Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:27](Cl)(=[O:35])[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:28]([C:27]([N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2ccncc2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N(C(=O)Oc2ccccc2)c2ccccc2/C=C/c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.00 g of (E)-4-[2-{2-[N-(4-methoxybenzenesulfonyl)amino]phenyl}ethenyl]pyridine was suspended in 40 ml of chloroform and, after adding 1.82 g of phenyl chlorocarbonate, 1.20 g of triethylamine was slowly added under ice cooling. Then, the mixture was stirred at room temperature for 5 minutes. The solvent was distilled off under reduced pressure and the desired product was purified by silica gel column (carrier: Wako Gel C200, developing solvent chloroform) to obtain the desired compound. The desired compound was treated with ethanol to obtain 0.71 g of a white granular crystal.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]6[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=56)[CH:23]=[CH:22][N:21]=4)=[C:12]([O:35][CH3:36])[CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[C:12]([O:35][CH3:36])[C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]6[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=56)[CH:23]=[CH:22][N:21]=4)=[CH:14][C:15]=3[NH2:16])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 32.6 %

Procedure:
A mixture of N-{4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 133, 400 mg, 0.82 mmol), iron (273 mg, 4.89 mmol) and NH4Cl (30.5 mg, 0.57 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 4 h and then stirred at r.t.overnight. Part-purification by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia provided crude material that was concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 provided impure product as a brown gum. Further purification by FCC, eluting with 0-2% 7N methanolic ammonia in CH2Cl2 provided the title compound (123 mg, 33%) as a brown gum; m/z: ES+ MH+ 461.26.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:20]2[C:19]([CH3:21])=[CH:18][C:17]([OH:22])=[CH:16][C:15]=2[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1cc(C)cc(O)c1
Product: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound is prepared by essentially following the procedures as described in Preparation 1, Procedure B, using 4-tert-butyl phenyl boronic acid and 3,5-dimethyl-phenol as starting materials.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Br.C(N(CC)CC)C.O>CN(C=O)C>[Br:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCCOCCBr
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCCOCCBr
Temperature: 45 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of N-hydroxyphthalimide (352 mg, 2.16 mmol) in 4 mL of DMF was added 2-bromoethyl ether (500 mg, 2.16 mmol) followed by triethylamine (218 mg, 2.16 mmol), and the resulting solution was stirred at 45° C. overnight. Water was added to quench the reaction, the aqueous layer was extracted with ethyl acetate for 3 times, the combined organic layers were washed with brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure, the crude product was purified by silica gel column chromatography (hexanes: ethyl acetate 2:1) to afford 2-(2-(2-bromoethoxy)ethoxy)isoindoline-1,3-dione (550 mg, 1.75 mmol, 81%) as colorless oil. 1H NMR (CDCl3, 500 MHz) δ (ppm): 3.38 (t, J=6.2 Hz, 2H), 3.81 (t, J=6.2 Hz, 2H), 3.87 (t, J=4.1 Hz, 2H), 4.37 (t, J=4.1 Hz, 2H), 7.73 (dd, J=3.0, 5.0 Hz, 2H), 7.82 (dd, J=3.2, 5.0 Hz, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([Si:15]([CH3:30])([CH3:29])[O:16][CH2:17][CH:18]([OH:28])[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:15]([O:16][CH2:17][C:18](=[O:28])[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC(O)CO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a stirring solution of oxalyl chloride (13.6 mL, 0.16 mol) in dry CH2Cl2 (150 mL) at −78° C. under N2 was added DMSO (15.2 mL, 0.21 mol) dropwise over 30 min. After complete addition the resulting solution was stirred at −78° C. for 1 h. A solution of tert-butyl 3-(tert-butyldimethyl-silyloxy)-2-hydroxypropylcarbamate (32.6 g, 0.11 mol) in CH2Cl2 (50 mL) was then added dropwise over 20 min. Stirring was continued for a further 1 hour at which time triethylamine (59.6 mL, 0.43 mol) was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was partitioned between water (100 mL) and CH2Cl2 (70 mL) and the aqueous layer was extracted with further CH2Cl2 (2×70 mL); the combined organics were dried over Na2SO4 and concentrated under a stream of nitrogen gas. The crude residue was purified over silica gel eluting with 5% ethylacetate in n-hexane to give tert-butyl 3-(tert-butyldimethylsilyloxy)-2-oxopropylcarbamate (29.8 g, 92%) as a pale yellow oil. 1H-NMR (300 MHz; CDCl3) δ ppm: 0.11 (6H, s), 0.94 (9H, s), 1.47 (9H, s), 3.92 (2H, s), 4.26 (2H, d, J 4.6 Hz), 5.22 (1H, br s).
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[O:20][CH2:19][CH2:18][NH:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Cl[C:22]1[N:23]([CH3:35])[C:24](=[O:34])[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:27]=1.C(N(CC)CC)C>O1CCCC1>[CH3:35][N:23]1[C:24](=[O:34])[CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:27]=[C:22]1[N:17]1[CH2:18][CH2:19][O:20][C@@H:15]([C:12]2[CH:11]=[CH:10][C:9]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:14][CH:13]=2)[CH2:16]1
Reactant: CN(c1ccc([C@H]2CNCCO2)cc1)c1ccccn1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1)c1ccccn1
Yield: 38.7 %

Procedure:
A solution of N-Methyl-N-(4-((2S)-morpholin-2-yl)phenyl)pyridin-2-amine (0.12 g, 0.46 mmol), 2-chloro-1-methyl-6-oxo-4-(pyridin-4-yl)-1,6-dihydropyrimidine (0.08 g, 0.37 mmol), and triethylamine (0.23 g, 2.3 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (chloroform-methanol, 10:1) to give 3-Methyl-2-((2S)-2-(4-(methyl(pyridin-2-yl)amino)phenyl)morpholin-4-yl)-6-(pyridin-4-yl)-pyrimidin-4(3H)-one (65 mg, 13%) as a yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][CH:7]([CH:13]1[CH2:18][C:17](=[O:19])[CH:16]([CH:20]([CH3:26])[CH2:21][C:22]([O:24]C)=[O:23])[CH2:15][C:14]1=[O:27])[CH2:8][C:9]([O:11]C)=[O:10]>>[CH3:26][CH:20]([CH:16]1[CH2:15][C:14](=[O:27])[CH:13]([CH:7]([CH3:6])[CH2:8][C:9]([OH:11])=[O:10])[CH2:18][C:17]1=[O:19])[CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)CC(C)C1CC(=O)C(C(C)CC(=O)OC)CC1=O
Agent: O=S(=O)(O)O
Product: CC(CC(=O)O)C1CC(=O)C(C(C)CC(=O)O)CC1=O
Yield: 87.9 %

Procedure:
In an aqueous medium in the presence of sulfuric acid as the catalyst, 3.0 g of the oil obtained in Example 4 was hydrolyzed under reflux for 8 hours. The procedure gave 2.4 g of crystals.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[CH2:27]([O:29][CH2:30][C:31](O)=[O:32])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:27]([O:29][CH2:30][C:31]([N:16]1[CH2:17][CH2:18][CH:13]([O:12][C:9]2[C:10]([CH3:11])=[C:5]([O:4][C:3]3[CH:19]=[CH:20][C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:22][C:2]=3[F:1])[N:6]=[CH:7][N:8]=2)[CH2:14][CH2:15]1)=[O:32])[CH3:28]
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Reactant: CCOCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCOCC(=O)N1CCC(Oc2ncnc(Oc3ccc(S(C)(=O)=O)cc3F)c2C)CC1
Temperature: 120 °C
Yield: 58.8 %

Procedure:
Mixture of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (76 mg, 0.2 mmole), 2-ethoxyacetic acid (0.26 mmole, 1.3 eq), HATU (0.26 mmole, 1.3 eq), and TEA (0.4 mmole, 2 eq) in 2 mL THF was heated under microwave irradiation at 120° C. for 30 minutes. Mixture was purified by HPLC to give compound C163 as a white solid (55 mg, 59%). 1H NMR (CDCl3, 400 MHz) δ 1.25 (t, 3H), 1.86-1.90 (m, 2H), 2.01-2.09 (m, 2H), 2.22 (s, 3H), 3.10 (s, 3H), 3.51-3.69 (m, 2H), 3.59 (q, 2H), 3.76-3.87 (m, 2H), 4.21 (s, 2H), 5.41-5.44 (m, 1H), 7.43 (t, 1H), 7.78-7.82 (m, 2H), 8.21 (s, 1H). Exact mass calculated for C21H26FN3O6S 467.2, found 468.5 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][OH:16].C[O-].[Na+]>O>[CH3:15][O:16][C:2]1[C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: O=C(c1cccs1)c1cccnc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ncccc1C(=O)c1cccs1
Reaction time: 0.5 h

Procedure:
A mixture of 1.64 g of 2-chloro-3-(2-thienylcarbonyl)pyridine, 4.5 ml of a methanol solution of 28% sodium methoxide and 2.0 ml of methanol was heated under stirring for 30 minutes. After cooling as it was, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed, to give 1.46 g of the target compound.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C:13]([CH2:15]Br)=[C:12]([CH2:17]Br)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:20][NH2:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][N:21]1[CH2:15][C:13]2[CH2:14][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:19])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:11][C:12]=2[CH2:17]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CBr)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CC3=C(CN(C)C3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 1-p-toluenesulfonyl-3,4-bis(bromomethyl)-3-pyrroline (6.1 g) was dissolved in acetonitrile (70 ml), 40% methylamine aqueous solution (1.5 ml) and anhydrous potassium carbonate powder (16 g) were added and stirred for 2 hours at room temperature. The solid was filtered off and the filtrate was purified by silicagel column chromatography to yield 3-methyl-7-p-toluenesulfonyl-3,7-diazabicyclo[3.3.0]oct-1(5)-ene (0.82 g, yield 20%). 0.8 g of this compound and 0.8 g of phenol were refluxed in 48% hydrobromic acid (15 ml) for 5 hours. The reaction mixture was washed with chloroform (20 ml×3), decolorized with active charcoal. The solvent was distilled off and washed with ethanol-ethylether (1:1) to give the title compound (0.5 g, yield 60%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1.C1COCC1>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:3]2[C:2]([NH:1][S:24]([C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=3)(=[O:26])=[O:25])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: Nc1cccnc1Nc1ccc(O)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of EXAMPLE 2 in pyridine (9 mL/g) at 0° C. was treated with a mixture of para-methoxybenzenesulfonyl chloride (1.05 equivalents) in THF (1.4 mL/g) at 0° C. at a rate which kept the reaction temperature below 5° C., warmed to 25° C., stirred for 15 minutes, and concentrated. The concentrate was treated with n-propanol to provide a composition having 9% pyridine in the solvent mixture and to precipitate a solid. The mixture was cooled to 0° C. and filtered. The filtrant and washed with ethyl acetate (5-7 mL/g starting material) and dried at 45° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][O:17]C(=O)CC)[CH2:10][O:11][C:12](=[O:15])[CH2:13][CH3:14].C([O-])(=O)C>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:22])([CH2:10][O:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:16][OH:17]
Reactant: CCC(=O)OCC(O)(COC(=O)CC)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Solvent: C1CCCCC1
Product: CCC(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Temperature: 30 °C
Yield: 62.8 %

Procedure:
A 200 ml reaction vessel was charged with 3 g of 2-(2,4-difluorophenyl)-1,3-dipropionyloxy-2-propanol, 200 mg of Lipase D made by Amano Pharmaceutical Co., Ltd. (derived from Rhizpus delermer, Enzyme No. 6), 100 ml of 50 mM acetate buffer (pH 5) and 10 ml of cyclohexane. The resulting mixture was stirred at 30° C. to react for 18 hours. After the reaction liquid was extracted three times with 50 ml of ethylacetate, the organic layers were combined and the combined organic layer was washed with saturated aqueous solution with sodium bicarbonate and with saturated aqueous solution with sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 1.55 g of oily (R)-2-(2,4-difluorophenyl)-3-propionyloxy-1,2-propanediol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 16.7 minutes ((R)-form) and 13.5 minutes ((S)-form)).
Reaction SMILES: [C:1]12([C:11]3[O:12][CH2:13][C@@H:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[P:22]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[S:23])[N:15]=3)[CH2:10]C3CC(CC(C3)[CH2:2]1)[CH2:8]2>C(Cl)(Cl)Cl>[C:1]([C:11]1[O:12][CH2:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[P:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[S:23])[N:15]=1)([CH3:10])([CH3:2])[CH3:8]
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1[C@@H]1COC(C23CC4CC(CC(C4)C2)C3)=N1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C1=N[C@H](c2ccccc2P(=S)(C2CCCCC2)C2CCCCC2)CO1

Procedure:
This compound was produced by the same method used for 4d as a colorless oil (52%). [α]20D=−78.0 (c=0.50, CHCl3); 1H NMR (CDCl3, 300 MHz) 6 7.54-7.49 (m, 2H), 7.37-7.31 (m, 2H), 6.53 (m, 1H), 4.94 (t, J=9.5 Hz, 1H), 3.92 (t, J=8.0 Hz, 1H), 2.54 (m, 1H), 2.31 (m, 1H), 2.09 (m, 1H), 1.91-1.13 (m, 19H), 1.34 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 175.7, 149.2, 131.7 (d, J=2.6 Hz), 131.3, 128.6 (d, J=9.0 Hz), 126.3 (d, J=10.5 Hz), 125.0 (d, J=63.8 Hz), 76.2, 66.5 (d, J=3.7 Hz), 41.2 (d, J=48.2 Hz), 36.5 (d, J=51.2 Hz), 33.3, 27.9, 26.6-25.2 (m); 31P NMR (CDCl3, 145 MHz) δ 57.27 (br); HRMS (M++1) m/z calculated for C25H39NOPS 432.24845, found 432.24619.
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([CH3:40])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH3:39])[CH2:22][N:23]4[CH2:28][CH2:27][N:26](C(OCC5C=CC=CC=5)=O)[CH2:25][CH2:24]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[H][H]>CO.[Pd]>[CH3:39][CH:21]([N:19]1[CH:20]=[C:16]([C:15]2[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:41])[CH3:40])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:17]=[N:18]1)[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1
Reactant: [H][H]
Reactant: CC(CN1CCN(C(=O)OCc2ccccc2)CC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [Pd]
Solvent: CO
Product: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Yield: 87.1 %

Procedure:
A mixture of benzyl 4-{2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperazine-1-carboxylate (0.30 g, 0.52 mmol; peak 1 from chiral separation) in methanol (10 mL) was hydrogenated in the presence of 10% palladium on carbon (10:90, Palladium:carbon black, 0.2 g, 0.2 mmol) under balloon pressure of hydrogen for 2 h. After filtering off catalyst, the filtrate was concentrated to give the desired product (0.20 g). LCMS calculated for C22H36N7OSi(M+H)+: m/z=442.3; Found: 442.4.
Reaction SMILES: [OH:1][CH:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][N:21]=[C:20]([C:24]([O:26]CC)=[O:25])[CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.O.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]1[C:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)c1cc(N2CCC(C3=Cc4ccccc4NC3O)CC2)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(N2CCC(c3cc4ccccc4[nH]c3=O)CC2)ncn1

Procedure:
1.10 g (2.91 mmol) ethyl 6-[4-(2-hydroxy-1,2-dihydro-quinolin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylate were stirred overnight at RT in 20 mL THF, 1.5 mL water and 1.5 mL of a 4 M NaOH solution. The organic solvent was eliminated by rotary evaporation and the precipitated solid was suction filtered. The filtrate was acidified with a 4 M HCl solution and the precipitated solid was suction filtered and dried.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:23][NH:24][C:25](=[O:37])[CH:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](O)=[O:28]>>[CH2:30]([CH:26]([C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28])[C:25]([NH:24][CH2:23][C:22]1[CH:38]=[C:39]([F:41])[CH:40]=[C:20]([F:19])[CH:21]=1)=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: O=C(O)C(Cc1ccccc1)C(=O)NCc1cc(F)cc(F)c1
Product: CN1C(=O)C(NC(=O)C(Cc2ccccc2)C(=O)NCc2cc(F)cc(F)c2)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=539.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-benzyl-malonamic acid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>>[Br:14][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:12])([CH3:11])[CH3:10])[N:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(O)c1cccc(CO)n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(O)c1cccc(CBr)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
To a solution of 2-hydroxymethyl-6-(1-hydroxy-1-methylethyl)pyridine (5.1 g, 30.5 mmol) in dicholoromethane (300 mL) was added carbon tetrabromide (8.81 g, 33.6 mmol) and triphenylphosphine (11.14 g, 33.6 mmol). The reaction was stirred at ambient temperature overnight then poured into a saturated solution of sodium bicarbonate. The organic layer was separated, concentrated to dryness and purified by column chromatography, eluting with a gradient of hexane to 3:1 hexane:ethyl acetate. The title compound (5.21 g, 74%) was obtained as a colourless oil; LC-MS Retention time 2.08 min, (M+H)+ 230, 232
Reaction SMILES: [Br-:1].[Mg+2].[Br-].S(O[CH2:9][CH2:10][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])[CH3:12])(=O)(=O)C.O>CCOCC>[CH2:9]([Br:1])[CH2:10][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])[CH3:12]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOS(C)(=O)=O
Reactant: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Reaction time: 8 h

Procedure:
Magnesium bromide etherate (17 g, 55 mmol) and a stir bar were added to a 500 mL round bottom flask. The flask was sealed and flushed with nitrogen and anhydrous diethyl ether (200 mL) added via cannula. A solution of phytanyl mesylate (23) (10.9 g, 28.9 mmol (FW=377)) in anhydrous ether (50 mL) was also added via canulla, and the suspension stirred overnight. The following morning a precipitate had formed on the side of the flask. Chilled water (200 mL) was added (ppte dissolved) and the mixture transferred to a 1000-mL separating funnel. After shaking, the organic phase was separated. The aqueous phase was then extracted with ether (2×150 mL) and all ether phases combined. The ether phase was washed with water (2×150 mL), brine (150 mL) and dried over anhydrous Mg2SO4. The solution was filtered, concentrated, and purified by flash chromatography. Final yield 9.5 g (26.3 mmol, 91.1%).
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1.[OH-].[Na+]>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[N:14]=[C:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:5]
Reactant: OCCCl
Reactant: Oc1nc2c(nc1Cc1ccccc1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: O=c1c(Cc2ccccc2)nc2c(n1CCO)CCCC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
Ethylene chlorohydrin (16.10 g, 0.2M) was added to a solution of 2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline (9.60 g, 40 mM) in dilute aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. The residue was extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 220 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 643 (10.90 g, yield: 83.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH3:15])[C@H:13]([O:16][Si](C(C)(C)C)(C)C)[C:12]([CH3:25])([CH3:24])[C:11]2=[O:26])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH3:15])[C@H:13]([OH:16])[C:12]([CH3:25])([CH3:24])[C:11]2=[O:26])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using rac-2-chloro-4-[(4R,5R)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethyl-2-oxopyrrolidin-1-yl]benzonitrile (400 mg) and tetrabutylammonium fluoride-THF solution (3 mL, 1 mol/L), and in the same manner as in Example 15, the title compound was obtained as a colorless solid (yield: 204 mg, 72%).