Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.Br[CH2:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[CH:7][CH:6]=1.Br[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CN(C=O)C.[Zn].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]>[Si:10]([O:9][C:8]1[CH:17]=[CH:18][C:5]([CH2:4][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:6][CH:7]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Brc1ncccn1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CBr)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc (0.33 g, 4.97 mmol) and iodine (0.008 g, 0.033 mmol) were added to an oven-dried flask (25 mL). The mixture was heated under vacuum with a heat gun for 10 min, cooled to RT, placed under argon atmosphere, suspended in 3 mL DMF (dry, degassed by bubbling nitrogen through it for 10 min), and cooled to 0° C. (4-(Bromomethyl)phenoxy)(tertbutyl)dimethylsilane (1.00 g, 3.31 mmol) was added as a solution in 3 mL DMF, the mixture was stirred at 0° C. for 30 min, then room temperature for 30 min. Next, 2-bromopyrimidine (526 mg, 3.31 mmol), Pd2 dba3 (0.091 mg, 0.099 mmol), and S-Phos (0.163 g, 0.40 mmol) were added. The flask was purged with argon and heated for 1 h at 60° C., cooled to RT, filtered through Celite, and concentrated in vacuo. The resulting solid was purified by flash chromatography to give title compound as a light yellow oil. MS (ESI) m/z: Calculated: 300.2; Observed: 301.5 (M++1).
Reaction SMILES: N[C:2]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][C:21]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:24])=[CH:22][C:15]=3[N:14]=2)=[CH:9][CH:8]=1)([CH3:6])C)=O.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:55])C.O>>[NH2:55][C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[C:16]3[CH:19]=[CH:20][C:21]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:24])=[CH:22][C:15]=3[N:14]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:2]
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(C)(C)C(N)=O)cc1)n2C
Reactant: CC#N
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C(C)(C)N)cc1)n2C

Procedure:
Prepared from 2-[4-(2-aminocarbonyl-2-propyl)-phenyl]-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-benzimidazole by treating with [bis(trifluoroacetoxy)-iodo]benzene in acetonitrile/water at ambient temperature.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:20][N:19]=2)=[O:23])[CH2:57][CH2:58]1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (30 mg, 0.1 mmol) in DMF (1 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (34 mg, 0.1 mmol), N,N-diisopropyl ethyl amine (83 μL, 0.48 mmol) and 4-aminotetrahydropyran (11 mg, 0.1 mmol). The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated and purification by chromatography (silica, heptane:ethyl acetate=100:0 to 2:3) afforded the title compound (29 mg, 76%) as a white solid. MS: m/e=395.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[C:17]3[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][C:13]([CH3:21])([CH3:20])[C:12]=3[CH:11]=[C:10]([CH:22]([OH:25])[C:23]#[CH:24])[CH:9]=2)=[CH:4][CH:3]=1.I[C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1>[Cu](I)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>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[C:17]3[C:16]([CH3:18])([CH3:19])[CH2:15][CH2:14][C:13]([CH3:21])([CH3:20])[C:12]=3[CH:11]=[C:10]([CH:22]([OH:25])[C:23]#[C:24][C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)[CH:9]=2)=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1cc(OCc2ccc(F)cc2)c2c(c1)C(C)(C)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CC1(C)CCC(C)(C)c2c(OCc3ccc(F)cc3)cc(C(O)C#Cc3ccc(C(=O)O)cc3)cc21
Yield: 67 %

Procedure:
In a manner similar to that of Example 1g, by reacting 580 mg (1.6 mmol) of 1-[4-(4-fluorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]prop-2-yn-1-ol with 330 mg (1.3 mmol) of 4-iodobenzoic acid in the presence of 12 mg of copper iodide and 23 mg of bis(triphenylphosphine)dichloropalladium. The desired product is obtained in the form of beige-colored crystals (m=420 mg; yield=67%; m.p. 188° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:2]1.[Na].Cl.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24]Cl)[CH3:20]>CN(C=O)C.C(O)C>[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][N:12]1[C:11](=[O:16])[CH:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[NH:14][C:13]1=[O:15])[CH3:20]
Reactant: O=C1NC(=O)C(c2c[nH]c3ccccc23)N1
Reactant: CCN(CC)CCCCl
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCN(CC)CCCN1C(=O)NC(c2c[nH]c3ccccc23)C1=O
Reaction time: 18 h

Procedure:
A solution of 5-(indol-3-yl)hydantoin (5.2 g, 0.024 mole) in 100 ml of DMF was added to a solution of sodium (1.1 g) in 100 ml of anhydrous C2H5OH. The solution was warmed warmed 3-diethylaminopropyl chloride hydrochloride (4.5 g, 0.024 mole) was added and the mixture was heated to reflux with stirring for 18 hours, filtered and diluted with H2O. The crude free base (2.5 g) and oxalic acid (1.5 g) was dissolved in methanol and diluted with ethyl acetate. The solid was collected and dried, yield 1.0 g, mp 231°-2°.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16](=[O:50])[CH:17]([CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:18]([C:27](N1C(CC2C=CC=CC=2)COC1=O)=[O:28])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1COCC1>[CH3:14][O:15][C:16](=[O:50])[CH:17]([CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:18]([C:27]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:28])[CH2:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21]
Reactant: OCc1ccccc1
Reactant: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)N1C(=O)OCC1Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of benzyl alcohol (0.5 mL, 4.41 mmol) in anhydrous THF (16 mL) at −70° C., was added n-butyl lithium (2.5M, 1.4 mL, 3.53 mmol). After 10 minutes of stirring, the solution was transferred by means of a cannula to a solution of the compound of example 51 in anhydrous THF (15 mL) at −70° C. The reaction was allowed to warm to −10° C. over a period of 2 h, after which time, it was placed in an ice bath and stirred for another 50 minutes. Finally, the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted several times using ethyl acetate. The recombined organic layer was extracted with brine, dried over sodium sulfate, filtered and evaporated. The resultant crude was flashed using 10% ethyl acetate in hexanes to give the product as a colorless oil. 1H-NMR(CDCl3, 300 MH: 1.39, 1.40(2 s, 9H); 1.70(m, 1H); 2.01(m, 1H); 2.31–2.74(m, 4H); 2.83(m, 1H); 3.21(m, 1H); 3.61, 3.64(2s, 3H); 5.11(m, 2H); 7.08–7.35(m, 10H).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][CH:24]2[O:26][CH2:25]2)=[CH:20][CH:19]=1>CO>[NH2:15][C:16](=[O:29])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH:24]([OH:26])[CH2:25][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)=[CH:27][CH:28]=1
Reactant: NCCCCn1cnc2ccccc21
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(OCC(O)CNCCCCn2cnc3ccccc32)cc1

Procedure:
A mixture of 2.84 grams of 1H-benzimidazole-1-butanamine and 3.11 grams of 1-[4-(2-amino-2-oxoethyl)phenoxy]-2,3-epoxypropane in 50 ml of 90% methanol was heated at reflux for 22 hours. The solvent was evaporated and the residue was triturated with ether to give an off-white solid. This was chromatographed on a silica gel column using methanol. The fractions containing the desired product were determined by thin-layer chromatography and combined. The solvent was then evaporated to give N-{3-[4-(2-amino-2-oxoethyl)phenoxy]-2-hydroxypropyl}-1H-benzimidazole-1-butanamine as an off-white solid melting at about 119°-123° C. This compound has the following structural formula: ##STR13##
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.ClCCl.[Cu]I>[O:24]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccccc1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: O=C(Nc1cc2ccc(Oc3ccccc3)cc2cn1)C1CC1
Yield: 32.9 %

Procedure:
N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (89 mg, 0.30 mmol), phenol (86.5 mg, 0.92 mmol, 3 eq), 3, 4,7,8-tetramethyl-1,10-phenanthrolin (35.4 mg, 0.15 mmol, 0.5 eq), copper(I) iodide (57.3 mg, 0.3 mmol, 1 eq) and cesium carbonate (293.2 mg, 0.9 mmol, 3 eq) in 1-methyl-2-pyrrolidinone (2.5 ml) were stirred under microwave irradiation at 180° C. for 99 min under nitrogen. The mixture was diluted with dichloromethane and filtered through a pad of Celite. The filer cake was washed with dichloromethane and the combined filtrate was concentrated and purified by prep-HPLC to give product (30 mg, 26%). LCMS (ESI): RT (min)=1.107, M+H+=305.0, method=A. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.38-7.00 (m, 5H), 1.55-1.52 (m, 1H), 1.10-1.06 (m, 2H), 0.87-0.82 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:39]=[CH:38][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][CH:22]=1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[S:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:39]=[CH:38][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCBr)cc1
Reactant: Sc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCSc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
To a mixture of 523 mg 2-mercaptopyrimidine and 25 ml anhydrous N,N-diemthylformamide, were added 640 mg anhydrous potassium carbonate and 2 g ethyl 6-[p-(5-bromopentyloxy)phenoxy]-2,2-dimethylhexanoate, and the resulting mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, the residue was extracted with chloroform, and the extract was washed with water and dried. The chloroform was distilled off, and the residue was purified by silica gel column chromatography (chloroform), affording 740 mg ethyl 6-[p-[5-(2-pyrimidylthio)pentyloxy]phenoxy]-2,2-dimethylhexanoate as oil.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)(Cl)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].C(OCC)(=O)C.C(O)C>[CH:1]([N:14]1[CH2:17][CH:16]([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)[CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC1(c2coc3ccccc23)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc(C(c2ccccc2)N2CC(c3coc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-benzhydryl-3-(benzofuran-3-yl)-3-chloroazetidine as obtained in the previous step (873 mg, ≦2.14 mmol), triethylamine (299 μL, 2.14 mmol) and 10% palladium on carbon (227 mg) in ethyl acetate (15 mL) and ethanol (15 mL) was stirred at room temperature under hydrogen atmosphere (˜1 atm) for 3 days. After removal of hydrogen, the mixture was diluted with dichloromethane (100 mL), filtered through Clarcel® and concentrated. The residue was taken up in dichloromethane (50 mL) and washed with aqueous saturated sodium hydrogencarbonate (50 mL). The aqueous layer was back-washed with dichloromethane (2×50 mL) and all the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (100:0 to 95:5) as eluent followed by preparative TLC on reversed phase C18 using acetonitrile/water (90:10) as eluent. The title compound was obtained as a yellow gum (52 mg, 7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.O>CS(C)=O>[Br:8][C:4]1[N:3]=[C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1COCCN1
Reactant: Brc1cccc(Br)n1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Brc1cccc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A stirred solution of 2,6-dibromopyridine (5.0 g, 20.7 mmol), triethylamine (3.0 ml, 21.7 mmol) and morpholine (1.8 g, 20.7 mmol) in dimethylsulfoxide (25 ml) was heated at 85° C. for 4 h. After cooling to ambient temperature the reaction was poured into water. After decanting off the aqueous, the gum was dissolved in dichloromethane, washed with water and saturated brine, then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with dichloromethane gave 4-(6-bromopyridin-2-yl)morpholine (3.0 g) as a white solid: δH (400 MHz, CDCl3) 3.50 (4H, t, J 5), 3.80 (4H, t, J 5), 6.50 (1H, d, J 8), 6.79 (1H, d, J 8), 7.31 (1H, dd, J 8 and 8); m/z (ES+) 242/244 (M++H).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][N:16]2[CH2:36][CH2:35][C:19]3([O:24][CH2:23][CH2:22][N:21]([C:25]([C:27]4[N:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[S:30][CH:31]=4)=[O:26])[CH2:20]3)[CH2:18][CH2:17]2)[CH:13]=1)(=O)C>CO>[OH:6][CH2:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][N:16]2[CH2:36][CH2:35][C:19]3([O:24][CH2:23][CH2:22][N:21]([C:25]([C:27]4[N:28]=[C:29]([CH:32]([CH3:33])[CH3:34])[S:30][CH:31]=4)=[O:26])[CH2:20]3)[CH2:18][CH2:17]2)[CH:13]=1
Reactant: CC(=O)OCCc1cc(CCN2CCC3(CC2)CN(C(=O)c2csc(C(C)C)n2)CCO3)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCc4csc(CCO)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide (1M, 4.9 mL) was added to a solution of 2-(4-(2-(4(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl)thiophen-2-yl)ethyl acetate [Example 78, step a] (1.0 g) in methanol (20 mL) and the resulting mixture was stirred for 1 hour at 20° C. The mixture was partitioned between ethyl acetate and brine and separated. The organic phase was dried, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.92 g.
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2].Cl[Cu]>[NH2:1][C:2](=[O:20])[C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(I)cc1)C(N)=O
Reactant: CC1(C)OB(c2ccccn2)OC1(C)C
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C(N)=O
Reaction time: 18 h
Yield: 33.5 %

Procedure:
A mixture of (R)-tert-butyl 1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamate (970 mg, 2.48 mmol), pyridine-2-boronic acid pinacol ester (505 mg, 2.46 mmol), dppf (275 mg, 0.496 mmol), Cs2CO3 (1.00 g, 3.06 mmol), Pd(OAc)2 (56 mg, 0.249 mmol) and CuCl (25 mg, 0.252 mmol) in DMF (10 mL) was degassed with argon, then was stirred at 100 C for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, which was eluted with 20-100% EtOAc in hexane to give (R)-tert-butyl 1-amino-1-oxo-3-(4-(pyridin-2-yl)phenyl)propan-2-ylcarbamate (281 mg).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O.[OH-].[NH4+:32]>O1CCCC1>[CH:25]1([CH2:24][N:6]2[CH2:7][C@@H:8]([NH:10][C:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[OH:23])=[O:12])[CH2:9][C@H:5]2[C:3]([NH2:32])=[O:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: [NH4+]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Temperature: 95 °C
Yield: 16 %

Procedure:
To a solution of (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (50 mg) in tetrahydrofuran (7 mL), aq. ammonium hydroxide (15 mL) was added in a seal tube and the mixture was heated for 24 hrs at 95° C. The reaction mixture was concentrated and the aqueous layer was extracted with diethyl ether, washed with brine, dried, concentrated and was purified by column chromatography to obtain (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid amide (8 mg, 16% yield) as a light brown solid. MS calcd. for C23H30N3O3 [(M+H)+] 396, obsd. 396.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC(C[O:15][C@H:16]([CH2:25][CH2:26][O:27]CC2C=CC([N+]([O-])=O)=CC=2)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=CC=1)([O-])=O>CO>[OH:15][C@H:16]([CH2:25][CH2:26][OH:27])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CCCC[C@@H](CCOCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CCCC[C@H](O)CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
Under an argon atmosphere, anhydrous potassium carbonate (130 mg, 0.94 mmol) was added to a solution of (6S)-(-)-methyl 6,8-bis(4-nitrobenzoxy)octanoate (461 mg, 0.94 mmol) in methanol (9.4 ml). The mixture was stirred at room temperature for 1 h and quenched with a saturated ammonium chloride solution (50 ml). The mixture was extracted with chloroform (3×50 ml) and the combined organic extracts were washed with brine (50 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with ethyl acetate to give (6S)-(-)-methyl 6,8-dihydroxyoctanoate (147 mg, 82% yield) as a colourless oil. Rf 0.30 (ethyl acetate, 100%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCN(c4cccc(Cl)c4)CC3)cc2)[nH]c1=O

Procedure:
From 12.9 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 23.7 g. of N-(m-chlorophenyl)-piperazine in 180 ml. of dimethyl sulfoxide; there is obtained 6-[p-[4-(m-chlorophenyl)-1-piperazinyl]phenyl]-1,2-dihydro-2-oxonicotinonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH2:25][CH3:26])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2ccc(F)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCC1c2cc(F)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])([C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCl
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Product: CCOC(=O)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
As shown in Scheme I,2-alkynyl-dihydropyridazinones of the present invention can be prepared by cyclization. For example, in step A, di-t-butyl malonate and ethyl chloroacetate can be condensed in the presence of a strong base in a polar aprotic solvent to provide 1,1-di-tert-butyl 2-ethyl ethane-1,1,2-tricarboxylate. In step B, the 1,1-di-tert-butyl 2-ethyl ethane-1,1,2-tricarboxylate can be reacted the appropriate pyridine or pyrimidine acid chloride in the presence of base to provide a tricarboxylate which can be decarboxylated in step C to provide the appropriate ethyl 4-(pyridin-2-yl or pyrimidin-2-yl)-4-oxobutanoate. In step D, the appropriate ethyl 4-(pyridin-2-yl or pyrimidin-2-yl)-4-oxobutanoate can be cyclized with hydrazine to provide the appropriate 6-(pyridin-2-yl or pyrimidin-2-yl)dihydropyridazinone which can be alkylated in step E with an alkyne having an appropriate leaving group (L represents halogen or alkyl or aryl sulfonate).