Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[N+:28]([O-:30])=[O:29])C=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.O1CCC[CH2:32]1>>[CH:14]1([O:19][C:20]2[CH:21]=[C:22](/[CH:5]=[CH:4]/[C:6]([O:8][CH3:32])=[O:7])[CH:25]=[CH:26][C:27]=2[N+:28]([O-:30])=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: C1CCOC1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc([N+](=O)[O-])c(OC2CCCC2)c1

Procedure:
To a stirred suspension of 0.89 g (22.3 mmol) of a 50% oil suspension of sodium hydride (previously washed with three, 10 mL portions of hexane) in 100 mL of dry tetrahydrofuran under a nitrogen atmosphere was added dropwise at room temperature 2.54 mL (15.7 mmol) of trimethylphosphonoacetate in 100 mL of dry tetrahydrofuran over a 30 minute period. The white suspension was stirred for an additional 10 minutes after which time 3.35 g (14.2 mmol) of 3-cyclopentoxy-4-nitrobenzaldehyde in 50 mL of dry tetrahydrofuran was added dropwise over a 20 minute period. The final reaction mixture was stirred for an additional hour after which time the mixture was quenched with excess saturated ammonium chloride. The mixture was extracted with three, 50 mL portions of methylene chloride and the combined organic fractions were washed with one, 50 mL portion of saturated sodium chloride, dried over magnesium sulfate and concentrated. Liquid chromatography of the crude product over 130 g of silica gel eluting with 50% ethyl acetate in hexane provided the desired, analytically pure solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:10]([CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:10]([CH2:17][CH:18]2[CH2:19][O:20][C:29](=[O:31])[O:21]2)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(N(CC(O)CO)C(=O)C(C)(C)C)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Br)c(N(CC2COC(=O)O2)C(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A solution of N-[3-bromo-6-(methyloxy)-2-pyridinyl]-N-(2,3-dihydroxypropyl)-2,2-dimethylpropanamide (7.628 g, 21.130 mmol) in DCM (100 ml) and pyridine (3.407 ml, 42.26 mmol) at −78° C. under argon was treated with a solution of triphosgene (6.27 g, 21.130 mmol) in DCM (20 ml) over 5 min and the reaction was then allowed warm to rt and stirred at rt for 30 min. The reaction was then carefully treated with saturated sodium bicarbonate solution (200 ml), extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), and evaporated and chromatographed (0-50% ethyl acetate:Hexane) to give the product as a white solid (5.722 g, 70%).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:6]([Cl:16])[N:5]=[CH:4][N:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:16][C:6]1[C:7]([CH2:8][CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=[CH:4][N:5]=1
Reactant: CCOC(Cc1c(Cl)ncnc1Cl)OCC
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(Cc1c(Cl)ncnc1-c1ccccc1)OCC
Temperature: 100 °C
Yield: 63.6 %

Procedure:
The 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (1.1 g), phenyl boronic acid (500 mg) and potassium carbonate (556 mg) were dissolved in toluene (15 mL) and water (1.5 mL). The reaction mixture was degassed with nitrogen for 30 minute and then Pd(PPh3)4 (230 mg) was added. The reaction mixture was again degassed with nitrogen for 20 minutes before heated to 100° C. for 3 hours in a sealed tube. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (2×20 mL). The combined filtrate was washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography using EtOAc/hexane (0.5:9.5) as eluent to afford 4-chloro-5-(2,2-diethoxyethyl)-6-phenylpyrimidine (800 mg) as colorless viscous liquid. 1H NMR (DMSO-d6): δ 1.07-1.10 (t, 6H), 3.21-3.23 (d, 2H), 3.32-3.36 (q, 2H), 3.37-4.00 (q, 2H), 4.79-4.81 (t, 1H), 7.47-7.49 (m, 3H), 7.63-7.66 (m, 2H), 8.91 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CC(O)C>[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: NC1CCC(F)(F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc2c(NC3CCC(F)(F)CC3)ncnc12
Yield: 61.2 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step 2, 200 mg, 0.954 mmol), 4,4-difluorocyclohexanamine (491 mg, 2.86 mmol) and DIPEA (367 mg, 2.86 mmol) in iPrOH (2 mL) was heated in a sealed tube at 80° C. for 2 h. Then the reaction mixture was quenched with water at rt and was extracted with CHCl3. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography using 3-5% EtOAc in CHCl3 to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.59-8.55 (m, 2H), 8.43-8.40 (d, J=7.2 Hz, 1H), 8.27-8.25 (d, J=7.8 Hz, 1H), 7.69-7.63 (t, J=7.8 Hz, 1H), 4.41 (m, 1H), 2.26-2.00 (m, 6H), 1.75-1.71 (m, 2H); MS (m/z): 309.18 (M+H)+.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.Cl[C:12](OC1C=CC=CC=1)=[O:13].C(N(CC)CC)C.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][NH:29]1>C(Cl)Cl>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:12]([N:29]3[CH2:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28]3)=[O:13])=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)OCO2)N1Cc2ccccc2C1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 3,4-(methylenedioxy)aniline (150 mg, 1.09 mmol) in dry DCM (4 mL) was added dropwise phenyl chloroformate (0.138 ml, 1.09 mmol) and triethylamine (0.153 ml, 1.09 mmol). After the reaction mixture was stirred at r.t for 8 hr., isoindoline (0.123 ml, 1.09 mmol) and triethylamine (0.153 ml, 1.09 mmo) were added, and the reaction mixture was stirred overnight. The solvent was then removed under reduced pressure, and the residue was purified by chromatographed on silica gel (EtOAC/Hexane: 1:3) to give the title compound (185 mg, 60%) as a white solid: m.p:165-166° C. 1H NMR (CDCl3, 500 MHz): 4.82 (s, 4H); 5.93 (s, 2H); 6.20 (s, 1H); 6.73 (s, 2H); 7.17 (s, 1H); 7.30 (m, 4H). MS (MH+, 283).
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21](=[O:26])[CH2:22][C@@H:23]([OH:25])[CH3:24].N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:19][O:20][C:21](=[O:26])[CH2:22][C@@H:23]([O:25][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:24]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C[C@H](C)O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl(chloro)diphenylsilane (15.282 g, 55.6 mmol) was added dropwise to an ice-cooled and stirred solution of (S)-3-hydroxybutanoic acid methyl ester (5.473 g, 46.3 mmol) and 1H-imidazole (6.939 g, 102 mmol) and DMAP (0.566 g, 4.63 mmol) in DMF (250 mL). After 10 min., the cloudy reaction mixture was allowed to warm to r.t. and stirred overnight. The reaction mixture was taken up in EtOAc, then washed successively with H2O (3×), 1N HCl and a sat. NaHCO3 solution. The organic phase was dried (Na2SO4), filtered and concentrated to give a viscous colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH2:9]([Li])CCC.[CH2:14]([N:21]1[CH2:27][CH:26]2[C:28](=[O:29])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.IC>CCOCC>[CH2:14]([N:21]1[CH2:27][CH:26]2[C:28]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=3)([O:29][CH3:9])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1C2CCC1CN(Cc1ccccc1)C2
Reactant: [Li]CCCC
Reactant: Brc1cccc(Br)c1
Solvent: CCOCC
Solvent: CI
Product: COC1(c2cccc(Br)c2)C2CCC1CN(Cc1ccccc1)C2
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1,3-Dibromobenzene (12.4 ml, 0.102 mol) in anhydrous ether (200 ml) in a flame dried 1LRB flask, at −78° C. was treated with a 2.5M solution of n-butyllithium in hexanes (41.0 ml, 0.102 mol) via an addition funnel over 15 min. After 1 h at −78° C., the mixture was treated with a suspension of 3-benzyl-3-aza-bicyclo[3.2.1]octan-8-one (11.02 g, 51.2 mmol) in anhydrous ether (100 ml) via addition funnel over 20 min. The reaction stirred at −78° C. 45 min, warmed to room temperature and judged complete by TLC. The reaction solution was carefully concentrated in vacuo under N2 to remove ˜250 mL of ether. The reaction slurry was charged with 250 ml of fresh anhydrous THF, followed by iodomethane (9.56 ml, 0.154 mol) and allowed to stir at room temperature for 60 h. After quenching with 1 N HCl (100 ml to pH 1), the layers were separated, then extracted with ether (2×100 ml). The acidic aqueous layer was basified with saturated aqueous Na2CO3 solution to pH 11, and extracted with EtOAc (2×100 ml). All organic extracts were combined, washed with saturated aqueous Na2CO3 solution (1×100 ml), saturated aqueous NaCl solution (1×100 ml), dried over Na2SO4, filtered and concentrated to a dark oil. Passage through a Silica pad (3×8 in) eluted with 5% EtOAc/hexanes yielded a light yellow oil (22.4 g, >100%). (TLC 20% EtOAc/Hexanes Rf 0.70); 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1H), 7.41–7.19 (m, 8H), 3.60 (s, 2H), 2.84 (s, 3H), 2.75 (d, J=9.9 Hz, 2H), 2.53 (d, J=7.9 Hz, 2H), 2.43 (br s, 2H), 1.80 (d, J=7.5 Hz, 2H), 1.38 (m, 2H); APCI MS m/z 386.1, 388.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[O:18])[CH2:8]1.[CH2:19](O)[CH2:20][OH:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH2:20]1[O:21][C:9]2([CH2:8][CH:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[CH2:16][C:15]3[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]2=3)[O:18][CH2:19]1
Reactant: Cc1ccnc2c1C(=O)CC(c1sccc1Cl)C2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccnc2c1C1(CC(c3sccc3Cl)C2)OCCO1
Yield: 89.1 %

Procedure:
A mixture of 7-(3-chlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (7.07 g), ethyleneglycol (6.2 g) and p-toluenesulfonic acid (6.9 g) in toluene (200 ml) was refluxed for 15 hours, with separating water, and to the reaction solution were added ethyl acetate (150 ml) and saturated sodium hydrogen carbonate solution (200 ml). The mixture was shaken, and the separated upper layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography to give 7-(3-chlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one-ethyleneacetal(7.3 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=S.O[Li].O.OO>O1CCCC1>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([NH:19][C:20]2[O:10][C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[N:1]=2)=[C:12]([F:11])[CH:17]=1
Reactant: Cc1cc(C)c(O)c(N)c1
Reactant: Fc1cc(Br)ccc1N=C=S
Agent: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2oc(Nc3ccc(Br)cc3F)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
An ambient solution of 2-amino-4,6-dimethylphenol (0.85 g, 6.2 mmol) and 2-fluoro-4-bromophenyl isothiocyanate (1.44 g, 6.20 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the dropwise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite; solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 335 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[F:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: Oc1c(F)cc(F)cc1I
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(F)cc(F)c3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 2,4-Difluoro-6-iodo-phenol (1.0 g, 3.9 mmol), 4-Methoxyphenylacetylene(0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and CuI (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH and filtered to give 86 as a solid.
Reaction SMILES: [OH:1][CH:2]1[O:21][C@H](CO)[C@@H]([O:8][C@@H:9]2[O:17][C@H](CO)[C@H](O)[C@H:12](O)[C@H:10]2O)[C@H:5](O)[C@H:3]1O.O=[Si]=O.[C:27]([O-])(=O)CCCCCCCCCCCCCCCCC.[Mg+2].C([O-])(=O)CCCCCCCCCCCCCCCCC>>[C:2]([O-:21])(=[O:1])[CH:3]=[CH2:5].[C:9]([O-:17])(=[O:8])[C:10]([CH3:27])=[CH2:12]
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=[Si]=O
Agent: [Mg+2]
Product: C=C(C)C(=O)[O-]
Product: C=CC(=O)[O-]

Procedure:
Following the same procedure as for Example 1, a powdery mixture consisting of 0.53% (w/w) thiametoxam, 58.97% (w/w) cellulose acetate (CA 398-10, Eastman), 40% (w/w) lactose, 0.4% (w/w) aerosil and 0.1% (w/w) magnesium stearate is compacted into tablet cores (nominal weight: 39±1 mg) using convex punches. A coating solution formed of a mixture of acrylate and methacrylate copolymers (commercially available as Eudragit RS 30 D and Eudragit RL 30 D, Röhm GmbH, Germany) is sprayed on the cores.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CCOCC
Product: OC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 2,5-dibromo-pyridine (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one in ether using the procedure described in Step A of Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.CN([CH:32]=[O:33])C.Cl>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]([CH:32]=[O:33])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The reaction takes place under argon, the apparatus is heat-dried and operated with a KPG stirrer. 15 g (65.6 mmol) of tert-butyl (6-chloropyridin-2-yl)carbamate (Example 25A) and 19 g (164 mmol) of 1,2-bis(dimethylamino)ethane are introduced into 270 ml of THF and cooled to −78° C. 102.5 ml (164 mmol) of butyllithium (1.6N) are added dropwise. After the dropwise addition is complete, the reaction is slowly warmed to −10° C. and kept at −10° C. for 2 h and then cooled again to −78° C., and 10 ml (131 mmol) of DMF are added. The reaction is slowly warmed to RT, and the reaction mixture is added to 1 l of ethyl acetate and 350 ml of 1N hydrochloric acid and stirred for 15 min, and the organic phase is separated off. It is washed with water and saturated sodium bicarbonate solution, dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is mixed with diethyl ether and the solid is filtered off with suction and dried. 12.3 g (73% of theory) of the product are obtained as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1)([O-:15])=[O:14].C(OC(=O)C)(=O)C.[H-].[Na+]>C(O)(=O)C.O>[N+:10]([C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][C:23](=[O:24])[C:22]([C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)=[CH:4]2)([O-:12])=[O:11]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=c1oc2ccc([N+](=O)[O-])cc2cc1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 70 %

Procedure:
2-Hydroxy-5-nitrobenzaldehyde (250 mg, 1.50 mmol) and p-nitrophenylacetic acid (271 mg, 1.50 mmol) were placed in a dry 25-mL round bottom flask. Acetic anhydride (2.8 mL, 30 mmol) was then added with stirring. To this suspension sodium hydride (60 mg, 1.50 mmol) was then added in small aliquots (60% oil suspension) and the reaction mixture was heated to 100° C. for 3 h. Then, 100 μL of water and 3 mL of acetic acid were added. The mixture was cooled to 4° C. for one hour and then filtered. The solid was rinsed with cold glacial acetic acid and placed in a 100-mL flask, to which was added 30 mL of toluene, which was then removed by rotary evaporation. This addition and removal of toluene was repeated two more times to remove the last traces of acetic acid. The resulting solid was then dried under vacuum to give a beige powder (11) in 70% yield (325 mg, 1.05 mmol). mp: 250° C. (dec). FTIR (KBr) (cm−1): 1620, 1480, 1750, 1540, 1350. 1H-NMR (DMSO-d6): δ (ppm) 8.80 (d, J=2.6 Hz, 1H), 8.62 (s, 1H), 8.47 (dd, J=9.1 Hz, J=2.7 Hz, 1H), 8.37 (dd, J=8.9 Hz, J=2.0 Hz, 1H), 8.02 (dd, J=8.9 Hz, J=2.0 Hz, 2H), 7.71 (d, J=9.1 Hz, 1H). 13C-NMR (DMSO-d6): δ (ppm) 159.43, 157.87, 148.46, 144.68, 142.30, 141.50, 130.85, 127.92, 125.77, 124.51, 120.53, 118.64. HRMS: expected, 312.038236; found, 312.039100. Elemental analysis for C15H8N2O6: expected: C, 57.70; H, 2.58; N, 8.97; found: C, 57.37; H, 2.62; N, 8.78.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.ClC(Cl)(O[C:21](=[O:27])OC(Cl)(Cl)Cl)Cl.[NH2:29][C:30]1[N:35]=[C:34]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([F:44])[CH:37]=2)[CH:33]=[C:32]([N:45]2[CH2:50][CH2:49][CH2:48][C@@H:47]([NH2:51])[CH2:46]2)[N:31]=1>C(Cl)Cl>[CH:1]1([O:7][C:21](=[O:27])[NH:51][C@@H:47]2[CH2:48][CH2:49][CH2:50][N:45]([C:32]3[CH:33]=[C:34]([C:36]4[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([F:44])[CH:37]=4)[N:35]=[C:30]([NH2:29])[N:31]=3)[CH2:46]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@@H](N)C3)nc(N)n2)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-c2cc(N3CCC[C@@H](NC(=O)OC4CCCCC4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A premixed solution of cyclohexanol (40.7 μl, 0.389 mmol) and Hunig's base (57 uL) in CH2Cl2 (1 mL) was slowly added to a solution of triphosgene (38.5 mg, 0.130 mmol) in CH2Cl2 (1 mL), and the resulting mixture was stirred for 1 hr at room temperature. A premixed solution of 4-{2-amino-6-[(3R)-3-amino-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (125 mg, 0.324 mmol) and Hunig's base (226 uL) in CH2Cl2 (5 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated, and then loaded on a Biotage SNAP 10 g column and purified with a gradient of 0 to 55% EtOAc in Hexane over 25 minutes to afford the title compound (45 mg) as a light yellow oil. LC-MS (ES) m/z=439 [M+H]+.
Reaction SMILES: C[C@H:2](N(C)C)[C@H:3]([OH:10])C1C=CC=CC=1.CCN(CC)CC.[CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:22][C:23]#[CH:24].C(=O)C>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2].C1(C)C=CC=CC=1>[C:25]1(/[CH:21]=[CH:22]/[C:23]#[C:24][C@@H:3]([OH:10])[CH3:2])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H]([C@H](O)c1ccccc1)N(C)C
Reactant: C#CC=Cc1ccccc1
Agent: CC=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[C@H](O)C#C/C=C/c1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A flask containing Zn(OTf)2 (Zinc triflate purchased from Fluka was found to give the best results, other vendor's proved inefficient; 557 mg, 1.50 mmol) and (−)—N-methylephedrine (275 mg, 1.50 mmol) was added toluene (1.5 mL) and Et3N (209 μL, 1.50 mmol) at 23° C. under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 23° C. before but-1-en-3-ynyl-benzene (192 μL, 1.50 mmol) was added in one portion. After stirring for 15 min at 23° C., the reaction was cooled to 0° C., then acetaldehyde (168 μL, 30.0 mmol) was added at the same temperature in one portion. The resulting mixture was warmed to 23° C. and stirred for 35 h, then quenched by the addition of saturated aqueous NH4Cl (3 mL). The mixture was poured into a separatory funnel and diluted with EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (0→20% EtOAc/hexanes) afforded compound 7 (106 mg, 41%, 72% ee; the ee was determined after making the acetate ester) as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[N:14]O)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[H][H]>C(Cl)(Cl)Cl.[Pt]=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:13])[NH2:14])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(CC(C)=NO)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CC(C)N)cc1

Procedure:
1-(4-Carbomethoxyphenyl)propan-2-one oxime (10.0 g) in absolute alcohol (200 ml) and chloroform (25 ml) was hydrogenated on a Parr hydrogenator at 50 psi and at 50° in the presence of platinum oxide (250 mg) until hydrogen uptake has ceased. The catalyst was removed and the residue was recrystallised as the hydrochloride from methanol/ethyl acetate, mp 206°-210° (8.5 g). γ (d6DMSO) 8.84 (3H, d, 6 Hz), 6.2-7.5 (3H, m), 6.17 (3H, s), 2.59 (2H, d, J=8 Hz), 2.09 (2H, d, J=8 Hz), 1.50 (2H, br).