Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I/[CH:2]=[CH:3]/[C@@H:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C([Li])(C)(C)C.C(N([CH2:29][C:30]1[C:31](=[O:43])[CH2:32][C@@H:33]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH:34]=1)CC)C.CCCCCC>CCOCC>[CH2:29]=[C:30]1[C@@H:34](/[CH:2]=[CH:3]/[C@@H:4]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[C@H:33]([O:35][Si:36]([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:37])[CH3:38])[CH2:32][C:31]1=[O:43]
Reactant: CCN(CC)CC1=C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H](/C=C/I)C1CCCCC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCCC
Product: C=C1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@@H](O[Si](C)(C)C(C)(C)C)C1CCCCC1
Temperature: 0 °C

Procedure:
(1E,3S)-1-Iodo-3-(tert-butyldimethylsiloxy)-3-cyclohexyl-1-propene (2.66 g) was dissolved in ether (28 ml), tert-butyl lithium (1.7 M, pentane solution, 8.24 ml) was added at −78° C. After stirring at the same temperature for an hour, lithium 2-thienylcyanocuprate (0.25 M, tetrahydrofuran solution, 39.2 ml) was added, followed by stirring at the same temperature for 20 minutes, and (4R)-2-(N,N-diethylamino)methyl-4-(tert-butyldimethylsiloxy)cyclopent-2-en-1-one (0.25 M, ether solution, 28 ml) was added. The temperature was raised to 0° C. with stirring over 1.5 hours. To the reaction solution were added hexane (70 ml) and a saturated aqueous ammonium chloride solution (105 ml) and, after extraction with hexane, the extract was washed with a saturated aqueous sodium chloride solution, dried, concentrated and purified by a silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=30:1) to give (3R, 4R)-2-methylene-3-[(1E,3S)-3-(tert-butyldimethylsiloxy)-3-cyclohexyl-1-propenyl]-4-(tert-butyldimethylsiloxy)cyclopentan-1-one (910 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19]O)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH2:47][CH2:48][NH:49][CH2:50][CH:51]=2)=[CH:42][CH:41]=1>C(#N)CC.O>[CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19][N:49]3[CH2:50][CH2:51][C:46]([C:43]4[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][CH:44]=4)=[CH:47][CH2:48]3)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: O=C1CN(Cc2ccccc2)c2ncc(CO)cc2N1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(Cc2ccccc2)c2ncc(CN3CC=C(c4ccc(Cl)cc4)CC3)cc2N1
Temperature: 90 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.37 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (45.3 mg, 27%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.57 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.41-7.48 (m, 2H), 7.23-7.41 (m, 7H), 7.03 (d, J=2.0 Hz, 1H), 6.19 (s, 1H), 4.72 (s, 2H), 3.86 (s, 2H), 3.43 (s, 2H), 3.03 (d, J=2.8 Hz, 2H), 2.58-2.65 (m, 2H), 2.44 (br. s., 2H). [M+H] calc'd for C26H25ClN4O, 445; found, 445.
Reaction SMILES: C(OC[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:32][C:33]#[N:34])[CH2:26][N:25]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=O)C(C)(C)C.[OH-].[Na+]>CO.O1CCCC1>[N:14]1[C:13]2[NH:9][CH:10]=[CH:11][C:12]=2[C:17]([C:18]2[CH:19]=[N:20][N:21]([C:23]3([CH2:32][C:33]#[N:34])[CH2:24][N:25]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])[CH2:26]3)[CH:22]=2)=[N:16][CH:15]=1
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COC(=O)C(C)(C)C)cn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
A suspension of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 1.0 g, 2.06 mmol) in methanol (MeOH, 5 mL) and tetrahydrofuran (THF, 20 mL) was treated with a 1 M aqueous sodium hydroxide solution (NaOH, 2.3 mL, 2.3 mmol, 1.12 equiv) at room temperature, and the resulting reaction mixture was stirred at room temperature for 2-3 h. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and a 1 N aqueous HCl solution (0.2 mL) to adjust pH to 7-7.5 at room temperature. The resulting mixture was stirred at room temperature for 30 min before the solids were collected by filtration. The solids were washed with a mixture of acetonitrile and water (⅔ by volume, 2×4 mL) and dried in vacuum at 40-45° C. for 24 h to afford crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (14, 658 mg, 765 mg theoretical, 86% yield) as off-white solids, which was found to be identical to the material prepared by Method A. For crude 14: 1H NMR (DMSO-d6, 300 MHz) δ 12.15 (s, 1H), 8.94 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.63 (d, 1H), 7.09 (d, 1H), 4.62 (d, 2H), 4.25 (d, 2H), 3.71 (s, 2H), 3.24 (q, 2H), 1.26 (t, 3H) ppm; C16H17N7O2S (MW, 371.42), LCMS (EI) m/e 372 (M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].O1CCOCC1>C(OCC)(=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClCCl.[Pd+2].O>[Cl:10][C:4]1[CH:3]=[C:2]([C:32]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:21][C:20]=2[CH3:19])[CH:7]=[N:6][C:5]=1[O:8][CH3:9]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ncc(Br)cc1Cl
Agent: [Fe+2]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a 250 mL RBF was added 5-bromo-3-chloro-2-methoxypyridine (1.5 g), tribasic potassium phosphate (2.86 g, 13.5 mmol), bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.275 g, 6.74 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.27 g, 7.13 mmol), dioxane (50 mL) and water (3 mL). The flask was sealed and was stirred at 80° C. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, filtered and concentrated. The resultant residue was purified by column chromatography to yield tert-butyl 4-(5-chloro-6-methoxypyridin-3-yl)-3-methylbenzoate (2.0 g, 5.99 mmol). MS ESI calc'd. for C18H21ClNO3 [M+H]+ 334.1. found 334.0.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[N:18]=[C:17]([NH:19][CH2:20][CH2:21][OH:22])[C:16]2[C:15]3[CH:23]=[CH:24][N:25]([CH3:26])[C:14]=3[C:13](I)=[CH:12][C:11]=2[N:10]=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C(=O)(O)[O-].[Na+]>COCCOC.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[N:18]=[C:17]([NH:19][CH2:20][CH2:21][OH:22])[C:16]2[C:15]3[CH:23]=[CH:24][N:25]([CH3:26])[C:14]=3[C:13]([C:29]3[S:28][CH:32]=[CH:31][CH:30]=3)=[CH:12][C:11]=2[N:10]=1
Reactant: Cn1ccc2c3c(NCCO)nc(N)nc3cc(I)c21
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc2c3c(NCCO)nc(N)nc3cc(-c3cccs3)c21
Reaction time: 0.25 h

Procedure:
A solution of 2-(3-amino-6-iodo-7-methyl-7H-pyrrolo[3,2-f]quinazolin-1-ylamino)-ethanol trifluoroactic acid salt (90 mg, 0.23 mmol) in ethylene glycol dimethyl ether (8.0 mL) and ethanol (4.0 mL) at 25° C. was treated with thiophene-2-boronic acid (60 mg, 0.47 mmol), a 2.0 M aqueous sodium bicarbonate solution (2.0 mL), and tetrakis(triphenylphosphine)-palladium (0) (5.0 mg). The resulting mixture was heated to reflux for 18 h. The resulting mixture was concentrated in vacuo and the residue suspended in acetonitrile and water and filtered. HPLC purification (21.2 mm×100 mm Zorbax CombiHT column using a 5:95 to 95:5 acetonitrile:water: 0.75% TFA gradient over 15 minutes) afforded 2-(3-amino-7-methyl-6-thiophen-2-yl-7H-pyrrolo[3,2-f]quinazolin-1-ylamino)-ethanol trifluoro-acetic acid salt as a light yellow solid; LRMS for C17H17N5O (M+H)+ at m/z=340.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH:13](Br)[C:12](=O)[C:11]=2[CH:10]=[CH:9][CH:8]=1)[CH3:2].[C:20]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:27][CH2:28][NH:29][C:30]([NH2:32])=[S:31])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(#N)C.C(N(CC)CC)C>O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][C:13]1[S:31][C:30]([NH:29][CH2:28][CH2:27][CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:32][C:12]=12)[CH3:2]
Reactant: NC(=S)NCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCC(Br)C2=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)COc1cccc2c1CCc1sc(NCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 38.3 %

Procedure:
To a mixture of ethyl[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate (1.20 g, 3.67 mmol), N-(3,3-diphenylpropyl)thiourea (1.10 g, 4.04 mmol), and acetonitrile (30 mL) was added triethylamine (0.56 mL, 4.04 mmol), and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid, saturated aqueous sodium chloride solution, and water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate=5:1) to provide 700 mg of ethyl[[2-(3,3-diphenylpropyl)amino-4,5-dihydronaphtho[1,2-d]thiazol-6-yl]oxy]acetate. To a solution of this compound in acetic acid (10 mL) was added concentrated hydrochloric acid (5 mL) and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water, dried over MgSO4, and filtered and the filtrate was concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to provide 500 mg of the title compound. Yield 17%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[C:9]([O:20][CH3:21])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5])C.[CH3:22][O:23][C:24](=[O:31])[C@@H:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:30][C@H:25]([C:24]([O:23][CH3:22])=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:14][C:13]2[C:8](=[C:9]([O:20][CH3:21])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C1Oc2c(OC)ccc(OC)c2C=C1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1Oc2c(OC)ccc(OC)c2C=C1CN[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 41.6 %

Procedure:
To a solution of 3-formyl-5,8-dimethoxy-2H-chromene-2-carboxylic acid ethyl ester (5.0 g, 17.11 mmol) (Example 13, Step 1) in methanol (40 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-4-methyl-pentanoic acid methyl ester (3.1 g, 17.11 mmol) and N,N′-diisopropylethylamine (4.42 mL, 34.21 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (2.15 g, 34.21 mmol) and acetic acid (1.95 mL, 34.21 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:19, Rf=0.6) over neutral alumina afforded 5,8-dimethoxy-3-[((S)-1-methoxycarbonyl-3-methyl-butylamino)-methyl]-2H chromene-2-carboxylic acid methyl ester (2.90 g, 39.2%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[N:23]2)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.C(OCC)(=O)C>O1CCCC1.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:9]([O:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][N:22]2[CH:26]=[C:25]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:24]=[N:23]2)=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnn(Cc2ccc(OCc3ccccc3)cc2)c1
Reactant: Nc1ncccc1Br
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cnn(Cc2ccc(OCc3ccccc3)cc2)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 1.9 %

Procedure:
To a solution of 2-amino-3-bromopyridine (44.1 mg, 0.26 mmol) in anhydrous tetrahydrofuran (7 mL) were added 1-(4-benzyloxy-benzyl)-4-tributylstannanyl-1H-pyrazole (141 mg, 0.26 mmol) described in Manufacturing Example 31-1-2, copper (I) iodide (19.4 mg, 0.10 mmol) and bis(triphenylphosphine)palladium (II) (35.8 mg, 0.05 mmol) under nitrogen atmosphere, which was stirred for 4 hours at 70° C. Water and ethyl acetate were added to the reaction mixture at room temperature, which was then filtered through a Celite pad, and the filtrate was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1, then ethyl acetate) to obtain the title compound (1.8 mg, 2%).
Reaction SMILES: C(O)(=O)C.N1C=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][C:12]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:15]=[C:14]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][CH:31]=3)[N:26]=2)[CH:13]=1.COC1CCC(OC)O1>O>[CH3:11][C:12]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[N:15]=[C:14]([C:25]2[O:29][N:28]=[C:27]([C:30]3[CH:31]=[CH:32][C:33]([CH2:36][N:37]4[CH:9]=[CH:8][CH:7]=[CH:6]4)=[CH:34][CH:35]=3)[N:26]=2)[CH:13]=1
Reactant: c1ccncc1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(CN)cc4)no3)cc2C)cc1
Agent: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(Cn5cccc5)cc4)no3)cc2C)cc1
Temperature: 100 °C
Yield: 32.4 %

Procedure:
To a solution of acetic acid (348 μL, 6.08 mmol) in water (194 μL) were added successively pyridine (491 μL, 6.08 mmol), 1-(4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}phenyl)methanamine (Example 139, 130 mg, 0.362 mmol) and 2,5-dimethoxytetrahydrofuran (47 μL, 0.362 mmol). The reaction mixture was heated to 100° C. for 20 h. After being cooled to rt, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate. After filtration and evaporation of the solvent, the crude product was first subjected to MPLC (silica, cyclohexane/ethyl acetate 4:1) and then to preparative HPLC affording the title compound as a white solid (48 mg, 31%): NMR (400 MHz, DMSO-d6) 8.02 (d, 2H), 7.35 (d, 2H), 7.18 (d, 2H), 7.11 (d, 2H), 6.91 (s, 1H), 6.86 (t, 2H), 6.05 (t, 2H), 5.42 (s, 2H), 5.21 (s, 2H), 2.32 (s, 3H), 2.27 (s, 3H); ES-MS m/z 410, HPLC RT (Method K) 1.54 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:6]=[CH2:7].B1C2CCCC1CCC2.I[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>C1COCC1.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.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][CH2:7][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: COc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: COC(=O)C(CCCc1ccc(OC)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) mixture comprising 2-tert-butoxycarbonylamino-pent-4-enoic acid methyl ester (4.0 g, 17.46 mmol) in dry THF (60 mL) under an inert atmosphere of argon is added 9-BBN (70 mL of a 0.5 M solution in THF, 35.0 mmol). The reaction is stirred at RT for 2 h. To this mixture is added degassed DMF (50 mL) followed by an aqueous solution of potassium phosphate (12 mL of a 3 M aqueous solution, 36 mmol). 4-Iodoanisole (4.3 g, 18.8 mmol) is added immediately followed by PdCl2(dppf) (0.63 g, 0.86 mmol) and the mixture is stirred at RT overnight. The solvent is removed in vacuo and the crude residue is dissolved in EtOAc and filtered through Celite® (filter material). The filtrate is washed with saturated sodium hydrogen carbonate solution, water (×3), brine, and then dried (MgSO4) and concentrated in vacuo. Purification of the crude product by flash chromatography (SiO2, iso-hexane:EtOAc, 9:1) affords the title compound as a light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16](=O)[C:17]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=3Cl)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC([N+]([O-])=O)=CC=1CC1NC(C(O)=O)=CC=1.O.[NH2:48][NH2:49].C1(C)C=CC=CC=1>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[NH:12][C:13]([C:16]3[C:17]4[C:18](=[CH:19][CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=4)[NH:49][N:48]=3)=[CH:14][CH:15]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C(Nc1cccc(F)c1)c1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)[nH]1
Agent: O=C(O)c1ccc(Cc2cc([N+](=O)[O-])ccc2Cl)[nH]1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(F)c1)c1ccc(-c2n[nH]c3ccc([N+](=O)[O-])cc23)[nH]1
Temperature: 120 °C

Procedure:
A mixture of 5-(2-chloro-5-nitro-benzoyl)-1H-pyrrole-2-carboxylic acid (3-fluoro-phenyl)-amide (250 mg, 0.6 mmol) (made from 5-(2-chloro-5-nitrobenzyl)-1H-pyrrole-2-carboxylic acid using a procedure adapted from that described in Example 32), hydrazine hydrate (0.3 mL), toluene (5 mL) and 1-methyl-pyrrolin-2-one (0.4 mL) was heated at 120° C. for 1.5 hours. The reaction was concentrated, mixed with water and filtered. The solid was washed to give 200 mg of the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[C:16]([CH3:19])([CH3:18])[CH3:17].[N:21]#[C:22][NH2:23].O1CCCC1.C(N(CC)CC)C>O>[NH2:23][C:22]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:21]=1
Reactant: CC(C)(C)C(Cl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#CN
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reaction time: 1 h
Yield: 75 %

Procedure:
7.0 g (0.02 mol) of 2,2-dimethylpropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 1.7 g (0.04 mol) of cyanamide were added to 100 ml of tetrahydrofuran. Then, 4.0 g (0.04 mol) of triethylamine was dropwise added under reflux and stirring. After completion of the dropwise addition, the stirring was continued at the same temperature for further 1 hour. After cooling, the reaction solution was poured into water, and the precipitate was extracted with toluene. The organic layer was washed with water and dried. Then, the solvent was distilled off under reduced pressure, and the residue was washed with n-hexane to obtain 5.3 g (yield: 74.6%) of the desired compound as white prismatic crystals. The melting point: 208°-212° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]([N:6]([C:13]1[C:18]([C:19](=[O:29])[CH2:20][CH2:21][C:22]2[CH:23]=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[CH:17][CH:16]=[C:15]([CH3:30])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.CO.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[C:18]([C:19](=[O:29])[C:20]=1[CH2:21][C:22]1[CH:23]=[N:24][C:25]([Cl:28])=[CH:26][CH:27]=1)=[CH:17][CH:16]=[C:15]([CH3:30])[N:14]=2)=[O:31]
Reactant: COC(=O)C(=O)N(c1ccccc1)c1nc(C)ccc1C(=O)CCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cc2ccc(Cl)nc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of N-{-3-[3-(6-chloropyridin-3-yl)-propionyl]-6-methyl-pyridin-2-yl}-N-phenyl-oxalamic acid methyl ester in toluene was added MeOH, and the mixture placed in a pre-heated hot bath at 80° C. K2CO3 (0.9 g) was added, which produced an immediate color change. The mixture was cooled to RT, diluted with EtOAc, and washed with LiCl (0.3 wt % aq, 2×). The organic layer was dried over MgSO4, filtered, and concentrated. The product was dissolved in hot EtOAc, and allowed to cool to RT. The resulting precipitate was filtered and washed with EtOAc to provide 3-(6-chloro-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (compound 83) (0.14 g) as a tan solid. M+H=420, mp=220.0-220.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1)#[CH:10].C(OCC)(=O)C.Cl>C1COCC1.C(NC(C)C)(C)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>[OH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([C:9]#[C:10][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C#Cc1ccc(CO)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: OCc1ccc(C#Cc2ccc(O)cc2)cc1

Procedure:
6.50 g (37.6 mmol) of 4-bromophenol and 5.00 g (37.8 mmol) of 4-ethynylbenzyl alcohol are initially introduced in 70 ml of THF and 10 ml of diisopropylamine, and, after addition of 1.50 g (2.14 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.40 g (2.10 mmol) of copper(I) iodide, the mixture is heated under reflux overnight. After addition of 100 ml of ethyl acetate, the mixture is acidified using 2 M hydrochloric acid, the aqueous phase is extracted three times with ethyl acetate, and the combined org. phases are dried over sodium sulfate. The solvent is removed in vacuo, and the residue is purified by chromatography on silica gel, giving 4-(4-hydroxymethylphenylethynyl)phenol as a colourless solid.