Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7][OH:8])[CH2:3][CH2:2]1.[CH3:9][CH:10]([CH3:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:28])[C:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O-:27])=[O:26])=[O:20])=[CH:14][CH:13]=1.IC1C=CC=CC=1>>[CH3:9][CH:10]([CH3:29])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:28])[C:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:4]2([N:7]=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:26])=[O:20])=[CH:16][CH:17]=1
Reactant: ON=C1CCOCC1
Reactant: CC(C)Cc1ccc(C(C)C(=O)OCCCC(=O)[O-])cc1
Solvent: Ic1ccccc1
Product: CC(C)Cc1ccc(C(C)C(=O)OCCCC(=O)OC2(N=O)CCOCC2)cc1

Procedure:
4-Nitrosotetrahydro-2H-pyran-4-yl 4-({2-[4-(2-methylpropyl)phenyl]propanoyl}oxy)butanoate was prepared from tetrahydropyran-4-one oxime and bis 4-({2-[4-(2methylpropyl)phenyl]propanoyl}oxy)butanoate)iodobenzene (synthesized from 4-({2-[4-(2-methylpropyl)phenyl]propanoyl}oxy)butanoic acid and iodobenzene diacetate) and using conditions of General Method 4. 1H NMR (250 MHz, CHLOROFORM-d) δ 7.16-7.25 (2H, m), 7.03-7.14 (2H, m), 4.15 (2H, dt, 12.3, 6.2 Hz), 3.98-4.09 (2H, m), 3.59-3.79 (3H, m), 2.40-2.53 (4H, m), 2.27-2.37 (1H, m), 2.11-2.28 (1H, m), 1.74-2.07 (5H, m), 1.50 (3H, dd, 7.2, 4.3 Hz), 0.90 (6H, d, 6.2 Hz).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[C:20]1([O:26][CH3:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl.CN(C=O)C>[CH3:27][O:26][C:20]1[CH:25]=[CH:24][C:23]([C:9]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: COc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
4-(Methylsulfonyl)benzoic acid (0.5 g, 2.42 mmol) was suspended in CH2Cl2 (15 mL). Oxalyl chloride (0.44 mL, 4.85 mmol) was added dropwise, followed by addition of two drops of DMF. The reaction mixture was stirred at room temperature for 3 h. CH2Cl2 and the excess of oxalyl chloride were removed under vacuum. The residue was dissolved in CH2Cl2 (10 mL) with anisole (0.54 mL, 4.84 mmol). Cooled in an ice bath, aluminum chloride (0.49 g, 3.63 mmol) was added in portions. The mixture was stirred at 0° C. for 2 h, then heated at reflux overnight. Cooled to room temperature, the mixture was poured into 1N HCl (15 mL) with ice, the pinkish solid was collected and washed with water, hexanes and dried to give 0.50 g (71%) of the title compound (92) as light pink solid. 1H NMR (400 MHz, DMSO-d6): δ 3.28 (s, 3H), 3.85 (s, 3H), 7.09 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 8.07 (d, J=8.2 Hz, 2H). LCMS (ESI): m/z 291 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([C:35]([CH3:40])([CH3:39])[CH:36]([CH3:38])[CH3:37])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[O:28])[CH2:14][CH2:13][C@H:12]([CH2:29]O)[CH2:11][O:10][C:9](=[O:31])[C:8]=2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:87]=[N+:88]=[N-:89])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:87]([CH2:29][C@@H:12]1[CH2:11][O:10][C:9](=[O:31])[C:8]2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=[C:4]([O:3][Si:2]([CH3:1])([CH3:41])[C:35]([CH3:40])([CH3:39])[CH:36]([CH3:37])[CH3:38])[C:21]=2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]2[O:26][N:25]=[C:24]([CH3:27])[N:23]=2)[NH:16][C:15](=[O:28])[CH2:14][CH2:13]1)=[N+:88]=[N-:89]
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@@H](CO)CCC(=O)N[C@H](c1nc(C)no1)CSC2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@@H](CN=[N+]=[N-])CCC(=O)N[C@H](c1nc(C)no1)CSC2
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of 140 mg of (4R,9R)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-9-hydroxymethyl-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-6,12-dione and 121 mg of triphenyl-phosphine in 2 ml of tetrahydrofuran were added at 0° C. 80 mg of diethyl azodicarboxylate and 127 mg of diphenylphosphoryl azide. The mixture was stirred at 0° C. for 35 min and then evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent, to yield (4R,9R)-9-azidomethyl-16-[dimethyl-(1,1,2 -trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl -4-(3-methyl-1,2,4-oxadiazol-5-yl)-1,3,4,5, 6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin -6,12-dione as a foam
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[C:8]([CH3:15])([CH2:11][C:12]([CH3:14])=[CH2:13])[CH2:9][OH:10].CC1C=CC(S(O)(=O)=O)=CC=1>CCCCCCC>[CH3:13][C:12]1([CH3:14])[CH2:11][C:8]([CH3:15])([CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[C:2]2([CH3:16])[CH3:1])[CH2:9][O:10]1
Reactant: C=C(C)CC(C)(CO)C1CC=C(C)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Product: CC1=CCC(C2(C)COC(C)(C)C2)C1(C)C
Yield: 96.8 %

Procedure:
A 1 liter 3 neck round bottomed flask was charged with 600 ml of heptane, 155.3 g of 2-(2,2,3-trimethylcyclopent-3-en-1-yl)-2,4-dimethyl-4-pentenol at 97.7% (0.68 mole) and 0.9 g of p-TSA. The batch was refluxed under nitrogen for 26 hours. Then batch was cooled and washed with 500 ml of 10% sodium carbonate, 500 ml of water and 500 ml of brine. The batch was dried with magnesium sulfate, filtered, and concentrated in vacuo to afford 163.3 g of crude product. Distillation of the product afforded 150.3 g of purified product (92.7%). BP 84° C./0.5 mmHg; 1H-NMR (300 MHz), δ0.92 (3H, s), 1.10 (3H, s), 1.20 (3H, s), 1.25 (3H, s), 1.33 (3H, s), 1.55 (4H, sharp m), 1.81-1.99 (2H, m), 2.16 (2H, br m), 3.60 (2H, AB quintet J=8.7 Hz), 5.24 (1H, s); 13C-NMR (75 MHz), δ12.35, 22.03, 24.57, 25.66, 28.69, 29.96, 32.48, 47.38, 48.36, 50.58, 57.22, 77.63, 80.60, 121.20, 148.01; IR (Neat), 3020, 2980, 1450, 1060 cm-1 ; MS (m/e), 222 (M+), 207, 191, 95, 43;
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:18]=[C:17](Cl)[S:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[O:38])=[N:28]1.C(N(CC)CC)C.O>CN(C)C=O>[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]([NH:36][C:37]([N:39]2[CH2:44][CH2:43][N:42]([C:17]3[S:16][N:15]=[C:14]([N:11]4[CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9][CH2:10]4)[N:18]=3)[CH2:41][CH2:40]2)=[O:38])=[N:28]1
Reactant: Clc1nc(N2CCN(Cc3ccccc3)CC2)ns1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(N3CCN(Cc4ccccc4)CC3)ns2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 1-benzyl-4-(5-chloro-1,2,4-thiadiazol-3-yl)piperazine (500 mg, 1.70 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (612 mg, 1.70 mmol) in N,N-dimethylformamide (5 ml) was added triethylamine (1.18 ml, 8.50 mmol) at room temperature, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give 347 mg (40.5%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:10]2([CH3:21])[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[O:13][C:12]([NH2:20])=[N:11]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH2:31])=[O:30])=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O1CCOCC1>[NH2:20][C:12]1[O:13][C@H:14]([C:16]([F:19])([F:18])[F:17])[CH2:15][C@:10]([C:4]2[CH:3]=[C:2]([NH:31][C:29](=[O:30])[C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=3)[CH:7]=[N:6][C:5]=2[O:8][CH3:9])([CH3:21])[N:11]=1
Reactant: NC(=O)c1ccc(Cl)cn1
Reactant: COc1ncc(Br)cc1[C@]1(C)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(NC(=O)c2ccc(Cl)cn2)cc1[C@]1(C)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 120 °C
Yield: 23.9 %

Procedure:
A microwave vial was charged with (4S,6S)-4-(5-bromo-2-methoxypyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.100 g, 0.272 mmol), 5-chloropicolinamide (0.064 g, 0.407 mmol), copper(I) iodide (10.35 mg, 0.054 mmol) and potassium carbonate powder (0.113 g, 0.815 mmol). The vial was purged with nitrogen followed by the addition of 1,4-dioxane 1 mL and (1R,2R)-(−)-N,N″-dimethylcyclohexane-1,2-diamine (0.043 ml, 0.272 mmol). The vial was sealed and heated at 120° C. overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc three times. The organic layers were combined, washed with brine and dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 15-85% EtOAc/hexane to give N-(5-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-6-methoxypyridin-3-yl)-5-chloropicolinamide (0.029 g, 0.065 mmol, 24.06% yield). MS m/z=443.9 [M+H]+. Calculated for C18H17ClF3N5O3: 443.8
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][C:14]([CH3:16])=[O:15].C(OC(=O)C)C>C1COCC1.CCCCCC>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[C:14]([OH:15])([CH3:16])[CH3:13]
Reactant: CC(C)=O
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccncc1Br
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
n-Butyl Lithium (10.28 mL, 16.455 mmol) was added to a solution of DIPA (2.66 mL, 18.98 mmol) in THF (25 mL) at -78° C. The reaction mixture was stirred at -10° C. for 10 mins, followed by the addition of 3-bromo-pyridine (500 mg, 2.212 mmol) in THF (10 mL) at -100° C. The reaction mixture was stirred for a further 15 minutes at -90° C. and was followed by the addition of acetone (1.675 mL, 22.78 mmol) in THF (10 mL) at -78° C. with stirring over a period of 1 hr. The reaction was monitored by TLC (5% ethylacetate in hexane). The reaction mixture was quenched with aqueous NaHCO3 solution and extracted with ethylacetate. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (15% ethylacetate in hexane) afforded 200 mg of the product (11% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][C@H:13]([S:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH2:35]O)=[N:8][CH:9]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:56]1(=[O:66])[NH:60][C:59](=[O:61])[C:58]2=[CH:62][CH:63]=[CH:64][CH:65]=[C:57]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:14][C@H:13]([S:15][C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH2:35][N:60]2[C:56](=[O:66])[C:57]3[C:58](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:59]2=[O:61])=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CO)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cnc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN2C(=O)c3ccccc3C2=O)nc1
Temperature: 0 °C
Yield: 96 %

Procedure:
1.0 g (2.0 mmol) (2S,4R)-[1-(5-Propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methanol in 15 ml THF were treated with 764 mg (2.82 mmol) triphenyl phosphine and 420 mg (2.82 mmol) phthalimide at RT. The solution was cooled to 0° C. and 615 μl (3.83 mmol) diethylazo dicarboxylate in 3 ml THF were added. The solution was stirred at RT over night, H2O was added and the inorganic layer was extracted with ETOAc. The combined layers were washed with 1M NaOH, sat. NaHCO3 solution and brine, and were dried over Na2SO4. Column chromatography with EtOAc:hexane 1:2 as eluent yielded 1.20 g (95%) (2S,4R)-2-[1-(5-Propyl-pyrimidin-2-yl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl]-isoindole-1,3-dione as white solid, MS: 625 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)=[O:4].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH2:2][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[N:6][CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CBr)c1ncc(Cl)cc1Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 8.6 %

Procedure:
To 3.00 g of the 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone prepared in Step 2 in Synthetic Example 2 in 30 ml of N,N-dimethylformamide, 4.13 g of potassium phthalimide was added, and the mixture was stirred at 80° C. for 3 hours and then at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 150 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was mixed with 40 ml of a mixture of diisopropyl ether and hexane (1:1), the insolubles were filtered off, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 15:85 to 25:75) as the eluent to obtain 0.32 g of the desired product as a dark brown resinous substance.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:1][CH2:2][CH:3]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(F)cc3)cc2)C1

Procedure:
The procedure is the same as for Example 1 (Stage 1.2) starting from 1.50 g (7.45 mmol) of tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (commercial), 2.15 g (11.18 mmol) of 4′-fluorobiphenyl-4-ol, 2.93 g (11.18 mmol) of triphenylphosphine and 2.26 g (11.18 mmol) of diisopropyl azodicarboxylate. After purification by chromatography on a column of silica gel, elution being carried out with dichloromethane, 1.55 g of the expected product are obtained in the form of an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1[C:15]2([CH2:20][CH2:19][CH2:18][CH:17]([C:21]([N:23]3[CH2:28][CH:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=O)[CH2:16]2)[O:14]CC1>C(OCC)C.O1CCCC1>[C:29]1([C:26]2[CH2:27][CH2:28][N:23]([CH2:21][CH:17]3[CH2:18][CH2:19][CH2:20][C:15](=[O:14])[CH2:16]3)[CH2:24][CH:25]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(C1CCCC2(C1)OCCO2)N1CC=C(c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CCCC(CN2CC=C(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of aluminum chloride (14.54 g) in 500 mL of anhydrous diethyl ether is added dropwise to a suspension of lithium aluminum hydride (12.4 g) in 500 mL of tetrahydrofuran. The mixture is stirred at room temperature for 30 minutes. A solution of 1-(1,4-dioxaspiro[4.5]dec-7-yl carbonyl)-1,2,3,6-tetrahydro-4-phenylpyridine (Step B) in 500 mL of tetrahydrofuran is added dropwise. The mixture is stirred at room temperature overnight, and it is quenched by careful addition of 13 mL of water, followed by 59 mL of 25% aqueous sodium hydroxide solution. The resulting mixture is stirred at room temperature for 2 hours, filtered through celite, and concentrated in vacuo. The title compound is obtained (90.40 g) as a light yellow oil (silica; Rf =0.2; 1% methanol, 99% chloroform).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[C:5]([CH3:19])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:7]2.Cl[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([NH2:44])[N:38]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[NH2:44][C:39]1[N:38]=[C:37]([C:23]2[CH:22]=[C:21]([NH:20][C:4]3[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[N:7]=[C:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:5]=3[CH3:19])[C:26]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:25][CH:24]=2)[CH:42]=[C:41]([CH3:43])[N:40]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(B(O)O)cnc1N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cnc(N3CCOCC3)c(Nc3c(C)c(-c4ccccn4)nc4cc(F)cc(F)c34)c2)nc(N)n1
Temperature: 120 °C

Procedure:
A solution of 5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-6-morpholinopyridin-3-ylboronic acid (0.026 mmol, described herein), 4-chloro-6-methylpyrimidin-2-amine (3.7 mg, 0.026 mmol), sodium carbonate (8.18 mg, 0.077 mmol), dichlorobis(triphenylphosphine)palladium(ii) (1.8 mg, 2.57 μmol), 1,4-dioxane (560 μL) and water (140 μL) heated in a microwave at 120° C. for 60 min. The reaction was then cooled to rt and partitioned between EtOAc and water. The organic layer was dried (magnesium sulfate) and concentrated, and chromatography afforded N-(5-(2-amino-6-methyl-4-pyrimidinyl)-2-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.72-8.81 (1H, m), 8.52-8.61 (1H, m), 7.85-7.96 (2H, m), 7.61-7.71 (1H, m), 7.52-7.61 (1H, m), 7.47-7.52 (1H, m), 7.41 (1H, m), 7.03 (1H, m), 6.84-6.93 (1H, m), 5.22 (2H, br. s.), 3.94 (4H, br. s.), 3.45-3.73 (2H, m), 3.00-3.40 (2H, br. s.), 2.33-2.52 (3H, m), 2.15-2.29 (3H, m). Mass Spectrum (ESI) m/e=541.0 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.Br[CH2:24][C:25]#[N:26].Cl>O1CCCC1.C(OCC)(=O)C>[C:25]([CH2:24][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)[C:19]([O:21][CH3:22])=[O:20])#[N:26]
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: N#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To lithium bis(trimethylsilyl)amide (1.0 Min tetrahydrofuran) (18.73 mL, 18.73 mmol) at −78° C. was added methyl 2-(4-fluorophenyl)acetate (3.00 g, 17.84 mmol) as a solution in tetrahydrofuran (5 mL) dropwise. During the addition, a white solid precipitated. After the addition, the reaction was placed in an ice bath and stirred for 1 hour. 2-Bromoacetonitrile (2.354 g, 19.62 mmol) was added as a solution in tetrahydrofuran (2 mL) and the reaction was allowed to stir for an additional 1 hour. The reaction was poured into a mixture of 1 N HCl (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate and concentrate. The resulting reside was chromatographed over silica gel (SF40-115, Analogix®) eluting with a gradient of 5% to 50% ethyl acetate/hexanes (Flow=85 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.31-7.19 (m, 2H), 7.13-7.01 (m, 2H), 3.93 (t, J=7.6, 1H), 3.73 (s, 3H), 3.02 (dd, J=7.2, 16.8, 1H), 2.81 (dd, J=8.0, 16.9, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2[CH3:20])[CH:5]=[N:4][C:3]=1[C:21]#[N:22].Cl.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:42]#[N:43])[CH2:36][CH2:35][N:34]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2[CH3:20])=[N:7][C:2]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:42]#[N:43])[CH2:36][CH2:35][N:34]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)#[N:22]
Reactant: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1c1cnc(C#N)c(Cl)n1
Reactant: N#CC1(c2ccc(N)cc2)CCN(C2CCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1c1cnc(C#N)c(Nc2ccc(C3(C#N)CCN(C4CCCC4)CC3)cc2)n1
Temperature: 115 °C
Reaction time: 2.5 h

Procedure:
The mixture of 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (100 mg, 0.31 mmol), 4-(4-aminophenyl)-1-cyclopentylpiperidine-4-carbonitrile hydrochloride (350) (114 mg, 0.37 mmol), fine-powder cesium carbonate (400 mg, 1.24 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), BINAP (62 mg, 0.1 mmol) in 20 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2.5 hours. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 10% MeOH in chloroform to isolate 3-((2R,3R)-1-(5-cyano-6-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (351). It was dissolved in 10 mL MeOH and 1 mL DMSO. To it were added one NaOH solid bead (about 100 mg), DIEA (60 μL), and then 1 mL 30% H2O2. The mixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was acidified with TFA (0.5 mL) and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide (352) as HCl salt (22 mg). LC-MS (ESI): adz (M+1) 574.6. UV: λ=270, 281, 309, 336, 371 nm. Proton NMR (CD3OD): δ 7.78 (2H, d, J=9.0 Hz), 7.67 (1H, s), 7.49 (2H, d, J=8.5 Hz), 5.09 (1H, m), 4.28 (1H, m), 3.88 (3H, m), 3.69 (1H, m), 3.36 (2H, m), 3.09 (1H, m), 2.97 (6H, s), 2.51 (2H, m), 2.40 (2H, m), 2.26 (2H, m), 1.89 (4H, m), 1.86-1.66 (6H, m), 1.17 (3H, d, J=6.5 Hz) ppm. Compound 353, 3-(4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide, was also found and isolated as a major by-product in the final step.