Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([O:15]C(=O)C)[N:8](C(=O)C)[C:9]=1[CH2:10]Br)=[O:4].[SH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:15])[NH:8][C:9]=1[CH2:10][S:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:4]
Reactant: COC(=O)c1nc(OC(C)=O)n(C(C)=O)c1CBr
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1[nH]c(=O)[nH]c1CSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.5 %

Procedure:
To a solution of 4c (640 mg, 2 mmol) in 20 mL of MeOH was added 4-mercaptophenol (380 mg, 3.0 mmol) and K2CO3 (550 mg, 4.0 mmol). The solution was stirred at rt for 6 h. 20 mL of water was then added and 2 mL of 1N HCl was carefully added. This aqueous solution was extracted with Et2O. The aqueous solution was then concentrated and the residue was first dissolved in 5 mL of MeOH and the diluted with 50 mL of CH2Cl2. Filtration and concentration provided 5-(4-hydroxy-phenylsulfanyl methyl)-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid methyl ester 4d (440 mg, 80%). MS (ESI+) (M+AcN+1)=322.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12]>C(O)C>[O:12]=[C:11]1[N:13]2[CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:15]=[C:14]2[CH:16]=[CH:17][NH:10]1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2c(=O)[nH]ccc2n1
Yield: 14.1 %

Procedure:
Ethyl bromopyruvate (18.00 mmol, 3.51 g) was dissolved in ethanol (50 ml). Cytosine (18.00 mmol, 2 g) was added and the resulting mixture was refluxed for 5.5 h. The mixture was evaporated and DCM was added. The precipitate was filtered and washed with water. The filtrate was washed with NaHCO3, water and evaporated. The evaporation residue and the previously filtered precipitate were purified by flash chromatography and trituration from water, respectively. 0.526 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.31 (t, 3H), 4.29 (q, 2H), 6.60 (d, 1H), 7.30-7.38 (m, 1H), 8.22 (s, 1H), 11.77 (bs, 1H).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:15]=[C:16]=[S:17])[CH:13]=[CH2:14].C>>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:15]([CH:12]=[CH:13][CH3:14])[C:16]2=[S:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CCN=C=S
Reactant: O=C(O)CNc1ccccc1
Product: CC=CN1C(=O)CN(c2ccccc2)C1=S
Reaction time: 8 h
Yield: 31.3 %

Procedure:
A mixture of N-phenyl glycine (15.1 grams, 0.1 moles) and allylisothiocyanate (12.0 grams, 0.12 moles) was refluxed for 6 hours and allowed to stand overnight at room temperature (21° C.). The reaction mixture became a solid mass which was ground and crystallized from ethanol using charcoal, 7.26 grams (31% yield) of the above-identified product was recovered having a melting point of about 74° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:2]/[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Product: CC(=O)Nc1cccc(C(=O)/C=C/N(C)C)c1
Yield: 90 %

Procedure:
A solution of N-(3-acetylphenyl)acetamide (1.77 g, 10.0 mmol) in DMF-DMA (6 mL) with molecular sieve (10 portions) was stirred at 100° C. under N2 for 2 hr. the mixture was concentrated and washed with MTBE (30 mL) to afford 2.1 g (90%) of (E)-N-(3-(3-(dimethylamino)acryloyl)phenyl)acetamide as a yellow solid.
Reaction SMILES: Br[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[N:4][CH2:3]1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:24]1[C:31]2[CH2:30][CH2:29][CH2:28][N+:27]=2[CH2:26][CH2:25]1.Cl>CCOCC.CCCCC>[C:8]1([C:2]2[CH:7]=[C:6]([C:31]34[CH2:30][CH2:29][CH2:28][N:27]3[CH2:26][CH2:25][CH2:24]4)[CH:5]=[N:4][CH:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrC1(c2ccccc2)C=CC=NC1
Reactant: C1CC2=[N+](C1)CCC2
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Solvent: CCOCC
Product: c1ccc(-c2cncc(C34CCCN3CCC4)c2)cc1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
3-Bromo-3-phenylpyridine (200 mg, 0.85 mmol) was dissolved in Et2O and cooled to -30° C. A solution of 2.5M t-BuLi (1.1 mL, 1.90 mmol) in pentane was added, and the reaction was stirred for 10 minutes. 1,2,3,5,6,7-Hexahydropyrrolizinium perchlorate (230 mg, 1.30 mmol) was added, and the reaction mixture was allowed to stir for 30 minutes at -30° C. then allowed to warm to room temperature and stir for 1 hour. Then 2N HCl was added, the phases were separated, and the aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The organic phases were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 95:5) to afford a clear oil (32.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1F.[C:12]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[H-].[Na+].C(O)(=O)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[CH:13]([C:12]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Fc1nc(F)c(Cl)c(F)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1c(Cl)c(F)nc(F)c1Cl
Reaction time: 17 h
Yield: 107.5 %

Procedure:
3,5-dichloro-2,4,6-trifluoropyridine (25 g, 15.4 mL, 123.7 mmol) and dibenzyl malonate (35.8 g, 31.5 mL, 126 mmol, Aldrich) were dissolved in anhydrous DMF (240 mL) under nitrogen atmosphere. The mixture was then cooled in an ice bath. To a stirred mixture, was added 60% sodium hydride (10 g, 250 mmol) portionwise (2 g) for 2 hr. The mixture was then stirred in a water bath for ca. 17 hr. Glacial acetic acid was added and the mixture was partitioned between ether and water. Ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and dried in vacuo to give 62 g of dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate as a yellow oil. dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate (62 g) was then dissolved in dimethyl sulfoxide (DMSO) (120 mL) and stirred with water (10 mL) in an oil bath (130-140° C.) for 3 hr. After cooling to room temperature, water was added to the mixture and the product was extracted with ether (Sometimes addition of EA is necessary to dissolve product completely). The ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light yellow solid. The crude product was recrystallized from MC/Hexane three times to afford 30.9 g (75% for two steps) of benzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)acetate as a white solid. m.p. 98-101° C. 1H NMR (200 MHz, CDCl3) δ 4.11 (2H, s), 5.19 (2H, s), 7.30-7.38 (5H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](Cl)=[O:13].[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([O:32][CH3:33])[CH:26]=3)[C:17]=12>ClCCl.N1C=CC=CC=1>[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]3)[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:12](=[O:13])[C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[F:1])=[C:27]([O:32][CH3:33])[CH:26]=3)[C:17]=12
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
2-Fluoro-4-(trifluoromethyl)-1-benzenecarbonyl chloride (3.05 mL, 20.2 mmol) in dichloromethane (25 mL) was added to a solution of tert-butyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (8.77 g, 20.0 mmol) in pyridine (50 mL) at 0° C. After 5 minutes, the ice water bath was removed and the reaction mixture stirred at room temperature for 1 hours. 2-Fluoro-4-(trifluoromethyl)-1-benzenecarbonyl chloride (0.5 mL, 3.31 mmol) was added and the reaction mixture was stirred for addition 30 minutes. The solvent was evaporated and the residue was dissolved in dichloromethane. The organic layer was washed with water, brine then dried over MgSO4. The solvent was evaporated and the residue was purified by flash column chromatography using ethyl acetate/dichloromethane (80:20 to 100:0) as mobile phase to give tert-Butyl 4-[4-amino-3-(4-[2-fluoro-4-(trifluoromethyl)benzoyl]amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (11.2 g, 89%). 1H NMR (CDCl3-d) δ 1.48 (s, 9H), 2.04 (m, 2H), 2.30 (m, 2H), 2.98 (m, 2H), 4.05 (s, 3H), 4.32 (m, 2H), 4.95 (m, 1H), 5.89 (bs, 2H), 7.33 (m, 2H), 7.51 (d, J=11.62 Hz, 1H), 7.61 (d, J=8.21 Hz, 1H), 8.36 (m, 2H), 8.72 (d, J=8.18 Hz, 1H), 9.32 (d, J=14.39 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1(O)[C:12]2([CH3:13])[C:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH2:5][CH:4]1[CH3:16])#[CH:2].[OH-:18].[Na+]>CC1C=CC=CC=1C>[CH3:16][C:4]1[CH2:5][CH:6]=[C:7]2[C:12]([CH3:13])([CH2:11][CH2:10][CH2:9][C:8]2([CH3:15])[CH3:14])[C:3]=1[CH2:1][CH:2]=[O:18]
Reactant: C#CC1(O)C(C)CC=C2C(C)(C)CCCC21C
Reactant: [OH-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC1=C(CC=O)C2(C)CCCC(C)(C)C2=CC1
Temperature: 145 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
A solution of 1-ethynyl-2,5,5,8a-tetramethyl-1,2,3,5,6,7,8,8a-octahydro-1-naphthalenol (4.00 g; 17.2 mmol) in o-xylene (60 ml) was treated with [V2O6SiPh2]n (400 mg) [Tetrahedron Lett. 1976, 17, 2981] and heated at reflux (145° C.). After 17 hours, the rearrangement was complete. The reaction mixture was poured into 5% aquous NaOH. The product was extracted twice with Et2O and washed successively with H2O and twice with satured aqueous NaCl, dried (Na2SO4) and evaporated. Bulb-to-bulb distillation (125° C. (oven temp.)/0.04 mbar) afforded 97% pure (2,5,5,8a-tetramethyl-3,5,6,7,8,8a-hexahydro-1-naphthalenyl)acetaldehyde (3.42 g; yield=83%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:22][CH:23]([CH3:25])[CH3:24])(=[O:21])[C@@H:12]([CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[OH:13].Br[CH2:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([N:35]2[C:39]([CH3:40])=[CH:38][CH:37]=[C:36]2[CH3:41])[N:29]=1>C1COCC1>[CH3:40][C:39]1[N:35]([C:30]2[N:29]=[C:28]([CH2:27][C@@H:14]([C@@H:12]([OH:13])[C:11]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:33]=[C:32]([CH3:34])[CH:31]=2)[C:36]([CH3:41])=[CH:37][CH:38]=1
Reactant: Cc1cc(CBr)nc(-n2c(C)ccc2C)c1
Reactant: CC(C)OC(=O)C[C@@H](O)C(=O)OC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C[C@H](C(=O)OC(C)C)[C@@H](O)C(=O)OC(C)C)nc(-n2c(C)ccc2C)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
To a dry flask containing THF (20 mL) at −78° C. was added fresh LHMDS (1.0 M in THF, 10 mL, 10 mmol). After 10 min, a solution of diisopropyl (R)-(+)-malate (5b, 1008 μL, 4.88 mmol) was added dropwise as a solution in THF (5 mL) through a cannula. The reaction was stirred at the same temperature for 10 min then transferred to an ice-bath (0° C.) for 30 min. The reaction was cooled to −78° C. again and 6 (1017 mg, 3.66 mmol) was added slowly (1 drop/sec) as a solution in THF (5 mL) through a cannula. The color of the reaction mixture turned light purple. The reaction was maintained at −78° C. for an additional 30 min then transferred to an ice-bath and slowly warm to room temperature. After 2 h, the reaction was quenched with NH4Cl (1 mL) then partitioned between EtOAc (200 mL) and saturated NH4Cl (150 mL). The inorganic layer was extracted with EtOAc (150 mL). The combined organic layer was washed by H2O (100 mL), brine (100 mL), dried over Na2SO4, and concentrated. The crude yellow oil was purified by flash column chromatography (EtOAc/hexanes, 1:9-1:4) to give 4b (1.76 g, 2.56 mmol, 70%) as a pale yellow oil (without detection of any cis-isomer): 1H NMR (500 MHz, CDCl3) δ 1.14-1.15 (d, J=6.5 Hz, 3H), 1.17-1.18 (d, J=6.0 Hz, 3H), 1.25-1.26 (d, J=6.5 Hz, 3H), 1.29-1.30 (d, J=6.0 Hz, 3H), 2.13 (s, 6H), 2.41 (s, 3H), 3.10-3.15 (dd, J=8.5, 14.0 Hz, 1H), 3.34-3.40 (m, 2H), 3.72-3.76 (dt, J=2.5, 8.0 Hz, 1H), 4.07-4.09 (dd, J=2.5, 7.0 Hz, 1H), 4.96-5.01 (m, 1H), 5.09-5.15 (m, 1H), 5.90 (s, 2H), 6.89 (s, 1H), 7.10 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.5, 21.2, 21.8, 21.9, 22.0, 36.1, 48.0, 68.8, 70.1, 70.6, 107.0, 120.7, 124.1, 128.7, 150.1, 158.7, 171.5, 173.4; LCQ-MS (M+H+) calcd for C23H33N2O5 417. found 417; LC-TOF-MS (M+H+) calcd for C23H33N2O5 417.23895. found 417.23834.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=2)=[CH:5][CH:4]=1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:28]([NH:27][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[S:29])[CH:10]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CSc2cc(N)ncc2Br)cc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CSc2cc(NC(=S)NC(=O)c3ccccc3)ncc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
4-(4-methoxybenzylthio)-5-bromopyridin-2-amine (7.45 g, 22.9 mmol) was dissolved in THF (80 mL). Benzoyl isothiocyanate (3.4 ml, 25 mmol) was added, and the reaction was stirred overnight at ambient temperature. The solution was diluted in 9:1 hexanes:EtOAc and stirred for 5 minutes, then filtered and dried to provide the desired product (8.5 g, 76% yield) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[C:14]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][CH:10]2[C:14]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:13][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(Nc2ccnc(Cl)n2)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (600 mg, 4.03 mmol) and tert-butyl 4-amino-2-azaspiro[4.4]nonane-2-carboxylate (1.07 g, 4.43 mmol) in EtOH (20 mL) was added Et3N (815.6 mg, 8.06 mmol). After addition, the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 1/1) to give the product as a white solid (528 mg, 37.2%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][C:35]([NH2:41])=[CH:36][CH:37]=2)[CH2:32]1>CC(O)C.Cl>[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:35]4[CH:34]=[C:33]5[C:38]([CH2:39][CH2:40][N:31]([CH3:30])[CH2:32]5)=[CH:37][CH:36]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: CN1CCc2ccc(N)cc2C1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)C(F)(F)F)c5)nn5ccccc45)n3)cc2C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (310 mg, 0.74 mmol, which may be prepared according to Example 11, Step C) and 2-methyl-1,2,3,4-tetrahydro-7-isoquinolinamine (150 mg, 0.92 mmol) in 2-propanol (10 mL) was added 6 drops concentrated HCl. The reaction was stirred for 18 h at 80° C., then partitioned between saturated aqueous NaHCO3 and 20% (v/v) MeOH in EtOAc. The aqueous layer was extracted with 20% (v/v) MeOH in EtOAc, and the combined organic layers were dried over Na2SO4, filtered, and adsorbed onto silica. The crude product was purified by column chromatography to generate the title compound in 72% yield (290 mg, 0.53 mmol). 1H NMR (400 MHz, d6-DMSO) δ 11.39 (s, 1H), 9.45 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.44 (d, J=8.6 Hz, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.44-7.55 (m, 4H), 7.38 (d, J=8.2 Hz, 1H), 7.14 (t, J=6.9 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.50 (d, J=5.3 Hz, 1H), 3.39 (s, 2H), 2.75 (t, J=5.7 Hz, 2H), 2.59 (t, J=5.7 Hz, 2H), 2.32 (s, 3H). MS (ESI) m/z=544 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:29])=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[C:10]=1[OH:25])=[O:8])([OH:3])=[O:2].C([O-])(O)=O.[Na+].ClC1C=C(CC2C=CC=CC=2O)C(O)=C(C=1)CC1C(O)=C(C=CC=1)C(O[CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:63]([NH:64][C:65](=[O:74])[CH2:66][O:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[C:62](=[O:75])[N:53]2[C:54]=1[C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=O>>[Cl:15][C:13]1[CH:12]=[C:11]([C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[C:10]([OH:25])=[C:9]([CH:14]=1)[C:7]([C:6]1[C:5]([OH:29])=[C:4]([CH:28]=[CH:27][CH:26]=1)[C:1]([O:3][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:63]([NH:64][C:65](=[O:74])[CH2:66][O:67][C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:62](=[O:75])[N:53]2[C:54]=1[C:55]([O:57][C:58]([CH3:59])([CH3:60])[CH3:61])=[O:56])=[O:2])=[O:8]
Reactant: O=C(O)c1cccc(C(=O)c2cc(Cl)cc(C(=O)c3ccccc3O)c2O)c1O
Reactant: CC(C)(C)OC(=O)C1=C(COC(=O)c2cccc(Cc3cc(Cl)cc(Cc4ccccc4O)c3O)c2O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)C1=C(COC(=O)c2cccc(C(=O)c3cc(Cl)cc(C(=O)c4ccccc4O)c3O)c2O)CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N12
Yield: 90 %

Procedure:
Compound 18 (7.33 g, 8.99 mmol) was prepared from 16 (5.30 g, 9.99 mmol), 15 (4.13 g, 10.0 mmol), and NaHCO3 (2.52 g, 30.0 mmol) in 90% yield by the same method used for the preparation of 17. For 18: mp 138-140° C.; 1H NMR (DMSO-d6) d 1.50 (s, 9H, 3×CH3), 3.72, 3.83 (AB, Jgem =19 Hz, 2H, CH2S), 4.60 (s, 2H, OCH2CO), 4.99, 5.29 (AB, Jgem =15 Hz, 2H, CH2O), 5.18 (d, J=5.0 Hz, 1H, HC(6)), 5.79 (dd, J=5.0 and 9.5 Hz, 1H, HC(7)), 6.20 (br, 3H, 3×OH), 6.90-7.50 (m, 14H, 4×ArH), 8.30 (d, J=9.5 Hz, 1H, NH); IR (nujol): 3290-3370 (OH, NH), 1792 (β-lactam), 1750 (ester), 1730 (ester), 1688 (amide), 1620 (C=O) cm-1. Anal. (C41H35N2O12SCl) C, H, N, S, Cl.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][C:15]([OH:19])([CH3:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][C:15]([CH3:18])([OH:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC1(O)CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.9 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-(4-hydroxy-4-methylpiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.74 mmol) in DCM/TFA (3 mL/3 mL). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-yl-4-methylpiperidin-4-ol as a colourless oil (0.107 g, 85%). 1H NMR (CDCl3, 400 MHz) δ 3.61 (t, J=7.3 Hz, 2 H); 3.54 (t, J=7.3 Hz, 2 H); 3.29-3.15 (m, 1 H); 3.04 (s, 2 H); 2.40 (d, J=10.8 Hz, 2 H); 2.30-2.18 (m, 2 H); 1.67-1.56 (m, 4 H); 1.23 (s, 3 H).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH:9]1([C@H:12]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:15]([CH2:24][OH:25])[CH:14]([OH:26])[CH2:13]2)[CH2:11][CH2:10]1>N1C=CC=CC=1.C(Cl)Cl>[Si:5]([O:25][CH2:24][CH:15]1[CH:14]([OH:26])[CH2:13][C@@H:12]([CH:9]2[CH2:10][CH2:11]2)[N:16]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C(CO)C(O)C[C@H]1C1CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(CO[Si](C)(C)C(C)(C)C)C(O)C[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
TBSCl (1.35 g, 9.00 mmol) was added to a solution of (5S)-tert-butyl 5-cyclopropyl-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (32) (1.93 g, 7.50 mmol) in pyridine (15 mL) and the resulting solution was stirred at rt for 18 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with 1 N aq. HCl (10 mL). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give (5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-cyclopropyl-3-hydroxypyrrolidine-1-carboxylate (33). Retention time (min)=3.261 method [1], MS (m/z) 394.2 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH3:13][O:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[I-].[K+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[O:12][CH2:16][CH2:15][O:14][CH3:13]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc([N+](=O)[O-])ccc1OC
Temperature: 80 °C
Yield: 97.5 %

Procedure:
A mixture of 2-methoxy-5-nitrophenol (6 g, 35 mmol), 2-bromoethyl methyl ether (4 ml, 40 mmol), potassium carbonate (5.8 g, 40 mmol) and potassium iodide (0.5 g) in DMF (50 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool and poured into water (400 ml). The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give 4-methoxy-3-(2-methoxyethoxy)nitrobenzene (7.75 g, 98%).