Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23][CH3:24])[C:18]([C:25](OCC)=[O:26])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1.C(OCC)(=O)C>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[N:20]=[C:19]([NH:21][CH2:22][CH2:23][CH3:24])[C:18]([CH2:25][OH:26])=[CH:17][N:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1CO
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a suspension of lithium aluminum hydride (160 mg) in tetrahydrofuran (14 mL), ethyl 2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (E3, 450 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. To the reaction mixture, lithium aluminum hydride (80 mg) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, ethyl acetate and an aqueous solution of the Rochell salt were added at room temperature, and the mixture was stirred at the same temperature for 2 hours and 30 minutes. The insoluble matter was removed by filtration through Cerite. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 90% ethyl acetate in methanol) to obtain (2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)methanol (E13, 212 mg).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[C:14]([Br:24])[CH:13]=[CH:12][CH:11]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Brc1cnc2cccc(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To concentrated H2SO4 (130 mL) was added dropwise at 0° C., over 80 min, 3-bromoquinoline (50 g) at a rate allowing the internal temperature to be maintained between 0° and 10° C. After the addition was complete, NBS (48 g) was added portionwise and the reaction mixture was stirred at rt overnight. The reaction mixture was poured onto ice (2 L) and the resulting solid was dissolved in DCM (600 mL). The aq. layer was further extracted with DCM (600 mL) and the combined extracts were washed with 1M NaOH (300 mL) and concentrated in vacuo. The residue was adsorbed on SiO2 and the resulting dispersal was loaded on the top of a column and eluted with a DCM-Hex (1-1, 3 L), then DCM (3 L) and finally DCM-ether (1-1, 2 L). The title compound was recovered from the last fraction after evaporation to yield 40 g of a white solid.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:65]=[C:64]([Cl:66])[C:63]([Cl:67])=[C:62]([Cl:68])[CH:61]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].[NH2:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76]>C(Cl)Cl>[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:61]=[C:62]([Cl:68])[C:63]([Cl:67])=[C:64]([Cl:66])[CH:65]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46]([NH:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:76])([CH3:78])[CH3:77])=[O:47]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)NCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
PyBOP (420 mg, 0.82 mmol) and DIPEA (0.410 mL, 2.46 mmol) were added to a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) and tert-butyl 2-aminoethylcarbamate (130 mg, 0.82 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was partitioned between water and CH2Cl2 (25 mL). The organic layer was washed with 2N HCl followed by saturated NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 40% EtOAc in petroleum ether to afford the title compound as a brown solid (200 mg, 39%): 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J=5.2 Hz, 1H), 7.91-7.89 (m, 3H), 7.58 (d, J=6.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.99 (dd, J=15.6, 9.2 Hz, 1H), 6.84 (t, J=6.0 Hz, 1H), 6.76 (t, J=15.6 Hz, 1H), 4.84-4.80 (m, 1H), 3.24-3.20 (m, 2H), 3.11-3.08 (m, 2H), 1.30 (s, 9H); ESIMS m/z 628.80 ([M+H]+); IR (thin film) 3365, 1701, 1167, 699, 555 cm−1.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:31])([CH3:30])[C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.C(#N)C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:28]=[C:27]5[C:23]([C:24]([CH3:31])([CH3:30])[C:25](=[O:29])[NH:26]5)=[CH:22][CH:21]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)C(=O)Nc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Temperature: 180 °C
Yield: 66 %

Procedure:
A mixture of the 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (50 mg, 0.18 mmol), 6-amino-3,3-dimethylindolin-2-one (63 mg, 0.36 mmol), and acetonitrile (3 mL) was heated in a sealed tube via at 180° C. for 60 min. The mixture was treated with EtOAc (50 mL) and sat. aq. solution of NaHCO3. The organic layer was separated and washed with brine, dried (Na2SO4), and evaporated. The residue was purified by flash chromatography over silica gel to give a light yellow solid (50 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[O:7].[N+:12]([CH2:15][CH3:16])([O-:14])=[O:13].[OH-].[Na+].C(O)(=O)C>CO>[F:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:15]([N+:12]([O-:14])=[O:13])[CH3:16])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CC[N+](=O)[O-]
Reactant: COc1cc(C=O)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(C(O)C(C)[N+](=O)[O-])ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a flame dried 100 mL round bottom flask was added 3-methoxy-4-fluorobenzaldehyde (367 mg, 2.38 mmol) and this was dissolved in methanol (23 mL). The reaction solution was cooled to 0° C. and nitroethane (357 mg, 4.76 mmol) was added to it followed by 5M NaOH (0.476 mL, 2.38 mmol). The solution was stirred for 80 min at 0° C. after which acetic acid (2% solution, 32 mL) was added and stirred for an additional 30 min. The reaction mixture was concentrated and water (10 mL) was added. The solution was extracted with dichloromethane (4×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentration to give afford an oil which was purified by silica gel flash chromatography using dichloromethane as eluant. Product (391 mg, 72%) product Was obtained as a colorless oil in a 1.88:1 ratio (A:B) of diastereomers. Pair A: 1H NMR (600 MHz, CDCl3): δ 7.07 (m, 1H), 7.0 (m, 1H), 6.8 (m, 1H), 5.34 (t, 1H, J=3 Hz), 4.65 (d of q, 1H, J=3.6, 6.6 Hz), 3.9 (s, 3H), 2.697 (d, 1H, J=3.6 Hz), 1.5 (d, 3H, J=6.6 Hz). 13C NMR (75 MHz, CDCl3): δ 153.3, 150.1, 147.44 (d, J=10.8 Hz), 134.1, 117.7 (d, J=7 Hz), 115.7 (d, J=18.6 Hz), 110.6, 86.8, 72.8, 55.8, 11.7. Pair B: NMR (600 MHz, CDCl3): δ 7.07 (m, 1H), 7.0 (m, 1H), 6.8 (m, 1H), 4.9 (d Of d, 1H, J=3.6, 9 Hz), 4.72 (m, 1H), 3.9 (s, 3H), 2.57 (d, 1H, J=4.2 Hz), 1.33 (d, 3H, J=5.4 Hz). 13C NMR (75 MHz, CDCl3): δ 153.8, 150.5, 147.76 (d, J=10.8 Hz), 134.1, 119 (d, J=7 Hz), 115.8 (d, J=18.6 Hz), 111, 87.7, 75.3, 55.8, 15.9. HRMS: Calc'd for C10H12FNO4 (M+Na): 252.0642; Found: 252.0643.
Reaction SMILES: [OH:1][C@:2]([CH3:18])([CH2:16][OH:17])[CH2:3][CH2:4][C:5]1[C:6](=[O:15])[C:7]([CH3:14])=[C:8]([CH3:13])[C:9](=[O:12])[C:10]=1[CH3:11].[H][H].C>C(OCC)(=O)C.[Pd]>[OH:1][C@:2]([CH3:18])([CH2:16][OH:17])[CH2:3][CH2:4][C:5]1[C:6]([OH:15])=[C:7]([CH3:14])[C:8]([CH3:13])=[C:9]([C:10]=1[CH3:11])[OH:12]
Reactant: [H][H]
Reactant: CC1=C(C)C(=O)C(CC[C@](C)(O)CO)=C(C)C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(C)c(O)c(CC[C@](C)(O)CO)c(C)c1O
Yield: 100.8 %

Procedure:
A solution of 0.405g (1.6mmoles) of (S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinone in 20 ml of ethyl acetate was stirred in an atmosphere of hydrogen, in the presence of 0.04g of 5% by weight palladium on 95% by weight charcoal until H2 uptake ceased (ca. 1hr; 38 ml H2 absorbed). The catalyst was filtered and the filtrate was concentrated giving 0.41 g of (S)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethylhydroquinone as a tan solid, mp 124°-131.5°.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1)=[O:35]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2c(-c3cccc([N+](=O)[O-])c3)nn3ccccc23)n1
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of 3-[2-(methylthio)-4-pyrimidinyl]-2-(3-nitrophenyl)pyrazolo[1,5-a]pyridine (0.82 g, 2.26 mmol) in DCM (22 mL) is added a solution of 50% mCPBA (818 mg, 2.37 mmol) in DCM (6 mL) through an addition funnel. The reaction is stirred for 10 min and saturated aqueous NaHCO3 and the layers are separated. The aqueous layer is extracted with DCM, and the combined organic layers are dried over MgSO4, filtered and concentrated. The residue is purified by silica gel chromatography (50% EtOAC/hexanes eluant) to provide the product (567 mg) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 8.93 (d, 1H, J=6.8), 8.68 (d, 1H, J=5.6), 8.57 (d, 1H, J=8.8), 8.44 (s, 1H, 8.37-8.35 (m, 1H, 8.08 (d, 1H, J=7.6), 7.78 (t, 1H, J=8.0), 7.61-7.65 (m, 1H), 7.21-7.26 (m, 2H), 2.84 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[SH2:20].[Na]>C(O)C>[C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([SH:20])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S
Reactant: O=C(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(c1ccccc1)c1nc(S)ccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 1 h

Procedure:
There were added to a mixture of 200 grams of 2-benzoyl-3-nitro-6-chloropyridine and 1 liter of ethanol with stirring 120 grams of sodium hydrogen sulfide monohydrate in portions. The temperature increased to 55° C. After the addition boiling was carried out for one hour at reflux, the solution filtered and acidified with glacial acetic acid. Upon addition of water, the reaction product crystallized. It was dissolved in dilute sodium hydroxide solution, the solution filtered, and the mercapto compound again precipitated with glacial acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])=[CH2:23]
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.8 %

Procedure:
To a solution of 5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2.10 g, 5.29 mmol) and O-(2-vinyloxyethyl)-hydroxylamine (0.87 g, 8.46 mmol) in DMF (30 mL) was added EDCI hydrochloride (1.31 g, 6.90 mmol), HOBt (0.93 g, 6.90 mmol) and DIPEA (1.17 mL, 6.90 mmol). The reaction mixture was stirred at room temperature for 5 hours before being concentrated in vacuo. The resultant residue was dissolved in 1:1 tert-butylmethylether: ethyl acetate (20 mL) and aqueous saturated sodium hydrogen carbonate solution (20 mL) was added. The resultant mixture was sonicated until a precipitate formed, the precipitate was collected by filtration and dried in vacuo at 45° C. to yield the title compound as a tan solid (1.55 g, 60%). LCMS (Method B): RT=2.80 min, M+H+=483.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]2[C:24]=1[CH2:25][CH2:26][C:27](=[O:34])[NH:28]2>ClCCl>[CH3:33][C:30]1[CH:31]=[CH:32][C:23]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:24]2[C:29]=1[NH:28][C:27](=[O:34])[CH2:26][CH2:25]2
Reactant: Cc1ccc(O)c2c1NC(=O)CC2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(OS(=O)(=O)C(F)(F)F)c2c1NC(=O)CC2
Reaction time: 1 h
Yield: 97 %

Procedure:
Pyridine (6.2 ml) and trifluoromethanesulfonic anhydride (10.3 ml) were added with stirring at 0° C. to an anhydrous dichloromethane solution (30 ml) of 5-hydroxy-8-methyl-3,4-dihydro-1H-quinolin-2-one (9.0 g), followed by stirring for 1 hour. The resulting mixture was concentrated under reduced pressure, water was added to the residue, and extraction with dichloromethane was performed. The extract was washed with water, an aqueous potassium hydrogensulfate solution and water in this order, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from an ethyl acetate-diisopropyl ether mixed solvent to thereby obtain 28 g (yield: 97%) of 8-methyl-5-trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one as a light brown powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-fluoro-4-nitrobenzoic acid suspended in CH2Cl2 under Ar was added DMF then oxalyl chloride. The reaction was stirred at room temperature 1.5 h then the solvent was evaporated. The residue was dissolved in THF and ammonia gas was bubbled through the reaction for 15 min. The solvent was evaporated and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The extracts were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-100% EtOAc/Hex) gave pure 2-fluoro-4-nitrobenzamide (E335).
Reaction SMILES: COCC1CCCCN1C1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1.[N:47]1([CH2:52][C@@H:53]2[CH2:57][CH2:56][CH2:55][NH:54]2)[CH2:51][CH2:50][CH2:49][CH2:48]1>>[N:47]1([CH2:52][C@@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:29]2[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=3)[N:30]=2)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@H]3CN3CCCC3)n2)c1

Procedure:
B32 was prepared following the procedure reported for B4 using A1 and (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine and obtained as a white crystalline solid; yield: 87 mg (23%). MS (ES) C19H27N7O2S requires: 417. found: 418 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1.CCN(CC)CC>CCO>[Br:1][C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[N:4][C:5]([NH:29][C@H:26]2[CH2:27][CH2:28][C@@H:23]([CH3:22])[CH2:24][CH2:25]2)=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@@H](N)CC1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2nc(Cl)ncc2Br)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 3-(5-bromo-2-chloropyrimidin-4-yloxy)azetidine-1-carboxylate (6 g, 16.4 mmol), cis-4-methylcyclohexanamine hydrochloride (2.4 5g, 16.4 mmol) and Et3N (7 mL, 49.2 mmol) in EtOH (20 mL) was executed in microwave reactor at 130° C. for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluted by 10 to 20% ethyl acetate in DCM) to give the titled compound (6.5 g, 90% yield). MS (ESI) m/z: Calc. 440.1 (M+). Found: 442.1 (M++2).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[CH:2].[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1.C(N(CC)CC)C>C(Cl)Cl.[H-].[Cl-].C1([Zr+2]C2C=CC=C2)C=CC=C1>[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][B:19](/[CH:2]=[CH:1]/[CH:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[O:18]1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OBOC1(C)C
Agent: C1=CC([Zr+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A solution of tert-butyl 4-ethynylpiperidine-1-carboxylate (0.414 g, 1.98 mmol) in methylene chloride (1 mL) was added with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.380 g, 2.97 mmol) and triethylamine (0.0201 g, 0.198 mmol), and the mixture was stirred at room temperature. The reaction mixture was added with bis(cyclopentadienyl)zirconium(IV) chloride hydride (0.0766 g, 0.297 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (E)-4-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]piperidine-1-carboxylate (0.600 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12.CCN(C(C)C)C(C)C.[F:24][C:25]([F:43])([F:42])[C:26]1[CH:27]=[C:28]([C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(Cl)Cl>[F:43][C:25]([F:24])([F:42])[C:26]1[CH:27]=[C:28]([C:36]([CH3:41])([CH3:40])[C:37]([N:8]([C:7]2[C:2]([Cl:1])=[C:3]3[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:4]3=[N:5][CH:6]=2)[CH3:9])=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCn1ncc2c(Cl)c(NC)cnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc2c(Cl)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cnc21
Temperature: 40 °C
Yield: 94.7 %

Procedure:
To a solution of (4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methyl-amine (2.24 g, 10.63 mmol) in CH2Cl2 (50 mL) was added iPr2NEt (3.69 mL, 21.20 mmol) and 2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (described in J. Org. Chem, 2006, 71, 2000-2008, 4.38 g, 13.70 mmol). The reaction mixture was heated at 40° C. for 2 hours, diluted with CH2Cl2 (100 mL), and washed with H2O. The organic phase was dried over Na2SO4, concentrated under vacuo, and column chromatography (SiO2, EtOAc/Heptane 1/4) afforded 4.96 g (95%) of the title compound as a light yellow solid. ES-MS m/e: 493.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][CH:18]=[C:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.C1C[O:54][CH2:53]C1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH:53]=[O:54])=[C:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2scc(COCC[Si](C)(C)C)c21
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(C=O)c(COCC[Si](C)(C)C)c21
Temperature: -78 °C

Procedure:
To a cold (−78° C.), stirred mixture of 2.03 g of N-(4-chlorobenzyl)-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 50 mL of dry TBF is added via cannula a solution of LDA, prepared as usual in 25 mL of dry THF from 2.5 mL of diisopropylamine and 5.3 mL of a 2.5 M solution of butyllithium in hexanes. The resulting deeply colored solution is stirred for 5 min at −78° C., then 1.7 mL of dry DMF is added, causing the mixture to solidify. The mixture is allowed to warm to 0° C. whereupon it becomes fluid, and is quenched with 50 mL of 1N HCl. Aqueous workup (CH2Cl2, dil. HCl) followed by flash chromatography on silica gel using 30-40% EtOAc in CH2Cl2 affords 1.56 g of the title compound as a yellow solid. Recrystallization from EtOAc provides pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]1([NH:38][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCC1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with cyclopentylamine (20 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with a 3:1 ethyl acetate-hexanes mixture. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 54 mg of the title compound as a colorless solid.