Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C@H:14]([CH2:27]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[S-2:39].[Na+].[Na+].CCOC(C)=O>CS(C)=O>[C@H:12]12[CH2:13][C@H:14]([N:15]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:16]1)[CH2:27][S:39]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OCc2ccccc2)cc1
Reactant: [S-2]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1C[C@@H]2C[C@H]1CS2
Temperature: 110 °C
Reaction time: 17 h
Yield: 60.6 %

Procedure:
(2S,4R)-benzyl 4-(tosyloxy)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (10 g, 17.87 mmol) and sodium sulfide (1.125 mL, 26.8 mmol) were combined in DMSO (80 mL) in a 150 mL medium pressure flask. The reaction mixture was purged with N2 (g) and the resulting slurry was heated to 110° C. under a N2 (g) atmosphere. The reaction became deep blue immediately. After 17 h, the resulting black reaction mixture was cooled to rt, diluted with 1:1 EtOAc:Et2O (150 mL) and washed with H2O (100 mL). The aqueous layer was extracted with 1:1 EtOAc:Et2O (100 mL). The combined organic layer was washed with 1N HCl (100 mL), brine, dried over MgSO4, filtered and concentrated to give dark red viscous oil. The crude material was loaded onto a silica gel column (60 g) and eluted with 3:1 hex:EtOAc to give (1S,4S)-benzyl 2-thia-5-azabicyclo[2.2.1]heptane-5-carboxylate (2.7 g, 61% yield) as red viscous oil. LC/MS: m/e 250.0 (M+H)+, 2.22 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.39-7.31 (m, 5H), 5.18-5.06 (m, 2H), 4.79-4.65 (m, 1H), 3.64 (d, J=7.8 Hz, 2H), 3.59 (br. s., 1H), 3.22-3.04 (m, 1H), 3.04-2.96 (m, 1H), 2.16 (t, J=10.0 Hz, 1H), 1.88 (d, J=10.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+]>CS(C)=O.C(OCC)(=O)C.[Cu](I)I>[CH3:11][S:12]([C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1)(=[O:14])=[O:13]
Reactant: CS(=O)[O-]
Reactant: CCC(=O)c1cnc(Br)s1
Agent: I[Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC(=O)c1cnc(S(C)(=O)=O)s1
Temperature: 120 °C
Yield: 56.3 %

Procedure:
To a solution of 1-(2-bromo-thiazol-5-yl)-propan-1-one (75 mg, 0.34 mmol) in dimethyl sulfoxide (3 mL) was added the sodium methylsulfinate (41 mg, 0.34 mmol) followed by copper iodide (65 mg, 0.34 mmol). The mixture was heated in a microwave at 120° C. for 1 h. The reaction was diluted with ethyl acetate (20 mL) and washed with sat. sodium bicarbonate solution (120 ml) and brine (10 ml). The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give 1-(2-methanesulfonyl-thiazol-5-yl)-propan-1-one (42 mg, 56%) that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:21][CH2:22][CH2:23][CH3:24])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH3:26][O:27][NH2:28]>>[CH3:26][O:27][N:28]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:21][CH2:22][CH2:23][CH3:24])[CH3:19]
Reactant: CON
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=O
Agent: Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCC(C)=NOC

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with O-methylhydroxylamine hydrochloride to provide 5-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-methyloxime in about a 7.9 to 1 mixture of E and Z isomers as light brown crystals after recrystallization from aqueous methanol, mp 157-159° C.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[CH:23]=[C:10]3[CH:11]=[C:12]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=[O:19])[CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:3][CH:2]=1.[C:25]([Mg]Br)#[CH:26]>O1CCCC1>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([C:7]2[CH:23]=[C:10]3[CH:11]=[C:12]([C:15]4[CH:16]=[C:17]([CH:18]([OH:19])[C:25]#[CH:26])[CH:20]=[CH:21][CH:22]=4)[CH:13]=[CH:14][N:9]3[N:8]=2)=[CH:5][CH:6]=1
Reactant: C#C[Mg]Br
Reactant: Cc1ccc(-c2cc3cc(-c4cccc(C=O)c4)ccn3n2)cc1
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(-c2ccn3nc(-c4ccc(C)cc4)cc3c2)c1
Yield: 53.9 %

Procedure:
The procedure described in stage 2.5 is followed, starting with 0.105 g (0.34 mmol) of 3-(2-{p-tolyl}pyrazolo[1,5-a]pyridin-5-yl)benzaldehyde obtained in stage 8.4, in solution in 15 ml of tetrahydrofuran, followed by addition of 3.20 ml (1.60 mmol) of an ethynylmagnesium bromide solution (0.5M in tetrahydrofuran) and after chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.062 g (54%) of the expected product is obtained in the form of a yellow powder.
Reaction SMILES: F[C:2](F)(F)[C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[CH:6][NH:5][CH:4]=1.[NH3:18]>O1CCOCC1>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:3]([C:2]#[N:18])=[CH:4][NH:5][CH:6]=1
Reactant: FC(F)(F)c1c[nH]cc1-c1cccc(Cl)c1Cl
Reactant: N
Solvent: C1COCCO1
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
4.0 g of 3-trifluoromethyl-4-(2,3-dichlorophenyl)-pyrrole, 21 ml of 25% aqueous ammonia and 40 ml of dioxane are stirred for 26 hours at 180° C. in an autoclave. After cooling to room temperature, the reaction mixture is filtered, and the clear filtrate is concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water and subsequently with diluted sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue is caused to crystallise by the addition of hexane; it is then filtered off and dried to thus obtain 3.4 g (100% of theory) of 4-(2,3-dichlorophenyl)-3-cyanopyrrole having a melting point of 150° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:16]=[CH:15][C:14](I)=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[F:20][C:21]([F:26])([F:25])C([O-])=O.[Na+].O.ClCCl>CN1CCCC1.[Cu]I>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:16]=[CH:15][C:14]([C:21]([F:26])([F:25])[F:20])=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(I)cnc1Oc1ccc(F)cc1
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: CN1CCCC1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C(F)(F)F)cnc1Oc1ccc(F)cc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 10.2 %

Procedure:
A mixture of methyl 2-(4-fluorophenoxy)-5-iodonicotinate (step 1, 373 mg, 1.0 mmol), sodium trifluoroacetate (1.36 g, 10 mmol), and copper(I) iodide (960 mg, 5.0 mmol) in 1-methyl-pyrolidine (8.0 mL) was stirred at 160° C. for 16 h under nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extacted with dichloromethane (50 mL×3). The combined organic extracts were washed with brine (50 mL) and dried (sodium sulfate). After removal of the solvent, the residue was purified by TLC plate developing with hexane/ethyl acetate (1/1) to afford 32 mg (10%) of the title compound: 1H-NMR (CDCl3) δ 8.5 (2H, s), 7.13 (1H, d, J=6.3 Hz), 3.99 (3H, s); MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [C:1]([C@H:4]([N:6]1[C:11](=[O:12])[C@@H:10]([NH2:13])[C@@H:9]([OH:14])[CH2:8][O:7]1)[CH3:5])([OH:3])=[O:2].C([O-])(O)=O.[Na+].[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC#N>O>[C:1]([C@H:4]([N:6]1[C:11](=[O:12])[C@@H:10]([NH:13][C:27](=[O:28])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:9]([OH:14])[CH2:8][O:7]1)[CH3:5])([OH:3])=[O:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](N)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C[C@H](C(=O)O)N1OC[C@H](O)[C@H](NC(=O)Cc2ccccc2)C1=O
Temperature: 5 °C
Yield: 91.1 %

Procedure:
To a solution of the amino acid 13 (0.290 g, 1.36 mmol) and NaHCO3 (0.343 g, 4.08 mmol) in water (7 mL), a solution of phenylacetyl chloride (0.191 g, 1.24 mmol) in abs. MeCN (3 mL) was added dropwise with cooling (−5˜−6° C.) and stirring. The reaction mixture was stirred for 2 h at 0˜−2° C. and for 1 hour at room temperature and was concentrated in vacuo to a volume of circa 5 mL. The solution was cooled to ca. 5° C. and adjusted to pH 2-3 with 1M aqueous HCl. (2.8 mL). The white precipitate was filtered off, washed with water and dried in vacuo to afford 0.364 g (91%) of the product 14 as a white solid with mp 194-195° C. (decomp.) (from iso-PrOH). 1H NMR (400 MHz) in CD3OD (J, Hz): δ 1.47 (3H, d, 3J=7.3, α-MeCH), 3.62 (1H, d, 2J=−14.8, CHAPh), 3.67 (1H, d, 2J=−14.8, CHBPh), 4.06 (1H, dd, 2J=−11.4, 3J=3.7, 6-HA), 4.12-4.06 (1H, m, 5-H), 4.33 (1H, dd, 2J=−11.4, 3J=5.6, 6-HB), 4.66 (1H, d, 3J=8.0, 4-H), 4.96 (1H, q, 3J=7.3, α-CH), 7.38-7.17 (5H, m, Ph). 13C (100 MHz) in CD3OD: δ 1371, 43.63, 55.70, 57.54, 71.84, 79.10, 127.85, 129.51, 130.37, 136.63, 169.61, 172.71, 174.89. IR (KBr), cm−1: 3361, 2913, 1729, 1666, 1630, 1542, 1440, 1233. MS (CI, isobutane), m/Z: 323 (M++1). Anal. Calcd for C15H18N2O6: C, 55.9; H, 5.6; N, 8.7. Found: C, 55.7; H, 5.7; N, 8.6%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17]3)=[C:12]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[O:9])=[CH:4][CH:3]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][N:39]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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>[CH3:24][C:23]([CH3:25])([CH3:26])[C:22]([C:12]1[C:11]([CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([O:32][CH3:33])=[O:31])=[C:10]([C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[C:3]([C:41]3[CH:40]=[N:39][C:38]([O:37][CH3:36])=[CH:43][CH:42]=3)[CH:4]=2)=[O:9])[N:18]2[C:13]=1[CH:14]=[C:15]([CH:19]([CH3:20])[CH3:21])[CH:16]=[CH:17]2)=[O:27]
Reactant: COc1ccc(B(O)O)cn1
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1ccc(Br)cc1
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: C1CCOC1
Product: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(C(C)C)ccn2c1C(=O)c1cccc(-c2ccc(OC)nc2)c1
Temperature: 23 °C
Yield: 88.4 %

Procedure:
A solution of methyl 3-{3-[(4-bromophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(propan-2-yl)indolizin-2-yl}-2,2-dimethylpropanoate (100 mg, 0.185 mmol), 2-(methoxy)pyridine-5-boronic acid (42.5 mg, 0.278 mmol), tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 0.019 mmol) in THF (2.0 mL) and aqueous 20% Na2CO3 (1.0 mL) is heated at 70° C. for 1 h. The mixture is cooled to 23° C. and partitioned between Et2O and water. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 30% EtOAc in hexanes) gives methyl 3-[1-(2,2-dimethylpropanoyl)-3-{[3-(6-methoxypyridin-3-yl)phenyl]carbonyl}-7-(propan-2-yl)indolizin-2-yl]-2,2-dimethylpropanoate (93 mg, 88%) which is dissolved in MeOH (1.5 mL), and 6M aqueous NaOH (1.5 mL) and heated at 70° C. for 1 h. The mixture is then cooled to 23° C., acidified to pH=1 with concentrated aqueous HCl, and partitioned between CH2Cl2 and brine. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo to give the title compound (68 mg, 75%).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:14](=[O:22])[O:15][C:16]3([CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]=2[C:11]2[C@@H:10]([OH:23])[CH2:9][C:8]([CH3:25])([CH3:24])[CH2:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[C:34]([Si:38](OS(C(F)(F)F)(=O)=O)([CH3:40])[CH3:39])([CH3:37])([CH3:36])[CH3:35]>O1CCCC1>[Si:38]([O:23][C@H:10]1[CH2:9][C:8]([CH3:25])([CH3:24])[CH2:7][C:6]2[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]3[C:14](=[O:22])[O:15][C:16]4([CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:12]=3[C:11]1=2)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:40])[CH3:39]
Reactant: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)[C@@H](O)CC(C)(C)C2
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.2 g (S)-4-Isopropyl-9-hydroxy-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one are dissolved in 15 ml tetrahydrofurane and 1.31 ml 2,6-lutidine and 2.44 ml trifluoromethanesulfonic acid-tert.-butyldimethylsilylester are added dropwise and the mixture is stirred for 4 hours at room temperature. Then the reaction is absorbed onto silica gel and chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 50:50).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1F.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[C:43]([O:45][CH2:46][CH3:47])=[O:44].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl>[CH2:46]([O:45][C:43]([C@@H:35]1[CH2:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:34]1[C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:44])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (5.26 g, 20.9 mmol, Eq: 2) and pyridine (2.8 mL, 34.5 mmol, Eq: 3.3) in DCM (60 mL), cyanuric fluoride (4.66 g, 2.99 mL, 34.5 mmol, Eq: 3.3) was added. The reaction mixture was stirred at 23° C. for 2 h. The resulting precipitate was filtered off and the mother liquor was concentrated in vacuo. The residue was taken up in EtOAc, and washed with saturated aqueous NaHCO3, 0.5 M aqueous citric acid and brine, and concentrated in vacuo. The light brown oil was taken up in DCM (20 mL) and cooled in an ice bath. To this acid fluoride solution was added a solution of (S)-ethyl indoline-2-carboxylate (2 g, 10.5 mmol, Eq: 1) and 2,6-di-tert-butylpyridine (4.00 g, 4.62 mL, 20.9 mmol, Eq: 2) in DCM (20 mL). The resulting mixture was stirred at rt overnight. The reaction was concentrated in vacuo and the crude material was purified by flash chromatography (silica gel, 5% to 20% EtOAc in hexanes) to give (S)-1-((S)-2-tert-butoxycarbonylamino-2-phenyl-acetyl)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.78 g) as a light yellow foam, m/z=425 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH:7]([OH:9])[CH2:6][CH2:5][CH:4]([C:10]2[N:11]([CH3:18])[N:12]=[CH:13][C:14]=2[N+:15]([O-])=O)[O:3]1.[NH2:19][C:20]1[S:24][C:23]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:22][C:21]=1[C:33](O)=[O:34].CCN(C(C)C)C(C)C.CCCP(=O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:19][C:20]1[S:24][C:23]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:22][C:21]=1[C:33]([NH:15][C:14]1[CH:13]=[N:12][N:11]([CH3:18])[C:10]=1[C@H:4]1[CH2:5][CH2:6][CH:7]([OH:9])[CH2:8][C@@H:2]([CH3:1])[O:3]1)=[O:34]
Reactant: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC1CC(O)CCC(c2c([N+](=O)[O-])cnn2C)O1
Agent: [Pd+2]
Agent: CCCP(=O)=O
Agent: [OH-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CC(O)CC[C@H](c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 2.9 %

Procedure:
A solution of 2-methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol (79 mg, 0.30 mmol) in MeOH (20 mL) was passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 20% Pd(OH)2/C cartridge). The solvent was removed under reduced pressure and the crude residue was re-dissolved in MeOH (1 mL). 5-Amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (94 mg, 0.37 mmol) and DIPEA (0.24 mL, 1.40 mmol) were added. Propylphosphonic anhydride solution (0.19 mL, 50% wt in EtOAc, 0.39 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL). The organic layer was washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL) and brine (10 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) gave 108 as a white solid (4 mg, 3% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J=11.8 Hz, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.37-7.30 (m, 1H), 7.04-6.97 (m, 2H), 6.15 (s, 2H), 5.00-4.93 (m, 1H), 4.17 (s, 1H), 4.03 (dd, J=8.0, 6.9 Hz, 1H), 3.77 (s, 3H), 2.11-1.74 (m, 5H), 1.28 (d, J=3.3 Hz, 1H), 1.21 (dd, J=9.2, 6.3 Hz, 3H). Alkyl OH not observed. LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]3[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=3[C:12]3[CH2:13][N:14]([C@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]4[OH:25])[C:15](=[O:18])[C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.[CH3:30][Zn]C.ClCCl>O1CCCC1.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]>[OH:25][C@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]1[N:14]1[CH2:13][C:12]2[C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([CH3:30])=[CH:3][CH:4]=3)=[CH:17][C:16]=2[C:15]1=[O:18]
Reactant: O=C1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Temperature: 50 °C

Procedure:
To a solution of 5-[(6-chloropyridin-3-yl)methyl]-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.040 g, 0.098 mmol) in 3 mL of tetrahydrofuran under an atmosphere of nitrogen was added dimethylzinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (7.2 mg, 0.0098 mmol). The mixture was heated at 50° C. for 3 hr and then cooled to ambient temperature. Additional dimethyl zinc (1.2 M in tetrahydrofuran, 0.16 mL, 0.20 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1 complex with dichloromethane (7.2 mg, 0.0098 mmol) were added and the mixture was heated at 50° C. for an additional 12 hr. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 387.4 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.92-7.84 (m, 3H), 7.69 (s, 1H), 7.65-7.61 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 4.87-4.73 (m, 2H), 4.53 (s, 2H), 4.23-4.16 (m, 1H), 3.81-3.75 (m, 1H), 2.77 (s, 3H), 2.23-2.20 (m, 1H), 2.02-1.99 (m, 1H), 1.87-1.84 (m, 2H), 1.84-1.64 (m, 1H), 1.55-1.33 (m, 3H) ppm.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][C:8]2(C)C)[CH2:3]1.[OH:12][CH2:13]CC1NC(=O)C1.C(OC)(OC)OC>>[O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][CH:8]2[O:12][CH3:13])[CH2:3]1
Reactant: CC1(C)OCCC2CC(=O)N21
Reactant: O=C1CC(CCO)N1
Solvent: COC(OC)OC
Product: COC1OCCC2CC(=O)N21

Procedure:
Following the procedure described for the preparation of 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane from 4-(2'-hydroxyethyl)-2-azetidinone and using trimethyl orthoformate instead of 2,2-dimethoxypropane one obtains 8-oxo-2-methoxy-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([OH:40])[CH2:38][CH2:39]3)(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(O)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(O)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)piperidin-4-ol. MS (ESI): mass calcd. for C21H21FN4O3S, 428.13; m/z found, 429.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36-8.31 (m, 2H), 8.10-8.06 (m, 1H), 7.99 (m, 1H), 7.73-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.40 (m, 1H), 7.34-7.28 (m, 2H), 3.66-3.55 (m, 1H), 3.20-3.08 (m, 2H), 2.71-2.61 (m, 2H), 1.72-1.63 (m, 2H), 1.39-1.26 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH3:19])[C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:20].[CH2:21]([NH:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24]>CS(C)=O>[CH2:21]([N:25]([CH2:26][CH3:27])[C:2]1[C:3]([CH3:20])=[C:4]([N:9]([CH3:19])[C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCNCC
Reactant: Cc1cc(C)c(N(C)c2nc(C)nc(Cl)c2C)c(C)c1
Solvent: CS(C)=O
Product: CCCCN(CC)c1nc(C)nc(N(C)c2c(C)cc(C)cc2C)c1C
Temperature: 160 °C

Procedure:
A mixture of (6-chloro-2,5-dimethyl-pyrimidin-4-yl)-methyl-(2,4,6-trimethylphenyl)-amine (200 mg) and N-butyl-ethylamine (0.3 ml) in 1 ml of DMSO was heated in oil bath of 160° C. for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give the crude material. After silica gel column purification using chloroform as eluent, the title compound was obtained as an oil. 1H NMR (CDCl3) δ 6.83 (s, 2H), 3.22 (s, 3H), 3.12 (m, 4H), 2.44 (s, 3H), 2.26 (s, 3H), 2.01 (s, 6H), 1.35-1.42 (m, 2H), 1.1-1.25 (m, 2H), 1.00 (t, 3H), 0.90 (t, 3H) ppm.