Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[C:13]([CH3:15])[C:12](I)=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:17]([C:12]1[C:13]([CH3:15])=[CH:14][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:18]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(I)c(C)cc1C1CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C)cc1C1CCC1
Temperature: 100 °C

Procedure:
A mixture of methyl 2-cyclobutyl-5-iodo-4-methylbenzoate (219.3, 3.0 g, 9.1 mmol), Zn(CN)2 (2.3 g, 19.6 mmol) and Pd(PPh3)4 (0.55 g, 0.47 mmol) in DMF (50 ml) was degassed and the flask was filled with argon through a balloon. The mixture was heated at 100° C. under argon overnight. After cooling to ambient temperature, the reaction was quenched with saturated aq. FeSO4 (20 ml) and diluted with EtOAc (200 ml). The mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The residue was purified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 2.0 g, 96%. 1H NMR (400 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.34 (s, 1H), 4.26-4.13 (m, 1H), 3.89 (s, 3H), 2.59 (s, 3H), 2.46-2.32 (m, 2H), 2.16-1.98 (m, 3H), 1.90-1.78 (m, 1H).
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:26][C:24]1[CH:23]=[C:22]([CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:21]=[C:20]([F:19])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(F)cc(C2CCOCC2)c1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3CCOCC3)cc2F)OC1(C)C
Yield: 100 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 equiv.), butyllithium (1.1 equiv.) and 4-(3,5-difluorophenyl)tetrahydro-2H-pyran (1.0 equiv.) to give 2-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 100% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.16-1.19 (m, 12H), 1.65-1.74 (m, 4H), 2.60-2.75 (m, 1H), 3.37-3.51 (m, 2H), 4.01 (dt, J=11.54, 3.42 Hz, 2H), 6.67 (d, J=8.22 Hz, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([O:8][C:9](=[O:14])[C:10](=[O:13])[CH2:11][CH3:12])[C@H:5]([C:15]([CH3:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:4][CH2:3]1.[C:24]([Mg]Br)(C)=[CH2:25].O1CCC[CH2:30]1>>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([O:8][C:9](=[O:14])[C@@:10]([CH2:24][CH3:25])([OH:13])[C:11]([CH3:30])=[CH2:12])[C@H:5]([C:15]([CH3:23])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[CH2:4][CH2:3]1
Reactant: C=C(C)[Mg]Br
Reactant: CCC(=O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)(C)c1ccccc1
Reactant: C1CCOC1
Product: C=C(C)[C@@](O)(CC)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)(C)c1ccccc1
Reaction time: 0.83 h

Procedure:
To a solution of 4.200 g of compound (17) as obtained from example 11 (13.27 mmol) in 168 mL tetrahydrofuran were added dropwise at −78° C. 39.8 mL isopropenylmagnesium bromide (19.91 mmol, 1.5 eq). After additional 50 min, the reaction mixture was quenched by addition of 110 mL saturated aqueous ammonium chloride solution, and was extracted twice with 110 mL ethyl acetate. The combined organic phases were washed with 110 mL brine, dried over 15 g sodium sulfate and were filtered. The filter cake was washed with 30 mL ethyl acetate. The organic phase was evaporated to dryness in a rotary evaporator (40° C., 8 mbar) yielding the title compound (4.790 g, 101% by weight, dr=93:7)as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH:43]1[CH2:50][CH:49]2[N:51]([CH3:52])[CH:45]([CH2:46][CH2:47][CH2:48]2)[CH2:44]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)C>[CH3:52][N:51]1[CH:45]2[CH2:46][CH2:47][CH2:48][CH:49]1[CH2:50][CH:43]([NH:42][C:17]([C:15]1[CH:16]=[C:2]([Br:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:44]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(Br)cc2oc(-c3ccccc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN1C2CCCC1CC(NC(=O)c1cc(Br)cc3oc(-c4ccccc4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.9 %

Procedure:
A mixture of 6-bromo-2-phenylbenzoxazole-4-carboxylic acid (82 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99 mg, 0.52 mmol), 1-hydroxybenzotriazole (70 mg, 0.52 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (48 mg, 0.31 mmol) in DMF (5 mL) was stirred 10 min at room temperature, then triethylamine (0.10 mL, 1.03 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether (50 mL) and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. During the concentration, a white solid was crashed out. The solid was isolated, washed with ether and dried under high vacuum to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-bromo-2-phenylbenzoxazole-4-carboxamide (40 mg, 34%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.89 (d, J=7.3 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.25-8.20 (m, 2H), 7.86 (d, J=1.8 Hz, 1H), 7.65-7.55 (m, 3H), 4.60-4.52 (m, 1H), 3.12 (d, J=10.8 Hz, 2H), 2.70-2.60 (m, 2H), 2.54 (s, 3H), 2.20-1.95 (m, 2H), 1.62-1.52 (m, 2H), 1.50-1.45 (m, 2H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 454 (M+H); HPLC>99% (AUC), tR=13.52 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:30][CH2:31][CH3:32])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C([Li])(C)(C)C.[C:38]1(=[O:42])[CH2:41][CH2:40][CH2:39]1.[Cl-].[NH4+]>O1CCCC1.CCCCC>[NH2:15][C:6]1[C:5]2=[N:4][N:3]([CH2:30][CH2:31][CH3:32])[C:2]([CH2:1][C:38]3([OH:42])[CH2:41][CH2:40][CH2:39]3)=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: O=C1CCC1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 31.9 %

Procedure:
A solution of di(tert-butyl) 1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (1.32 g, 3.00 mmol) in anhydrous tetrahydrofuran (THF) (30 mL) was cooled to −78° C. under an argon atmosphere. tert-Butyllithium (7.06 mL of a 1.7 M solution in pentane) was added over a period of eight minutes, and the resulting dark-colored solution was stirred at −78° C. for 40 minutes. Cyclobutanone (1.05 g, 15 mmol) was added over a period of two minutes, and the −78° C. bath was replaced with a 0° C. bath. The reaction mixture was stirred for 10 minutes, and then saturated aqueous ammonium chloride (30 mL) was added. The aqueous layer was separated and extracted three times with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.3 g) was purified by automated flash chromatography and then boiled in 2 M hydrochloric acid for 30 minutes. The solution was allowed to cool to room temperature overnight and then made basic with the addition of 2 M aqueous sodium carbonate. The resulting solution was extracted four times with chloroform, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.2 g) was purified twice by automated flash chromatography and recrystallized from acetonitrile to provide 297 mg of 1-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]cyclobutanol as a white solid, mp 191-193° C.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:32]1[N:37]=[CH:36][N:35]=[C:34]2[N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=3[CH3:48])[N:39]=[CH:40][C:33]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:30][C:32]1[C:33]2[CH:40]=[N:39][N:38]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=3[CH3:48])[C:34]=2[N:35]=[CH:36][N:37]=1)[C:26]([O:28][CH3:29])=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1c(Cl)cccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Sodium hydride (60% in mineral oil) (0.191 g, 4.77 mmol) was added in one portion to (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (Intermediate AB3) (1.6 g, 3.97 mmol) in THF (15 mL) cooled to 0° C. under nitrogen. Slow gas evolution. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(3-chloro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate AE5) (1.109 g, 3.97 mmol) in THF (10 mL) was added dropwise over 2 minutes. The resulting suspension was stirred at 0° C. for 10 minutes, allowed to warm to ambient temperature and stirred for 72 hours to give an orange solution. Cooled to ˜5° C., 1M citric acid (30 mL) added, the mixture stirred for 10 minutes, diluted with EtOAc (50 mL), the organic phase separated and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford the product (2.1 g, 82%). 1H NMR (400 MHz, DMSO) δ 0.95 (9H, s), 2.03 (3H, s), 3.68 (3H, s), 3.67-3.74 (2H, m), 3.78-3.82 (2H, m), 4.04-4.07 (1H, m), 5.87-5.91 (1H, m), 7.37-7.45 (8H, m), 7.61-7.65 (4H, m), 7.67-7.69 (1H, m), 8.48 (1H, s), 8.57 (1H, s); m/z (ESI+) (M+H)+=645; HPLC tR=3.65 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[N:6][CH:7]=1.[OH:14][C:15]([CH3:48])([CH3:47])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH3:25])[CH2:19][CH2:18]1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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>[OH:14][C:15]([CH3:47])([CH3:48])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:3]=[N:4][C:5]([N:8]4[CH2:12][CH2:11][NH:10][C:9]4=[O:13])=[N:6][CH:7]=3)=[CH:30][CH:31]=2)[CH3:25])[CH2:19][CH2:18]1
Reactant: O=C1NCCN1c1ncc(Br)cn1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
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: O
Solvent: CCO
Product: C[C@@H](c1ccc(-c2cnc(N3CCNC3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Pd(PPh3)4 (1 mg) was added to a mixture of 1-(5-bromopyrimidin-2-yl)imidazolidin-2-one (13 mg), (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one (38.6 mg) and Na2CO3 (17 mg) in toluene (3 mL), ethanol (2 mL), and H2O (1 mL) at room temperature. The reaction mixture was heated to 100° C. under nitrogen and stirred at this temperature for 2 h. After cooling to room temperature, the mixture was concentrated to give an oil, which was purified by preparative HPLC to afford the title compound. Yield: 3.1 mg (11% of theory); LC (method 4): tR=0.93 min; Mass spectrum (ESI+): m/z=516 [M+H]+; 1H NMR (CD3OD) δ 0.92 (s, 3H), 1.32 (s, 3H), 1.58 (d, 3H), 2.06 (s, 2H), 2.19 (m, 2H), 2.50 (m, 2H), 3.58 (m, 2H), 4.20 (m, 2H), 5.62 (m, 1H), 7.11 (d, 2H), 7.33 (m, 5H), 7.42 (d, 2H), 8.78 (m, 2H).
Reaction SMILES: CC(N(C)C)=O.Cl[C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[H-].[Na+].[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>O>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:19]([F:24])[CH:18]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1cc(Br)ccc1Nc1ncccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
Dimethylacetamide (10 ml) was added slowly to a mixture of 2-chloropyrimidine (1 g, 8.7 mmol), sodium hydride (0.8 g, 34.9 mmol), and 4-bromo-2-fluoro-aniline (1.6 g, 8.7 mmol) and the resulting mixture was stirred overnight at room temperature. Water was added slowly and the resulting mixture extracted three times with ethyl acetate. The organic phase bas washed with brine, dried over sodium sulfate and concentrated to dryness. Flash chromatography on silica gel chromatography using a gradient of ethyl acetate and hexane afforded (4-bromo-2-fluoro-phenyl)-pyrimidin-2-yl-amine (1.3 g, 56% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.85 (m, 1H), 7.37 (d, 1H), 7.55 (d, 1H), 7.74 (m, 1H), 8.44 (s, 2H), 9.21 (s, 1H). MS: m/z 269.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>O>[Br:12][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CC(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 50 g (0.33 mol) of 4-methylphenyl acetic acid, 62 g (0.35mol) of N-bromosuccinimide, 200 ml of carbon tetrachloride and 0.1 g of 2,2-azobis(isobutyronitrile) are placed in a 500 ml flask and heated to reflux with stirring for 4 hours. After the reaction mixture is cooled to room temperature, it is poured into 500 ml of water. The obtained precipitate is filtered off, and then washed with water. After drying under an atmosphere of reduced pressure, 55 g of a white powder are obtained (72%).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][O:16][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=1)([O-:7])=[O:6].O1CCOCC1.O>CO>[CH3:2][O:3][N:4]=[C:14]([C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=1)[CH2:15][OH:16]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CON
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CON=C(CO)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
69 mg of O-methylhydroxylamine hydrochloride were added to a solution of 0.12 g (0.41 mmol) of 4'-nitro-2-t-butyldimethylsilyloxyacetophenone (obtained above) in a mixture of methanol (1.2 ml), 1,4-dioxane (2.0 ml) and water (2.0 ml). The resulting mixture was stirred for 1.5 hours at 80° C., then poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography, eluted with a stepwise gradient of ethyl acetate (10-40%) in hexane, to give 58 mg (67% yield) of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:13]1[C:14]2[C:21]3([CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([N+:30]([O-])=O)[CH:27]=4)[CH2:22]3)[C:20](=[O:33])[NH:19][C:15]=2[N:16]=[CH:17]N=1.[CH2:34](Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:33]=[C:20]1[NH:19][C:15]2=[N:16][CH:17]=[CH:34][CH:13]=[C:14]2[C:21]21[CH2:29][C:28]1[C:23](=[CH:24][CH:25]=[C:26]([NH:30][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:27]=1)[CH2:22]2
Reactant: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Reactant: O=C(O)CCc1ccccc1
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCc1ccccc1)Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A mixture of 3-phenylpropionic acid (20 mg, 0.13 mmol), (+)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (30 mg, 0.12 mmol, described in Intermediate 5), EDC (25 mg, 0.13 mmol), HOBT (20 mg, 0.13 mmol), and N,N-diisopropylethylamine (0.023 mmol) was stirred in DMF (0.5 mL) at ambient temperature for 3 h. The crude mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=384 (M+1). HRMS: m/z=384.1725; calculated m/z=384.1707 for C24H22N3O2.
Reaction SMILES: [C:1](=[O:33])([O:7][C:8]1[C:13](I)=[C:12]([CH3:15])[N:11]=[C:10]([CH3:16])[C:9]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Cl-].[Li+].[CH2:36]([Sn](CCCC)(CCCC)C=C)[CH2:37]CC>O1CCOCC1.C(Cl)(Cl)Cl.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:1](=[O:33])([O:7][C:8]1[C:13]([CH:36]=[CH2:37])=[C:12]([CH3:15])[N:11]=[C:10]([CH3:16])[C:9]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCCCCCCCCCCCCCc1c(C)nc(C)c(I)c1OC(=O)OC(C)(C)C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: C=Cc1c(C)nc(C)c(CCCCCCCCCCCCCCCC)c1OC(=O)OC(C)(C)C
Yield: 4.6 %

Procedure:
To a solution of 8 (85 mg, 0.864 mmol) in 1,4-dioxane (4 ml) were added lithium chloride (73.2 mg, 1.73 mmol), tetrakis(triphenylphosphine)palladium (99.8 mg, 10 mol %) and tributyl(vinyl)tin (0.327 ml, 1.12 mmol). The mixture was heated at reflux for 3 h then cooled and diluted with CHCl3. The mixture was washed with brine, dried over Na2SO4, filtered, and concentrated in under diminished pressure. The residue was purified by column chromatography on silica gel [AcOEt/MeOH (20:1)] to afford tert-butyl 3-hexadecyl-2,6-dimethyl-5-vinylpyridin-4-yl carbonate (10) (19 mg, 27%). 1H NMR (CDCl3) δ 0.02-0.03 (m, 3H), 1.20-1.27 (m, 28H), 1.46 (s, 9H), 2.45 (s, 3H), 2.48 (s, 3H), 2.54-2.56 (m, 2H), 5.55 (dd, 2H, J=17.6 Hz, 11.6 Hz) and 6.50 (dd, 1H, J=11.2 Hz, 11.2 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[H-].[Na+].I[CH2:15][C:16]([NH2:18])=[O:17]>CN(C=O)C>[CH:4]([C:3]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=1[O:1][CH2:15][C:16]([NH2:18])=[O:17])=[O:5]
Reactant: NC(=O)CI
Reactant: COc1cccc(O)c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OCC(N)=O)c1C=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
1.1 1.0 g (6.57 mmol) of 2-hydroxy-6-methoxybenzaldehyde 1 is dissolved in 30 ml of DMF, 0.29 g of NaH (60% suspension in paraffin oil) is carefully added with cooling, and the mixture is stirred at RT for 45 min. 1.34 g of 2-iodoacetamide 2 are then added, and the reaction mixture is stirred overnight. The mixture is subsequently subjected to conventional work-up, giving 0.81 g (59%) of 2-(2-formyl-3-methoxyphenoxy)acetamide 3 as solid. MS-EI (M+)=209.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:11])[CH:10]=1.[H-].[Na+].Br[CH2:16][CH2:17]Br.O>CN(C)C=O.O1CCCC1>[Br:11][C:9]1[CH:10]=[C:5]([C:4]2([C:3]([O:2][CH3:1])=[O:12])[CH2:17][CH2:16]2)[CH:6]=[N:7][CH:8]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(c2cncc(Br)c2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of the title compound from Example 71 Step A (0.50 g, 2.17 mmol) in N,N-dimethylformamide (6.8 mL) and tetrahydrofuran (6.8 mL) was added sodium hydride (60% dispersion in mineral oil, 0.435 g, 10.9 mmol). After stirring for 15 minutes, 1,2-dibromoethane (0.56 ml, 6.5 mmol) was added. After stirring overnight, the reaction was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (20-80% ethyl acetate in hexanes) provided the title compound: LCMS m/z 257.78 [M+2+H]+; 1H NMR (500 MHz, CD3OD) δ 8.53 (s, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 3.63 (s, 3H), 1.64 (m, 2H), 1.29 (m, 2H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]2[C:14](SC)=[N:15][C:16]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:12]2=[N:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](OCC)(=[O:27])C=C.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([S:8][C:9]1[N:13]=[C:12]2[N:11]([C:14]([O:27][CH3:24])=[N:15][C:16]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=32)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1nc2ncccc2c2nnc(SCc3ccccc3)n12
Reactant: C=CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc2ncccc2c2nc(SCc3ccccc3)nn12
Yield: 86.8 %

Procedure:
A mixture of 17.7 g (52 mmol) of 3-benzylthio-5-methylthiopyrido[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine in 200 mL of methanol was prepared and to this was added at ambient temperature with stirring 8.5 mL (7.8 g, 78 mmol) of ethyl acrylate and 2.4 mL of 25 percent sodium methoxide in methanol (10 mmol). Everything dissolved fairly quickly and after 15 min new precipitate formed. After about 1 hour the mixture was acidified with acetic acid and the volatile components were removed by evaporation under reduced pressure. The residue was dissolved in dichloromethane and the resulting solution was washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was diluted with ether, recovered by filtration, and dried to obtain 14.6 g of the title compound as a brown powder melting at 282°-284° C. with decomposition.