Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:14][C:15](=[C:18]=[O:19])OC)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)([CH2:14][CH2:15][CH:18]=[O:19])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=C=O)CC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCC=O)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99 %

Procedure:
To a cooled (−78° C.) solution of 4-cyclohexyl-4-(2-methoxy-carbonylethyl)-piperidine-1-carboxylic acid tert-butyl ester, 9, (1.0 g, 2.833 mmol) in 40 ml of anhydrous methylene chloride is added diisobutylaluminum hydride (5.75 ml, 1 M, 5.75 mmol). The reaction is stirred at room temperature for 40 min before it is quenched by adding methanol (3 mL) and water (20 mL). The reaction mixture is warmed to room temperature and the organic layer separated, dried over sodium sulfate, filtered and concentrated in vacuo to afford 915 mg (>99% yield) of the desired compound as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C(=O)(O)[O-]>C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: C1=COCCC1
Reactant: OCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: CCOCC
Product: BrCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 35 g (0.251 mol) of 3-bromopropanol and 1 g of p-toluenesulphonic acid in 500 ml of diethylether, 32.5 ml (0.357 mol) of 3,4-dihydro-2H-pyran is added dropwise under cooling with ice water and the solution is stirred for 2 hours at room temperature. The mixture is neutralized with saturated aqueous bicarbonate. washed with brine and concentrated after drying, affording 56 g of 2-(3-bromopropyloxy)tetrahydropyran in practically quantitative yield as a viscous liquid, which may be used without further purification. (C8H15BrO2 ; F.W. 223.1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:30](=[O:31])([O:32][CH2:33][CH3:34])[O:21][C@H:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=1)[C@H:12]([NH:15][C:16](=[O:17])[CH:18]([Cl:20])[Cl:19])[CH2:13][F:14]
Reactant: CCOC(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)O[C@H](c1ccc(S(C)(=O)=O)cc1)[C@@H](CF)NC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of florfenicol (250 g, 0.7 mol), 4-dimethylaminopyridine (42 g, 0.35 mol,), triethylamine (130 mL, 0.91 mol) in 1.2 L of tetrahydrofuran was stirred at 0-5° C. while neat ethyl chloroformate (80 mL, 0.83 mol) was added drop-wise with an addition funnel. The reaction proceeded as indicated by the precipitation of triethylamine hydrochloride salt. The mixture was allowed to stir at room temperature for 30 minutes and the salt was removed from the mixture by filtration. The filtrate was concentrated and 600 mL of ethyl acetate was added and the solution was washed with 1 M HCl (2×200 mL) followed by saturated NaCl (200 mL) and filtered through a layer of Na2SO4/silica gel. The filtrate was concentrated and the crude oil was crystallized from 450 mL of isopropanol to give the pure title product (286 g). m.p. 110-112° C.; H1-NMR (DMSO-d6), δ=1.2 ppm (t, 3 H), 3.2 ppm (s, 3H), 4.1 ppm (q, 2H), 4.3-4.7 ppm (m, 3H), 5.9 ppm (d, 1H), 6.4 ppm (s, 1H), 7.6 ppm (d, 2H), 7.9 ppm (d, 2H), 9.2 ppm (d, 1H); mass spectrum 452.0 (M+Na).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1>>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1
Reactant: c1cn[nH]c1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Product: FC(F)(F)c1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (140° C., 24 hours), 1H-pyrazole (102 mg, 1.5 mmol) is coupled with 1-chloro-4-(trifluoromethyl)benzene (134 μL, 1.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 80 mg (38% isolated yield) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:17]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH:19]=[N:18]1)=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([NH:3][C:4]([N:17]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH:19]=[N:18]1)=[N:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH3:2]
Reactant: CCNC(=NS(=O)(=O)c1ccc(OC)cc1)N1N=CCC1c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1ccc(O)cc1)N1N=CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
Under N2 atmosphere, to a solution of 1.05 g N-[ethylamino-(5-phenyl-4,5-dihydro-pyrazol-1-yl)-methylene]-4-methoxy-benzenesulfonamide in 25 mL DCM, 12.91 mL of a 1M solution of boron tribromide in DCM was added. The mixture was stirred overnight at room temperature under N2 atmosphere, quenched with water, and stirred for another 30 minutes. The solids were filtered off and the filtrate was extracted with water. The organic layer was dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography (stepwise gradient DCM→DCM/MeOH 95:5). The pure fractions were concentrated and triturated with Et2O. The solids were filtered off and dried in vacuo to give 0.34 g (34%) of N-[ethylamino-(5-phenyl-4,5-dihydro-pyrazol-1-yl)-methylene]-4-hydroxy-benzenesulfonamide as a grey crystalline material, m.p. 158-160° C. 1H NMR (400 MHz, DMSO-d6) δ 1.07 (t, J=7.2 Hz, 3H), 2.69-2.81 (m, 1H), 3.36-3.47 (m, 1H), 3.49-3.59 (m, 2H), 5.40-5.51 (m, 1H), 6.55 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 7.04-7.12 (m, 3H), 7.22-7.29 (m, 3H), 9.71 (s, 1H) [guanidine NH invisible].
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:7]=[C:6]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]=1)[CH3:2].C(O)C>[Pd].O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:7][CH:8]=1)[CH3:16]
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=CC(=O)OCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCNc1nc(Nc2ccccc2)ncc1CCC(=O)OCC
Yield: 47.7 %

Procedure:
A mixture of ethyl 3-(4-ethylamino-2-phenylamino-pyrimidin-5-yl)acrylate (152 mg, 0.48 mmol) and 5% palladium on carbon in a solvent mixture of ethanol and tetrahydrofuran was hydrogenated under pressure. The catalyst was filtered off and the filtrate concentrated. The residue was purified by flash chromatography eluting with 2:1 ethyl acetate:hexane to give 72 mg (47%) of 3-(4-ethylamino-2-phenylamino-pyrimidin-5-yl)propionic acid ethyl ester, mp 106-107° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:26]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:34][C:35]([CH3:37])=[O:36]>CN(C=O)C>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:26]=1)[C:6]1[CH:7]=[C:8]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([O:19][CH2:34][C:35](=[O:36])[CH3:37])=[CH:15][CH:14]=1
Reactant: CC(=O)CCl
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(-c3cccnc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A vial was charged with (S)-2-amino-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (0.300 g, 0.869 mmol), cesium carbonate (0.425 g, 1.303 mmol). DMF (3.47 mL) was added, the vial was sonicated for 30 s, and the mixture was stirred vigorously for 20 min, at which time some white solid still remained. The vial was cooled in an ice-bath for 10 min, then 1-chloroacetone (0.083 mL, 1.042 mmol) was added dropwise and the reaction was stirred over the weekend, during which the bath warmed to RT. The reaction was cooled back to 0° C. and 1-chloroacetone (0.083 mL, 1.042 mmol) was added. The reaction was stirred for two hours before 0.5 equivalents of cesium carbonate and chloroacetone were added at one hour intervals until the reaction was complete. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The material was purified via column chromatography (RediSep 40 g, gradient elution 0-5% MeOH:DCM) to afford (S)-1-(2-amino-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)propan-2-one as a white solid. The remaining fractions were combined and concentrated to afford impure material as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH:13]=O.Cl.[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH3:27])[N:23]=[C:24]([NH2:26])[CH:25]=1)=[O:20])[CH3:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:27][N:22]1[C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])=[CH:25][C:24]([NH:26][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:23]1
Reactant: CCOC(=O)c1cc(N)nn1C
Reactant: Cc1onc(-c2ccccn2)c1C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(NCc2c(-c3ccccn3)noc2C)nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a mixture of 5-methyl-3-(pyridin-2-yl)isoxazole-4-carbaldehyde (811 mg, 4.31 mmol) and 5-amino-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester hydrochloride (886 mg, 4.31 mmol) in MeOH (36 mL) was added molecular sieves (1.3 g). The reaction mixture was stirred at RT for 1 h. Then acetic acid (3.45 mL, 60.3 mmol) was added. After stirring for additional 5 min, sodium cyanoborohydride (542 mg, 8.62 mmol) was added in portions over 2 min and the reaction mixture was stirred at RT for 30 min, then evaporated. The residue was extracted with dichloromethane and then washed with a saturated solution of sodium hydrogen carbonate. The organic layers were washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, dichloromethane) afforded the title compound as a white solid (814 mg, 55%). MS: m/e=342.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[CH:10][C:8](=[O:9])[N:7]([CH2:13][CH:14]=[CH2:15])[C:5]1=[O:6])[CH:2]=[CH2:3].C(O)(=O)C.Cl.[N:21]([O-])=[O:22].[Na+]>O>[CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([N:21]=[O:22])[C:8](=[O:9])[N:7]([CH2:13][CH:14]=[CH2:15])[C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: O=N[O-]
Reactant: C=CCn1c(N)cc(=O)n(CC=C)c1=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CCn1c(N)c(N=O)c(=O)n(CC=C)c1=O
Reaction time: 4 h
Yield: 86.7 %

Procedure:
1,3-Diallyl-6-aminouracil (5 g) was suspended in 400 ml of water in a 1 L round bottom flask with overhead stirring. Acetic acid (6.7 ml of a 20% solution) was added, followed by intermittent addition of 2 ml of concentrated hydrochloric acid and a sodium nitrite solution (1.53 g in 7 ml water). After 4 hours, this solution was filtered, washed with water, collected and dried in a vacuum oven at 80° C. for 20 hours to yield 4.54 g of 1,3-diallyl-5-nitroso-6-aminouracil as a purple solid, m.p. 170°-180° C. (87% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14]C(=O)OCC)=S)[N:4]=1.Cl.NO.C([N:26](C(C)C)CC)(C)C>C(O)C>[NH2:26][C:12]1[N:11]=[C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]2[N:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1cc(OC)n2nc(N)nc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
Ethyl N-[N′-(4,6-dimethoxypyrimidin-2-yl)-thiocarbamoyl]carbamate (0.50 g, 1.7 mmol) was mixed with ethanol (5 mL). To this mixture was added hydroxylamine hydrochloride (0.12 g, 1.7 mmol) and diisopropylethylamine (0.30 mL, 1.7 mmol). The resulting mixture was allowed to stir at room temperature. After 2.5 hours, additional diisopropylethylamine (0.30 mL, 1.7 mmol) was added to the mixture. After 48 hours the ethanol was removed in vacuo and the residue was partitioned between H2O and Et2O to give a powder. The powder was filtered and dried to afford the product as a tan powder (0.27 g, 82%). mp 215-220° C. 1H NMR (DMSO-d6): δ6.04 (s, 1H); 5.97 (bs, 2H); 4.04 (s, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10](O)=[O:11]>C1C=CC=CC=1>[Cl:5][C:6]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([Cl:3])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Product: O=C(Cl)COc1ccc(Cl)cc1Cl

Procedure:
46 ml of thionyl chloride were added over 30 minutes to a solution of 130 g of 2,4-dichlorophenoxy-acetic acid in 150 ml of benzene, and the mixture was refluxed for one hour. The solvent and the excess thionyl chloride were eliminated under reduced pressure and the residue was distilled under 0.1 mm of mercury to obtain 91.4 g of the sought product with a boiling point of 120° C. at 0.1 mm of mercury.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[N:9][CH:10]=1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17]I.[Na+].[Cl-]>CN(C=O)C.O>[Cl:14][CH2:15][CH2:16][CH2:17][O:11][C:7]1[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:10]=[N:9][CH:8]=1
Reactant: CC(C)Oc1cncc(O)c1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cncc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-isopropoxypyridin-3-ol (1.04 g, 6.80 mmol) in DMF (10 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.25 g of an 80% dispersion in mineral oil, 8.33 mmol) in DMF (15 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1 h. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (1.67 g, 8.16 mmol), and the resulting dark brown mixture was stirred at ambient temperature for 4 h. Cold water (25 mL) was carefully added, followed by saturated NaCl solution (25 mL). The resulting mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation producing a dark-brown oil (0.92 g, 59.0%).
Reaction SMILES: [C:1]([N:8]([CH3:13])[CH:9]1[CH2:12][NH:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1>CC(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:13][N:8]([CH:9]1[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=2)[CH2:10]1)[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cc(Cl)ccn1
Reactant: CN(C(=O)OC(C)(C)C)C1CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cc(N2CC(N(C)C(=O)OC(C)(C)C)C2)ccn1
Yield: 51 %

Procedure:
3-(Boc-methylamino)azetidine (2.74 mmol, 1.0 eq) and 4-chloro-2-methylpyridine HCl (8.21 mmol, 3.0 eq) were dissolved in 2-propanol (5 ml) and DI PEA (13.69 mmol. 5.0 eq) and refluxed for 24 hours. After monitoring by TLC, the reaction solution was diluted with ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was washed with ethyl acetate. The combined organic phases were washed 1× with sat. NaCl solution, dried over magnesium sulfate, concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia solution). Yield: 51%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1/[CH:14]=[CH:15]/[C:16](OCC)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1/[CH:14]=[CH:15]/[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/[C@@H]1COCCN1C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1/C=C/CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of ethyl (2E)-3-[(3R)-4-(tert-butoxycarbonyl)morpholin-3-yl]acrylate (1.0 g) in toluene (10 ml) was added diisobutylaluminum hydride (1.02 M in toluene, 7.6 ml) at −78° C.˜−40° C. After stirring for 2 hours at 0° C., the mixture was quenched with methanol (1.2 ml), and stirred for 1 hour at room temperature. After the resulting precipitate was filtered off, the filtrate was evaporated and purified by column chromatography on a silica gel using a mixture of ethyl acetate and hexane (3:7˜4:6) as eluent to give (3R)-4-(tert-butoxycarbonyl)-3-[(E)-3-hydroxy-1-propenyl]morpholine (0.71 g) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11](Cl)=[N:12][C:13]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:30]2[CH:29]=[CH:28][C:27]([F:26])=[CH:32][C:31]=2[F:33])=[N:12][C:13]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Cc2c(F)cccc2F)nc1Cl
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cc2c(F)cccc2F)nc1-c1ccc(F)cc1F
Temperature: 90 °C

Procedure:
To a crude 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-6-(2,6-difluorobenzyl)pyridine (from Step C above) in DME was added 2,4-difluorophenylboronic acid (6.5 g), tetrakis(triphenylphosphine)palladium (2 g) and 2N Na2CO3 (40 mL), and heated to 90° C. for a couple of hours until reaction completed. The mixture was cooled to room temperature and filtered through celite. The mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (100% methylene chloride) to give title compound (4.81 g).
Reaction SMILES: N1([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:23])[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[O:7])C=CN=C1.CI.C(N(CC)CC)C.[CH2:33]([O:40][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:44]=[C:43]([CH2:51][OH:52])[C:42]=1[CH3:53])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[C:17]1([CH2:16][CH2:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:52][CH2:51][C:43]3[C:42]([CH3:53])=[C:41]([O:40][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:50]4[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=4)[N:44]=3)=[O:7])[CH2:9][CH2:10]2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(CO)nc2ccccc2c1OCc1ccccc1
Reactant: O=C(CCc1ccccc1)N1CCN(C(=O)n2ccnc2)CC1
Solvent: CCN(CC)CC
Solvent: CI
Solvent: CC#N
Product: Cc1c(COC(=O)N2CCN(C(=O)CCc3ccccc3)CC2)nc2ccccc2c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
To a solution of 1-(1H-imidazol-1-ylcarbonyl)-4-(3-phenylpropanoyl)piperazine (1.03 g) in acetonitrile (20 mL) was added dropwise methyl iodide (1.40 mL) and triethylamine (2.20 mL) at room temperature, followed by stirring at 60° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, and then [4-(benzyloxy)-3-methylquinolin-2-yl]methanol (300 mg) was added thereto, followed by dropwise addition of triethylamine (0.50 mL) and stirring at 70° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10) to obtain [4-(benzyloxy)-3-methylquinolin-2-yl]methyl 4-(3-phenylpropanoyl)piperazine-1-carboxylate (405 mg).
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:14]([CH3:23])=[C:13]2[C:24]1[C:33]2[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1.[C:35]([OH:38])(=[O:37])[CH3:36]>ClCCCl>[C:35]([O:38][CH2:23][C:14]1[N:15]([CH2:19][C:20]([OH:22])=[O:21])[C:16]2[C:12]([C:13]=1[C:24]1[C:33]3[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=3)[N:27]=[CH:26][CH:25]=1)=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=2)(=[O:37])[CH3:36]
Reactant: CC(=O)O
Reactant: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCCl
Product: CC(=O)OCc1c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
1-Bromo-2,5-pyrrolidinedione (50 mg) was added to a solution of the product from Example 27 step b) (0.1 g) in 1,2-dichloroethane (5 ml) and acetic acid (2 ml), and the solution stirred for 1 hour. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. After evaporation in vacuo the oily residue was treated with ether to give a solid, which was filtered and dried to yield the title compound as a white solid (40 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:28]#[N:29])=[C:23](B(O)O)[CH:24]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:28]#[N:29])=[C:21]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4](=[O:17])[CH:3]=2)[CH:20]=1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Reactant: CC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C(=O)OC(C)(C)C)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
2.4 g (purity 74%, 5.9 mmol) of tert-butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 1.2 g (6.8 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 1.86 g (purity 87%, 77% of theory)