trifluoromethyl)pyridin-2-amine (3.0 g, 8.056 mmol) in a mixture of methanol (30 mL) and AcOH (3 mL) was added palladium hydroxide (0.3 g, 0.43 mmol) under a nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (55 psi, 25° C.) overnight. The catalyst was removed by filtration through a pad of celite and the filtrate was neutralized by saturated Na2CO3. The aqueous layer was extracted with CH2Cl2 (30 mL×3) and the combined organic layers were concentrated under vacuum to give 6-methoxy-5-(trifluoromethyl)pyridin-2-amine (1.4 g, 90%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=8.4 Hz, 1H), 6.03 (d, J=8.0 Hz, 1H), 4.64 (brs, 2H), 3.93 (s, 3H). MS (ESI) m/e (M+H+) 193. 13C NMR (100 MHz, CDCl3) 159.4, 138.0 (d, J=5.9 Hz), 125.9, 122.3, 101.9 (d, J=44.4 Hz), 98.3, 53.6. 19F NMR (282.4 MHz, CDCl3) −62.6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:27])[NH:18][C:17](=[O:19])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32]>CN(C=O)C>[CH2:32]([N:18]1[C:17](=[O:19])[C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:10][C@:9]1([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:27])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)NC(=O)C12CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)C[C@@]1(C)c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl (8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]decane-6-carboxylate (500 mg, 1.314 mmol) in 2 ml of DMF was added to a suspension of sodium hydride (49.8 mg, 1.971 mmol). When the gas evolution had ceased, allyl bromide (0.171 mL, 1.971 mmol) was added to the ice cooled solution. After 18 hours, the reaction was quenched with brine and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The oily residue was purified on silica gel, eluting with a gradient of ethyl acetate:hexanes—0:100 to 50:50. The clean fractions were concentrated in vacuo to yield the title compound. MS: m/z=421 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[C:12]3[CH:18]=[CH:19][CH:20]=[N:21][C:11]=3[S:10][CH2:9][C:8]2=1.[CH3:22]I>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:22])[C:13]1[C:12]3[CH:18]=[CH:19][CH:20]=[N:21][C:11]=3[S:10][CH2:9][C:8]2=1
Reactant: CI
Reactant: COc1ccc2[nH]c3c(c2c1)CSc1ncccc1-3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c(n2C)-c2cccnc2SC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (60%, 41 mg, 1.03 mmoL) was added into 8-methoxy-6,11-dihydro-5-thia-4,11-diaza-benzo[a]fluorene (250 mg, 0.933 mmoL) in DMF (3 mL) at 0° C. After 10 minutes, MeI (0.064 mL, 0.93 mmoL) was added dropwise into the reaction at 0° C. The reaction mixture was slowly warmed to room temperature over 2 hours. The reaction mixture was then partitioned between EtOAc and saturated NH4Cl. The aqueous phase was extracted two times with EtOAc. The organic layer from each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes:EtOAc 1:1 as eluent) to yield the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[N:3]=1.[F:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH2:23][C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)=[N:19][N:18]=4)[CH:15]=3)[N:10]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[N:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Reactant: OB(O)c1ccccc1F
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: O
Solvent: C1COCCO1
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(-c5ccccc5F)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Yield: 72.8 %

Procedure:
To a solution of 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (500 mg, 0.85 mmol) and 2-fluorophenylboronic acid (143.5 mg, 1.02 mmol) in p-dioxane/H2O (3:1, 15 mL) was added K2CO3 (235.5 mg, 1.71 mmol) and Pd(PPh3)4 (49 mg, 0.0427 mmol). The reaction was heated at reflux for 24 h, quenched with H2O and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 50% EtOAc in Hex) to give to 5-(3-(4-(2-fluorophenyl)pyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (400 mg, 72.8%). MS (ESI, pos. ion) m/z: 647.1 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 9.06-8.97 (m, 2H), 8.42-8.17 (m, 2H), 8.12-8.03 (m, 3H), 7.91 (dd, J=8, 1.6 Hz, 1H), 7.65-7.53 (m, 5H), 7.46-7.40 (m, 4H), 7.28 (m, 2H), 6.88 (d, J=8 Hz, 2H), 4.35 (d, J=8 Hz, 2H), 3.72 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[C:16]([C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:33][CH3:34])=[C:27]([C:30](=O)[CH3:31])[CH:28]=2)[O:23][C:22]([CH3:36])([CH3:35])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[F:7]/[C:6](=[C:30](/[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:33][CH3:34])[O:23][C:22]([CH3:36])([CH3:35])[CH:21]=[C:20]2[C:16]([CH3:17])([CH3:19])[CH3:18])\[CH3:31])/[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: COc1cc2c(cc1C(C)=O)C(C(C)(C)C)=CC(C)(C)O2
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.47 mL, 2.3 mmol) and 1-(4-tert-butyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 55, 133 mg, 0.46 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16](/[CH:19]=[CH:20]/OCC)=[CH:17][N:18]=1)[C:12](OC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[NH3:36]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16]([CH:19]=[CH:20][N:36]=[C:12]2[OH:13])=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCO/C=C/c1cnc(OCc2ccccc2)cc1C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Oc1nccc2cnc(OCc3ccccc3)cc12
Temperature: 80 °C
Yield: 97 %

Procedure:
(E)-methyl 2-(benzyloxy)-5-(2-ethoxyvinyl)isonicotinate (Preparation 85, 1.2 g, 3.83 mmol) was dissolved in methanolic ammonia (7M, 28 mL) in 3 microwave tubes. The reaction mixture was sealed and heated to 80° C. for 3 days. The reaction mixture was concentrated in vacuo. The residue was dissolved in toluene (30 mL) and pTsOH.H2O (150 mg, 0.789 mmol) was added. The reaction mixture was heated at 90° C. for 2 hours. The reaction mixture was filtered and dried under vacuum, to give the title compound (937 mg, 97%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[CH3:18][C:15]1[CH:14]=[C:13]([C:6]2[C:7](=[O:12])[NH:8][C:9]3[C:4]([C:5]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:3][C:2]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:10]=3)[O:17][N:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(Br)ccc3[nH]c2=O)on1
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+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(-c4ccccc4)ccc3[nH]c2=O)on1
Temperature: 80 °C

Procedure:
A flask was charged with 6-bromo-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (25 mg, 0.066 mmol)(Example 39), phenyl boronic acid (12 mg, 0.098 mmol), Pd(PPh3)4 (7 mg, 10 mol %), 2 M Na2CO3 (0.25 mL), EtOH (0.25 mL), and toluene (0.5 mL) and heated for 2 hrs at 80° C. The reaction was diluted with EtAc (10 mL) and washed with brine (2×10 mL). The organic layer was concentrated and the title product (12 mg, 50%) eluted from a 5 g SPE with 50% EtAc/hex. 1H NMR (400 MHz, CDCl3) δ 11.42 (s, 1H), 7.82 (dd, 1H), 7.20 (m, 12H), 6.52 (s, 1H), 2.24 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C25H18N2O2 378.1, found 379.1 (M+H).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[N:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N+:7]=[N-:8]>C(#N)C.[Cu](I)I.C(N(CC)CC)C>[CH:1]1([C:4]2[N:8]=[N:7][N:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C#CC1CC1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1cc(C2CC2)nn1
Yield: 95.4 %

Procedure:
Cyclopropylacetylene (15 g, 0.116 mol), ethyl azidoacetate (11.5 g, 0.174 mol), triethylamine (0.32 mL, 2.33 mmol) and copper iodide (442 mg, 2.33 mmol) in acetonitrile (100 mL) were stirred at 25° C. for 18 hours. The mixture was evaporated in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by silica gel column chromatography eluting with EtOAc: Hexane 40: 60 to afford the title compound as a colorless liquid (95%, 21.6 g).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20]3([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1)=[N:9]2.C(OCC)(=O)C>O1CCOCC1>[NH:1]([C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20]3([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1)=[N:9]2)[NH2:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CCC1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Temperature: 95 °C

Procedure:
Anhydrous hydrazine (25 mL, 797 mmol) was added to a stirred solution of chloronaphthyridine (1-5) (25.12 g, 51.7 mmol) in 1,4-dioxane (200 mL) under an atmosphere of nitrogen and the reaction mixture was heated to 95° C. After 30 min the solution was cooled to room temperature, ethyl acetate (400 mL) was added and the solution was washed with a saturated solution of sodium bicarbonate, followed by water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give (1-6) as an orange solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:26][N:25]=1>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:25]=[CH:26][C:27]([C:30]4[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=4)=[CH:28][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Clc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Solvent: CN(C)C=O
Product: Clc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1

Procedure:
Following the same procedure as outlined in Example 12 above, 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (295 mg, 1 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-(4-chlorophenyl)pyrimidine (113 mg, 0.5 mmol) in DMF (5 mL, anhydrous) were reacted to yield the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:3]=1[C:4]#[N:5].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:4]([C:3]1[CH:6]=[C:7]([CH:8]=[CH:9][C:2]=1[F:1])[CH2:10][N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1)#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)c(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
2-Fluoro-5-formylbenzonitrile (25 g, 167.6 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (450 mL) at RT. To this solution was added tert-butyl piperazine-1-carboxylate (31.2 g, 167.6 mmol, 1 equiv.) followed by the portion-wise addition of sodium triacetoxyborohydride (49.7 g, 234.6 mmol, 1.4 equiv.). The reaction vessel was placed under an atmosphere of nitrogen and allowed to stir at room temperature for 1 hour. Saturated NaHCO3 was added and the resultant mixture stirred for 10 minutes. The mixture was concentrated under reduced pressure, diluted with EtOAc (700 mL), and extracted into IN KHSO4 (3×150 mL). The aqueous layer was basified to pH 10 using 50% NaOH solution, saturated with NaCl, extracted into DCM (2×100 mL) and EtOAc (1×200 mL), and dried over Na2SO4. Concentration in vacuo resulted in the isolation of 10.2 g of tert-butyl 4-(3-cyano-4-fluorobenzyl)piperazine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][C:15]=2[OH:25])=[C:4]([CH3:26])[N:3]=1.[Li+].[OH-]>C1COCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[OH:25])=[C:4]([CH3:26])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the product of example 77 (100 mg) in THF (5 mL), LiOH (35.1 mg) in water (5 mL) was added and stirred for 16 h at rt. The solvent was evaporated, the residue redissolved in water and AcOH was added. The precipitate was filtered and dried to give the subtitle compound as a white solid, 50 mg.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[O:14]=[C:15]1[C:20]2=[CH:21][NH:22][C:23]([CH:24]=O)=[C:19]2[CH2:18][CH2:17][O:16]1>>[O:1]=[C:2]1[C:10](=[CH:24][C:23]2[NH:22][CH:21]=[C:20]3[C:15](=[O:14])[O:16][CH2:17][CH2:18][C:19]=23)[C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Product: O=C1Nc2cc(C(=O)O)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:13]4[CH:14]=[C:15]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[C:16]([C:18]#[N:19])=[CH:17][C:12]=4[N:11]=[CH:10]3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-:30].[K+]>CO.OO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:13]4[CH:14]=[C:15]([NH:20][C@H:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[CH3:22])[C:16]([C:18]([NH2:19])=[O:30])=[CH:17][C:12]=4[N:11]=[CH:10]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: C[C@H](Nc1cc2c(cc1C#N)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@H](Nc1cc2c(cc1C(N)=O)ncn2-c1cc(C2CC2)[nH]n1)c1ccc(F)cc1
Temperature: 75 °C
Yield: 44 %

Procedure:
1-(5-Cyclopropyl-1H-pyrazol-3-yl)-6-[(S)-1-(4-fluorophenyl)ethylamino]-1H-benzo[d]imidazol-5-carbonitrile (Example 33; 0.30 g, 0.77 mmol) was dissolved in MeOH (10 ml), followed by addition of 25% aqueous KOH solution (0.87 ml, 3.88 mol) and 15 drops of 30% H2O2 solution. The reaction was heated at 75° C. for 48 hours. After cooling, the reaction was diluted with H2O (5 ml). The resulted solid was collected by filtration and dried under vacuum to give the title compound (0.137 g, 44%) as a white solid. NMR (400 MHz) 12.70 (s, 1H), 8.66 (d, J=4.8 Hz, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 8.03 (br, 1H), 7.42 (m, 2H), 7.24 (br, 1H), 7.13 (m, 1H), 6.80 (s, 1H), 6.00 (s, 1H), 4.57 (m, 1H), 1.95 (m, 1H), 1.47 (d, J=6.0 Hz, 3H), 1.02 (m, 2H), 0.74 (m, 2H). MS: Calcd.: 404; Found: [M+H]+ 405.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH2:20][CH3:21].O>CN(C)C=O>[I:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:19][CH2:20][CH3:21])[C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: CCCI
Reactant: NS(=O)(=O)c1c(O)cccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cccc(I)c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.00 g (16.72 mmol) of 2-hydroxy-6-iodobenzenesulfonamide are introduced in 50 ml of dimethylformamide and this initial charge is admixed with 2.54 g (18.39 mmol) of potassium carbonate. This mixture is stirred at room temperature for 1 h. Thereafter 3.13 g (18.39 mmol) of propyl iodide are added dropwise and the reaction mixture is stirred at room temperature for 3 h. It is then poured into water, and the product precipitates out. The solid is washed with water and dried. This gives 4.00 g (70% of theory) of 2-iodo-6-propoxybenzenesulfonamide.