Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28](O)=[O:29])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[N+:37]([C:40]1[CH:61]=[CH:60][C:43]([CH2:44][O:45][C:46]([NH:48][CH2:49][CH2:50][CH2:51][C:52]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[O:53])=[O:47])=[CH:42][CH:41]=1)([O-:39])=[O:38].C(N(CC)CC)C>ClCCl.CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[C@H:12]([C:28]([N:57]2[CH2:56][CH2:55][N:54]([C:52](=[O:53])[CH2:51][CH2:50][CH2:49][NH:48][C:46]([O:45][CH2:44][C:43]3[CH:42]=[CH:41][C:40]([N+:37]([O-:39])=[O:38])=[CH:61][CH:60]=3)=[O:47])[CH2:59][CH2:58]2)=[O:29])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCC(=O)N1CCNCC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(S[C@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(NCCCC(=O)N1CCN(C(=O)[C@@H]2C[C@H](SC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A 0.86 g portion of (2S,4S)-4-benzoylthio-1-(p-nitrobenzyloxycarbonyl)proline was suspended in 10 ml of dichloromethane, and 0.51 g of oxalyl chloride and one drop of dimethylformamide were added to the suspension, followed by 1 hour of reaction at room temperature. With cooling on an ice bath, to the solution were added 0.74 g of 1-(4-(p-nitrobenzyloxycarbonyl)aminobutyryl)piperazine and 0.41 g of triethylamine, followed by 3 hours of reaction at room temperature. The resulting reaction mixture was mixed with chloroform, washed with sodium bicarbonate aqueous solution, citric acid aqueous solution and sodium chloride aqueous solution in that order and then dried over sodium sulfate, followed by evaporation of the solvent under a reduced pressure. Thereafter, a residue was subjected to a silica gel column chromatography to yield 1.64 g of foamy (2S,4S)-4-benzoylthio -1-(p-nitrobenzyloxycarbonyl)-2-((1-(4-(p-nitrobenzyloxycarbonyl) aminobutyryl)piperazine-4-yl)carbonyl)pyrrolidine.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28](O)=[O:29])[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:39][NH2:40]>>[CH3:39][NH:40][C:28]([C:25]1([C:22]2[N:23]=[N:24][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:38])[CH3:37])([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:20][CH:21]=2)[CH2:26][CH2:27]1)=[O:29]
Reactant: CN
Reactant: C[C@@H](c1ccc(-c2ccc(C3(C(=O)O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CNC(=O)C1(c2ccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)nn2)CC1
Yield: 49 %

Procedure:
The title compound was prepared from 1-[6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridazin-3-yl]-cyclopropanecarboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 49% of theory; LC (method 1): tR=1.76 min; Mass spectrum (ESI+): m/z=529 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[N:3]=1.C1COCC1.[NH3:29]>CCOC(C)=O>[NH2:29][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])[N:3]=1
Reactant: O=C(COc1nc(Cl)nc(Cl)n1)Nc1cccc(C(F)(F)F)c1
Reactant: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nc(Cl)nc(OCC(=O)Nc2cccc(C(F)(F)F)c2)n1
Temperature: -78 °C
Yield: 25.2 %

Procedure:
To a 25 mL recovery flask was added 2-(4,6-dichloro-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide (293 mg, 0.798 mmol, 1.0 eq.) and a stirbar. THF (7 mL) was added and the resulting solution was cooled to −78° C. Ammonia (NH3, 2.0 M in EtOH, 2.00 mL, 6 mmol, 5 eq.) was added in 400 μl aliquots until the reaction was complete by LC/MS analysis. The reaction mixture was diluted with EtOAc (50 mL) and washed with H2O (1×50 mL) and brine (1×50 mL). The combined aqueous phases were extracted with EtOAc (2×25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give an off-white solid. The solid washed with EtOAc to give 2-(4-Amino-6-chloro-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide as a white solid (70 mg, 25%). LC/MSD (HP Series 1100 MSD) Expected MW: 357.04, Observed M−H, 358.1, Retention time: 1.37. 1H-NMR, DMSO-d6, Varian 400 MHz δ 10.54 (s, 1H), 8.10-8.07 (m, 2H), 8.02 (s, 1H), 7.78 (d, 1H), 7.57 (t, 1H), 7.43 (d, 1H), 4.96 (s, 2H) ppm.
Reaction SMILES: [C:1]1([C:7]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18]O>>[CH3:18][O:15][C:14]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:16]
Reactant: O=C(O)C1(c2ccccc2)CCCCCC1
Reactant: CO
Agent: Cl
Product: COC(=O)C1(c2ccccc2)CCCCCC1

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (Example 1c) (4.15 g) was refluxed in methanol (150 mL) and concentrated hydrochloric acid (5 mL) for 24 hours. The solvent was evaporated and the residue was dissolved in ether (100 mL) which was washed with water (100 mL), saturated sodium bicarbonate (50 mL) and water (100 mL), dried (MgSO4) and evaporated to afford the sub-titled compound (3.5 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]I.[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21][CH3:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (commercially available) 4-(2-hydroxymethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and (1 eq) MeI dissolved in THF was treated with NaH (2 eq) and stirred at RT for 2 h. After work-up, the crude solid was purified by SiO2 chromatography (Ethyl acetate-Heptane 1:4) to give the title compound.
Reaction SMILES: C([O:4][C@@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH2:28][Cl:29])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12])(=O)C.Cl>CCOCC>[OH:4][C@@H:5]([CH3:31])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]([CH2:28][Cl:29])=[N:15][C:14]=2[N:13]([CH3:30])[C:11]1=[O:12]
Reactant: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(nc(CCl)n2Cc2ccccc2)n(C)c1=O
Agent: Cl
Solvent: CCOCC
Product: C[C@H](O)CCCCn1c(=O)c2c(nc(CCl)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.7 %

Procedure:
To a solution of (S)-1-(5-acetoxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine (8.7 g, 19.5 mmol) was added a solution of hydrogen chloride in ether (1.0 M, 20 ml). After stirring at room temperature for 24 hours, the solvent was evaporated under reduced pressure to give (S)-1-(5-hydroxyhexyl)-7-benzyl-8-chloromethyl-3-methylxanthine (7.0 g, 89% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:32]=[CH:31]1>[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.C1(C)C=CC=CC=1>[F:25][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([C:34]3[N:30]([CH3:29])[CH:31]=[N:32][CH:33]=3)[C:11]=12)[NH2:24]
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(-c3cncn3C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Yield: 78.3 %

Procedure:
4-(1-(4-Methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (300 mg, 0.612 mmol, prepared in Example 7, step B), 1-methyl-5-(tributylstannyl)-1H-imidazole (681 mg, 1.84 mmol) (Org. Proc. Res. & Dev., 2003, 7(5), 676-683), tetrakis (triphenylphosphine) palladium (0) (141 mg, 0.122 mmol) and toluene (5 mL) were charged in a 25 mL, single-neck, round-bottomed flask. The reaction mixture was stirred at 100° C. until the starting material had been consumed (2 days). Then the reaction was cooled to room temperature and then partitioned between EtOAc (50 mL) and water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (213 mg, 78.3%). LRMS (APCI pos): >95% purity, 254 nm, m/e 445 (M+1). 1H NMR (400 MHz, CDCl3 δ 8.32 (d, 1H), 7.71 (m, 1H), 7.50 (m, 1H), 7.36 (m, 2H), 6.96 (m, 1H), 6.83 (m, 2H), 6.52 (m, 1H), 6.46 (m, 1H), 6.28 (d, 1H), 5.65 (s, 2H), 3.92 (s, 3H), 3.77 (s, 3H), 3.67 (s, 2H, NH2),
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.CCCCCC>[OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)c1ncccc1O
Reaction time: 8 h
Yield: 41 %

Procedure:
3-Hydroxypicolinic acid (5.0 g) was dissolved in 350 ml of toluene and 100 ml of methanol. A 2 M solution (25 ml) of trimethylsilyldiazomethane in hexane was added dropwise to the solution, and a reaction was allowed to proceed at room temperature overnight. The reaction solution was concentrated under the reduced pressure. Methylene chloride (100 ml) and water (100 ml) were then added to the concentrate to conduct extraction. The aqueous layer was then extracted with methylene chloride. The organic layer was dried over magnesium sulfate, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-hexane) to give 2.3 g (yield 41%) of methyl 3-hydroxypicolinate.
Reaction SMILES: [CH:1]1([CH:5]=O)[CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]([S@@:11]([NH2:13])=[O:12])([CH3:10])[CH3:9].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH:1]1(/[CH:5]=[N:13]/[S@:11]([C:8]([CH3:10])([CH3:9])[CH3:7])=[O:12])[CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCC1
Reactant: CC(C)(C)[S@@](N)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
To a solution of cyclobutanecarbaldehyde (1.0 g, 11.89 mmol, 1.00 equiv) in CH2Cl2 (10 mL) were added pyridinium p-toluenesulfonate (0.143 g, 0.57 mmol, 0.05 equiv), (S)-(−)-2-methylpropane-2-sulfinamide (1.22 g, 10.07 mmol, 0.85 equiv), and magnesium sulfate (7.14 g, 59.32 mmol, 5.00 equiv). The resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, 30% EtOAc in petroleum ether) to provide 2.0 g (90%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, J=10.8 Hz, 1H), 3.36-3.32 (m, 1H), 2.25-2.16 (m, 4H), 2.03-1.90 (m, 2H), 1.15 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH:10]#[C:11][CH:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CC(OC)(C)C>[C:11]([CH:12]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])#[CH:10]
Reactant: Oc1cccc(F)c1F
Reactant: C#CC(O)CCCCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C#CC(CCCCC)Oc1cccc(F)c1F
Reaction time: 19 h

Procedure:
2.4 g (0.33 mol) of 2,3-difluorophenol are initially introduced in 1.2 l of THF together with 50.0 ml (0.34 mol) of 1-octyn-3-ol and 94.1 g (0.36 mol) of triphenylphosphine, and a solution of 76.1 ml (0.39 mol) of DIAD in 100 ml of THF is added dropwise. After 19 h at RT, the batch is diluted with MTBE and washed with water. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with saturated sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, 1-chlorobutane), giving 1-(1-ethynylhexyloxy)-2,3-difluorobenzene as a colourless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[CH3:24][C:23]([C:27]1[CH:32]=[CH:31][C:30]([O:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:20])([F:21])[F:22])[C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:16])([F:15])[F:17])[CH:7]=2)=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: N#Cc1ccc(N(CCCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(OCCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(3-hydroxypropyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-tert-butylphenol: MS (ES) m/z 459 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH2:25].O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NCc1ccccn1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(NCc2ccccn2)ncn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.7 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (1 g, 7 mmol) in iPrOH (40 mL) and DIPEA (1.16 g, 9 mmol) was added a solution of 2-pyridinylmethanamine (970 g, 9 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2.5 hours. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by flash chromatography on silica to obtain the title compound (1.2 g, yield: 78%). MS (ESI): 221 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:20][CH2:21]OC)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH:7]1[OH:19])=[O:5])C.[F:24][C:25]([F:35])([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[Cl-].C[Al+]C>C1(C)C=CC=CC=1>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:31]([C:30]3[CH:32]=[CH:33][C:27]([O:26][C:25]([F:24])([F:34])[F:35])=[CH:28][CH:29]=3)[CH2:21][CH2:20]2)[CH:7]([OH:19])[CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(CCOC)CCN(Cc2ccccc2)CC1O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(Cc1ccccc1)CC2O
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-3-hydroxy-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (618 mg, 1.92 mmol) and 4-(trifluoromethoxy)aniline (516 μL, 3.85 mmol) in toluene (5 ml) under an argon atmosphere at room temperature, was added dimethylaluminium chloride (0.9M solution in heptane, 4.27 ml, 3.85 mmol) and the mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and quenched with sat. Na2SO4 (aq) solution and the mixture was filtered through Celite® and evaporated under reduced pressure. The crude residue was purified by flash column chromatography (1:1 AcOEt/heptane) to give (5SR,6RS)-8-benzyl-6-hydroxy-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (620 mg, 77%) as a white solid. MS (ESI): 405.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:14][C:15](=[S:17])[NH2:16])[CH2:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>C(#N)C>[CH2:1]([O:8][CH2:9][C:10]1([CH2:14][C:15]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:16]=2)[CH2:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC(=S)CC1(COCc2ccccc2)CCC1
Solvent: CC#N
Product: c1ccc(COCC2(Cc3nc(-c4ccccc4)cs3)CCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of 0.5 g (2.01 mmol) of 2-{1-[(benzyloxy)methyl]cyclobutyl}ethanethioamide in 10 mL of acetonitrile was added 0.39 g (2.01 mmol) of phenacyl bromide and the contents stirred at room temperature for 3 h. The mixture was concentrated under vacuum and the residue was purified by silica gel chromatography using ethyl acetate:hexane (2:8) as the eluent to afford 0.68 g (97%) of 2-({1-[(benzyloxy)methyl]cyclobutyl}methyl)-4-phenyl-1,3-thiazole as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 7.96-7.30 (m, 5H), 4.60 (s, 2H), 3.50 (s, 2H), 3.35 (s, 2H), 2.13-1.95 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[CH3:25][O:26][C:27](=[O:33])[CH:28]([CH2:31][NH2:32])[CH2:29][CH3:30]>CO>[CH3:25][O:26][C:27](=[O:33])[CH:28]([CH2:31][NH:32][C:21]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[OH:20])=[CH:8][CH:9]=[C:10]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=2)=[O:22])[CH2:29][CH3:30]
Reactant: CCC(CN)C(=O)OC
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CO
Product: CCC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (60 mg, 0.19 mmol) and 2-aminomethyl-butyric acid methyl ester (crude, 1.57 mmol) in MeOH (3 mL) were heated at 150° C. in a microwave for 3 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 55 mg. MS: (−) m/z 418.14 (M−1).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)=[N:5]/[O:6][CH3:7].[H-].[Na+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1>CN(C=O)C.O>[CH3:1][NH:2][C:3](=[O:22])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:26]2[S:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[N:30]=2)[CH:16]=1)=[N:5]/[O:6][CH3:7]
Reactant: Clc1nc2ccccc2s1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1cccc(Oc2nc3ccccc3s2)c1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a solution of (E)-N-methyl-2-[2-(3-hydroxyphenoxy)phenyl]-2-methoxyiminoacetamide (0.21 g) in DMF (3 ml), sodium hydride (34 mg) and 2-chloro-1,3-benzothiazole (0.18 g) were added, and the resultant mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water and extracted with ether. The solvent was dried and the residue was purified by silica gel column chromatography to give 0.27 g of the objective compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]([C:14]3[S:15][C:16]([CH3:22])=[C:17]([N+:19]([O-])=O)[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1>O1CCCC1.[Ni]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]([C:14]3[S:15][C:16]([CH3:22])=[C:17]([NH2:19])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1N

Procedure:
Sponge nickel (0.5 g water wet) was added to a solution of 5-methyl-4-nitro-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester (0.55 g, 1.7 mmol) from Step 1 in tetrahydrofuran (100 mL) and the mixture was hydrogenated at room temperature under a hydrogen atmosphere at a starting pressure of 50 psi. After a reaction time of 2.79 hours, the pressure was released, and the mixture was filtered. The slurry was washed with tetrahydrofuran, and the filtrate was stripped of solvent under reduced pressure to afford a crystalline residue. The residue was triturated in diethyl ether and filtered to afford 5-methyl-4-amino-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester. Chromatography on silica gel in ethyl acetate, then evaporation of the effluent under reduced pressure gave 0.14 g of 5-methyl-4-amino-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[N:12](C(OC(C)(C)C)=O)[N:11]=3)[N:7]=[N:8][C:4]=2[C:3]=1[O:28][C:29]1[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[C:31]([Cl:37])[CH:30]=1>C(O)(C(F)(F)F)=O>[Cl:37][C:31]1[CH:32]=[C:33]([CH:34]=[C:29]([O:28][C:3]2[C:4]3[N:8]=[N:7][N:6]([CH2:9][C:10]4[C:18]5[C:13](=[N:14][CH:15]=[CH:16][CH:17]=5)[NH:12][N:11]=4)[C:5]=3[CH:26]=[CH:27][C:2]=2[Cl:1])[CH:30]=1)[C:35]#[N:36]
Reactant: CC(C)(C)OC(=O)n1nc(Cn2nnc3c(Oc4cc(Cl)cc(C#N)c4)c(Cl)ccc32)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3ncccc23)c1
Reaction time: 0.08 h

Procedure:
tert-Butyl 3-{[5-chloro-4-(3-chloro-5-cyanophenoxy)-1H-1,2,3-benzotriazol-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.001 g, 1.86 μmol) was dissolved in TFA (2 mL) at room temperature. After 5 minutes, the solvent was evaporated in vacuo to afford the title product.
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[CH:23])[CH:19]=[CH:20][CH:21]=1>CN(C=O)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>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:2]2[N:6]=[C:5]([CH3:7])[NH:4][CH:3]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ncc(I)[nH]1
Reactant: C#Cc1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a solution of 500 mg (2.40 mmol) of 5-iodo-2-methyl-1H-imidazole (CAS: [73746-45-9]) in 7 ml of DMF were added under an argon atmosphere 118 mg (0.17 mmol) of Bis(triphenylphosphine)palladium dichloride and 0.67 ml (4.81 mmol) of triethylamine. The mixture was stirred for 10 min at room temperature. Then 0.52 ml (575 mg, 4.09 mmol) of 3-chloro-1-ethynyl-benzene and 13.7 mg (0.072 mmol) of copper(I) iodide were added and the mixture was stirred for 1.5 h at 60° C. The mixture was concentrated in vaccuo, dissolved in a minimal volume of methylene chloride and purified by chromatography on 20 g of silicagel (gradient Heptane/EtOAc 85:15->EtOAc) to yield 430 mg (83%) of the title compound as an orange crystalline solid, MS: m/e=217.2, 219.2 (M+H+).