Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:7]=1.[Zn](C)[CH3:29]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:23]([CH:22]([CH2:25][CH3:26])[CH2:21][O:20][C:14]1[CH:15]=[CH:16][C:17]([CH3:29])=[CH:18][C:13]=1[CH2:12][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[N:7]1)[CH3:24]
Reactant: CCC(CC)COc1ccc(Br)cc1Cn1nc(CCC(=O)OC)cc1C
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCC(CC)COc1ccc(C)cc1Cn1nc(CCC(=O)O)cc1C
Temperature: 105 °C

Procedure:
A mixture of 3-{1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yl}-propionic acid methyl ester (0.1363 g, 0.31 mmol), Pd(dppf)Cl2 (0.00506 g, 0.00621 mmol), Zn(CH3)2 (0.31 mlg, 0.62 mmol in 1,4-dioxane (0.93 ml) heated at 105° C. under a N2 atmosphere for 1 h 50 min. The mixture was cooled to RT, quenched with MeOH (0.2 ml) and partitioned between 1 M HCl and EtOAc. The organic layer was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was converted to the title compound following the method in Example 1, Step 8.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Nc1cccc(O)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
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: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of the (4-adamantan-1-yl-phenoxy)-acetic acid (85.9 mg, 0.3 mmol) and 3-amino-phenol (65.5 mg, 0.6 mmol) in DMF (5.0 mL) were added benzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (312.2 mg, 0.6 mmol), and N,N-diisopropylethylamine (DIPEA) (0.11 ml, 0.6 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (n-Hexane:EtOAc:MeOH=15:3:1) gave 2-(4-Adamantan-1-yl-phenoxy)-N-(3-hydroxyl-phenyl)acetamide as a white solid (67.6 mg, 59.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.C(OC([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:34]3[CH:35]=[N:31][NH:32][CH:33]=3)=[CH:17][C:9]1=2
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(-c3cn[nH]c3)cc21
Yield: 44 %

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (109 mg) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylic acid-tert-butyl ester as in General Procedure 4B, then added 6 mL CH2Cl2 and TFA (0.6 mL), and purified on normal phase silica gel chromatography to give the title compound as an off-white solid (44% yield). m.p.=271° C., LCMS: m/z=394.24 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.50 (2H, m), 3.66 (2H, m), 4.05 (3H, s), 4.61 (2H, s), 6.50 (1H, d, J=1.5 Hz), 7.40 (1H, s), 7.50 (1H, s), 7.56 (3H, m), 7.68 (1H, d, J=8.6 Hz).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].CO[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[O:10][CH3:11].C(N(CC)CC)C>CCCCCC>[Cl:1][C:2]1[C:3](=[O:4])[C:9]([O:10][CH3:11])([O:12][CH3:13])[C:8]=1[O:14][CH3:15]
Reactant: COC(OC)=C(OC)OC
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC1=C(Cl)C(=O)C1(OC)OC
Temperature: 20 °C
Reaction time: 3 h
Yield: 0.5 %

Procedure:
A solution of 23.7 g (0.21 mole) of chloroacetyl chloride is added dropwise, in the course of 40 minutes, to a solution, cooled to 0°-5° C. and vigorously stirred, of 14.8 g (0.1 mole) of 1,1,2,2-tetramethoxyethylene and 23.2 g (0.23 mole) of triethylamine in 100 ml of absolute n-hexane. The greyish-brown suspension formed is stirred for 3 hours at 20° C.; the resulting salt is then filtered off with suction and washed with n-hexane, and the yellow filtrate is concentrated by evaporation. The intensive IR-absorption bands of the residue (30.4 g) confirm the formation of 2-chloro-3,3,4,4-tetramethoxy-1-chloroacetoxycyclobutene (5.71μ) and 2-chloro-3,4,4-trimethoxycyclobutenone (5.58; 6.1μ). According to the NMR spectrum, the reaction mixture contains 80±5% by weight of 2-chloro-3,3,4,4,-tetramethoxy-1-chloroacetoxybutene and 12±3% by weight of 2-chloro-3,4,4-trimethoxycyclobutenone, besides small amounts of unidentifiable by-products. By rapid separation by columnchromatography of 0.5 g of the crude residue, it is possible to obtain 0.1 g of pure 2-chloro-3,4,4-trimethoxycyclobutenone (eluant: hexane/diethyl ether in a volume ratio of 4:1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[CH3:27][O:28][CH:29]([O:49][CH3:50])[C:30]1[C:39]([CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][C:42]2=[O:48])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:11]([NH:10][C:8]1[C:5]([C:6]#[N:7])=[CH:4][N:3]=[C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([CH2:40][N:41]4[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][C:42]4=[O:48])=[C:30]([CH:29]([O:49][CH3:50])[O:28][CH3:27])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])[CH:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)Nc1cc(N)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2
Reactant: O=C(n1cncn1)n1cncn1
Solvent: CN(C)C=O
Product: COC(OC)c1nc2c(cc1CN1CCN(C)CC1=O)CCCN2C(=O)Nc1cc(NC(C)(C)C)c(C#N)cn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of 6-amino-4-(tert-butylamino)nicotinonitrile (intermediate 197, 402 mg, 1.794 mmol) in anhydrous DMF (3 ml) was added drop wise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (327 mg, 1.794 mmol) and DMF (3 ml) cooled at 0° C. After stirring for 45 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and a solution 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-4-methylpiperazin-2-one (intermediate 81, 300 mg, 0.897 mmol) in DMF (3 ml) was added. The reaction mixture was stirred for approximately 7 h at room temperature, quenched by the addition of MeOH and concentrated. The residue was diluted with EtOAc and water, filtered to remove insoluble byproducts. Phases were separated and the aqueous layer was washed with EtOAc. The organic layers were combined, washed with brine, dried using Na2SO4, filtered and evaporated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (0-3%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a yellow solid. (UPLC-MS 3) tR 0.93 min, ESI-MS 551.4 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 13.68 (s, 1H), 8.17 (s, 1H), 7.88 (s, 1H), 7.47 (s, 1H), 5.42 (s, 1H), 4.89 (s, 1H), 4.85 (s, 2H), 4.05-4.00 (m, 2H), 3.48 (s, 6H), 3.30 (br s, 2H), 3.25 (br s, 2H), 2.82 (t, 2H), 2.66 (br s, 2H), 2.39 (br s, 3H), 2.00-1.93 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4].[I-].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O.O1CCCC1>[CH2:28]([O:4][C:3]1[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][CH:10]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: Oc1cccc(O)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1cccc(O)c1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
To a suspension of 29.6 g of sodium hydride in 215 ml of N,N-dimethylformamide was added dropwise over 1.5 hours a solution of 54.33 g of resorcinol in 145 ml of N,N-dimethylformamide and 72 ml of tetrahydrofuran. The resulting mixture was cooled to 0° C. and 7.4 g of sodium iodide added followed by the dropwise addition of 155.0 g of hexadecylbromide over 1 hour. The bath was removed and the mixture stirred at ambient temperature for 17 hours. The mixture was diluted with 500 ml of iced dilute hydrochloric acid, extracted with ether and filtered. The ether layer was dried over magnesium sulfate and evaporated to an oil which was purified by chromatography on silica gel using ethyl acetate-hexanes giving 37.2 g of the desired compound as a white solid, m.p. 58°-59° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CS(O[CH:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH2:20]1)(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH2:20]1
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc(OC2CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4.5 grams (0.028 mole) of 3-trifluoromethylphenol and 1.1 grams (0.028 mole) of sodium hydride (60% in mineral oil) in 100 mL of toluene is stirred at ambient temperature for about 20 minutes, and a solution of 6.6 grams (0.028 mole) of 8-methylsulfonyloxy-1,4-dioxaspiro[4.5]decane (prepared as in Step C of Example 8) in 20 mL of toluene is added dropwise. Upon complete addition, the reaction mixture is heated to reflux where it is stirred for about four hours. The reaction mixture is cooled and concentrated under reduced pressure, yielding 8-(3-trifluoromethylphenoxy)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.O.[Cu]>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(I)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2ccc3ccccc32)cc1
Temperature: 150 °C
Yield: 79.1 %

Procedure:
A mixture of 1-H-indole (58.5 mg, 0.500 mmol), 1-iodo-4-methylbenzene (0.218 g, 1.00 mmol), copper powder (32.0 mg, 0.500 mmol), and K2CO3 (0.138 g, 1.00 mmol) in 1-methyl-2-pyrrolidinone (1.00 mL) was heated at 150° C. for 12 h under argon. The resulting mixture was diluted with H2O (6 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc:hexane (1:4) to give the desired product (82.0 mg, 79.0%): 1H NMR (400 MHz, CDCl3) δ 7.67 (d, 1H, J=7.7 Hz), 7.52 (d, 1H, J=7.4 Hz), 7.38 (d, 2H, J=8.4 Hz), 7.34-7.29 (m, 3H), 7.21 (t, 1H, J=7.0 Hz), 7.15 (t, 1H, J=7.0 Hz), 6.66 (d, 1H, J=3.3 Hz), 2.43 (s, 3H); ESMS m/e: 208.0 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[N:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=[C:11]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:33][NH2:34]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:33][N:34]=[C:11]([NH:10][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=4)[C:7]=3[CH2:8][C:2]1=2
Reactant: NN
Reactant: O=C1CCc2sccc21
Reactant: COc1ccc(N=C=S)cc1OC
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2n[nH]c3c2Cc2sccc2-3)cc1OC
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 4-Isothiocyanato-1,2-dimethoxy-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(3,4-dimethoxy-phenyl)-amine as brown solid in 30% yield.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:23](=[O:29])OC(Cl)(Cl)Cl)Cl.C[O:32][C:33](=O)[C:34]([NH2:37])([CH3:36])[CH3:35].Cl>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[N:4]1[C:33](=[O:32])[C:34]([CH3:36])([CH3:35])[NH:37][C:23]1=[O:29]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Br)c(N)cc1Cl
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(Br)c(N2C(=O)NC(C)(C)C2=O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 118 %

Procedure:
To a solution of 0.60 g (2.54 mmol) 2-bromo-5-chloro-4-methoxy aniline and 0.88 ml (6.35 mmol) triethylamine in 20 ml chloroform was added 0.30 g (1.0 mmol) triphosgene at room temperature. The reaction mixture was stirred for 5 hours at r.t., then 0.47 g (3.0 mmol) 2-Amino-2-methyl-propionic acid methyl ester×HCl was added and the mixture was stirred at 60° C. overnight. The reaction was quenched with NaHCO3 solution, extracted into ethyl acetate. The organic phase was dried, evaporated and the product was purified by RP-HPLC to give 0.41 g (47%) of the desired hydantoin.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)=[O:11])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(CNC(=O)c1ccc(Cl)cc1)c1ccoc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccoc1
Yield: 77.2 %

Procedure:
8.3 g of N-(4-chlorobenzoyl)-(3-furylcarbonyl)methylamine, 1.5 g of 61% sodium hydride and 5.8 g of ethyl bromoacetate are treated in the same manner as described in Preparation 1-(2). 8.5 g of ethyl 3-(4-chlorobenzoylamino)-3-(3-furylcarbonyl)propionate are thereby obtained. Yield: 77.3%
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][C:14]([NH:23][C:24]4[N:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])[C:27]([Cl:43])=[CH:26][N:25]=4)=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:16]=3)[C:11]2=[O:44])[CH2:7][NH:6]1)=O.CO.[NH3:47]>>[Cl:43][C:27]1[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[S:37]([CH:40]([CH3:41])[CH3:42])(=[O:39])=[O:38])=[N:29][C:24]([NH:23][C:14]2[CH:13]=[C:12]3[C:17]([CH2:18][N:10]([C@@H:8]4[CH2:7][NH:6][C@H:5]([C:3]([NH2:47])=[O:2])[CH2:9]4)[C:11]3=[O:44])=[CH:16][C:15]=2[O:19][CH:20]([CH3:21])[CH3:22])=[N:25][CH:26]=1
Reactant: N
Reactant: COC(=O)[C@@H]1C[C@H](N2Cc3cc(OC(C)C)c(Nc4ncc(Cl)c(Nc5ccccc5S(=O)(=O)C(C)C)n4)cc3C2=O)CN1
Solvent: CO
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N([C@@H]1CN[C@H](C(N)=O)C1)C2
Temperature: 25 °C

Procedure:
(2S,4S)-4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-pyrrolidine-2-carboxylic acid methyl ester generated in Step 1 (20 mg, 0.03 mmol) is dissolved in 7 N ammonia solution in MeOH (3 mL, 21 mmol). The resulting solution is heated using microwave irradiation to 120° C. for 1 h. After cooling to room temperature, the reaction mixture is concentrated in vacuo, neutralized to pH=8 with saturated aqueous NaHCO3, and extracted with DCM. The organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo to give (2S,4S)-4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-pyrrolidine-2-carboxylic acid amide (177) as a yellow solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.47 (d, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.78 (dd, 1H), 7.68 (m, 1H), 7.31 (t, 1H), 7.24 (s, 1H), 4.71 (m, 2H), 4.43 (dd, 2H), 3.60 (m, 1H), 3.44 (m, 1H), 3.35 (m, 1H), 2.63 (m, 1H), 2.28 (m, 1H), 1.22 (d, 6H), 1.10 (d, 6H); MS m/z 628 (M+1).
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17]([NH:19][NH2:20])=[O:18])[C:13]=1[CH2:14][CH3:15]>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[O:8][C:9]1[C:10]([CH2:21][CH3:22])=[N:11][N:12]([CH2:16][C:17]2[O:18][C:2]([NH2:1])=[N:20][N:19]=2)[C:13]=1[CH2:14][CH3:15]
Reactant: N#CBr
Reactant: CCc1nn(CC(=O)NN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Solvent: CCO
Product: CCc1nn(Cc2nnc(N)o2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 44.2 %

Procedure:
Cyanogen bromide (49 mg, 0.462 mmol) was added to a stirred solution of the hydrazide of Example 11 (150 mg, 0.420 mmol) in ethanol (30 ml), at room temperature, under nitrogen and the resulting solution was heated to reflux for 2.5 hours. After cooling, the mixture was concentrated under reduced pressure to leave a brown oil. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:1.75:0.25, by volume) to provide the title compound (71 mg) as a white powder, m.p. 226–228° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C=C[NH+]=CC=1.[O-:37][Cr](Cl)(=O)=O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:21]3[CH:16]([CH2:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:37])[CH2:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Agent: B1C2CCCC1CCC2
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C1CC=CC=C12
Temperature: 70 °C
Yield: 46.5 %

Procedure:
To a solution of 661 mg (2.31 mmol) of 1'-(t-butyloxycarbonyl)spiro[1H-indene-1,4'-piperidine] [prepared by the method of Chambers, et al, J. Med. Chem., 1992, 35, 2036] in 5.0 ml of THF was added 5.8 ml (1.0M THF, 2.9 mmol) of 9-BBN. The reaction mixture was heated at 70° C. until TLC analysis indicated that the starting material was consumed. The solution was concentrated and the residue was dissolved in dichloromethane. The solution was cooled to 0° C. and 4.1 g (19.2 mmol) of PCC was added slowly over 15 minutes. The reaction mixture was warmed to room temperature and then to reflux for 30 minutes. The solution was then diluted with ether and filtered through a pad of a mixture of celite and florisil. Purification by flash chromotography (silica gel, hexane/ethyl acetate, 4:1) gave 326 mg (47%) of the title compound.
Reaction SMILES: CO.CN(C)C[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1.[CH3:17][NH:18][CH3:19].C1C(=O)CC2C(=CC=CC=2)C1>O1CCCC1>[CH3:17][N:18]([CH3:19])[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: CNC
Reactant: CN(C)CC1CCc2ccccc2C1
Agent: O=C1CCc2ccccc2C1
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C1CCc2ccccc2C1
Temperature: 25 °C

Procedure:
46 ml of a methanol solution of 0.3 M sodium cyanoborohydride-1/2 zinc chloride and 6.9 mL of a tetrahydrofuran solution of 2 M dimethylamine were added to a tetrahydrofuran (10 mL) solution of 2.02 g of β-tetralone, and stirred for a day at room temperature. The reaction liquid was concentrated, and 1 N hydrochloric acid was added thereto. The acidic solution was washed with ethyl acetate, then made alkaline with aqueous 5 M sodium hydroxide solution, and extracted with ethyl acetate. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated away to obtain 857 mg of the entitled compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:26](O)=[O:27])[NH:11][C:12](=[O:25])[C:13]([CH3:24])([CH3:23])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH2:35])[CH3:31].ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O.CN1CCOCC1>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH:35][C:26](=[O:27])[C@@H:10]([CH2:9][S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:11][C:12](=[O:25])[C:13]([CH3:23])([CH3:24])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:31]
Reactant: CC(C)(CSCc1ccccc1)C(=O)N[C@H](CSCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)[C@@H](CSCc1ccccc1)NC(=O)C(C)(C)CSCc1ccccc1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a stirred solution of S-benzyl-N-(3-benzylthio-2,2-dimethyl-propionyl)-D-cysteine (0.32 g) and glycine ethyl ester hydro-chloride (0.12 g) in N,N-dimethylformamide (DMF, 3 ml), N-methylmorpholine (NMM, 0.19 ml), 1-hydroxybenzotriazole (HOBt, 0.17 g) and then a solution of N,N,-dicyclohexylcarbodiimide (DCC, 0.18 g) in DMF (2 ml) were added under ice cooling. The mixture was stirred for 2 hr. at 0° C. and for 2 hr. at room temperature, and stood overnight. 1 N hydrochloric acid (30 ml) was added into the reaction mixture and the mixture was extracted with ether. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 0.35 g (91%) of the titled compound.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:10])[CH2:4][CH2:5][CH2:6][C:7](=[CH2:9])[CH3:8].Cl[CH2:12][C:13]([CH2:15][CH2:16][CH2:17][C:18](=[CH2:21])[CH:19]=[CH2:20])=[CH2:14].CC(C)([Mg]Cl)CCCCCCC>>[CH2:10]=[C:3]([CH2:4][CH2:5][CH2:6][C:7](=[CH2:8])[CH2:9][CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16][CH2:15][CH:13]([CH3:14])[CH3:12])[CH:2]=[CH2:1]
Reactant: C=CC(=C)CCCC(=C)C
Reactant: C=CC(=C)CCCC(=C)CCl
Agent: CCCCCCCC(C)(C)[Mg]Cl
Product: C=CC(=C)CCCC(=C)CCCC(C)CCCC(C)C

Procedure:
Alpha-myrcene (6-methylene-2-methylocta-1,7-diene) is chlorinated to 2-chloromethyl-6-methyleneocta-1,7-diene. This is reacted with dimethyloctyl magnesium chloride to produce 3,7-dimethylene-11,15-dimethylhexadec-1-ene. This compound yields 7-methylene-3,11,15-trimethylhexadec-2-en-1-ol which, when reacted with TMHQ and hydrogenated, produces Vitamin E.