Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CCCCN>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
6.29 (6), Tyr; 0.97 (1), Lys; 2.99 (3),
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(OC(C)C)(=O)C.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>>[CH3:26][N:27]([CH3:29])[CH:28]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Solvent: CC(=O)OC(C)C
Product: CN(C)C=C(C(=O)c1ccccc1)c1ccc(F)cc1

Procedure:
Following the procedure of example 1B, 13.8 g (0.0645 mol) of 2-(4-fluorophenyl)-1-phenylethanone was reacted with 20 mL of dimethyl formamide dimethyl acetal to yield 13.6 g of 3-(dimethylamino)-2-(4-fluorophenyl)-1-phenyl-2-propen-1-one, mp 115°-116° from isopropyl acetate. The enamine (10.5 g, 0.039 mol) was reacted with 6.03 g (0.039 mol) of ethyl hydrazinoacetate hydrochloride to yield 12.1 g of product mp 86°-87° C. from methyl-t-butyl ether.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[C@@H:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O)(C)(C)C>C(Cl)Cl>[C:22]1([C@H:16]2[C:17](=[O:21])[CH2:18][CH2:19][CH2:20][NH:15]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (4 mL) is added to a stirred, cooled (0° C.) solution of (2S)- 1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (40 mg) in methylene chloride (2 mL) and the mixture is stirred at room temperature for 3 h. The solvent is evaporated under reduced pressure and the residue is partitioned between aqueous saturated sodium bicarbonate (50 ml) and ethyl acetate (3×50 ml). The combined organic fractions are washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo to give (2S)-2-phenylpiperidin-3-one.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].[NH2:14][C@H:15]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:18])[CH3:16].Cl.N(C(OC(C)(C)C)=O)[C@H](C(N1CCC[C@H]1C(OCC1C=CC=CC=1)=O)=O)C>>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:14][C@H:15]([C:17]([N:19]1[CH2:33][CH2:32][CH2:31][C@H:20]1[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[O:18])[CH3:16])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 36.5 %

Procedure:
Boc-Ala-OH (11.5 g, 48.4 mmoles) was coupled to H-AlaPro-OBzl·HCl (14.9, 47.8 mmoles) by procedures substantially similar to those described above for the preparation of Boc-AlaPro-OBzl, yielding a foam, 22 g. This product crystallized from ethyl acetate to yield Boc-AlaAlaPro-OBzl (7.8 g, mp 120°-121°) in the first crop and 11.1 g (mp 111°-117°) in a second crop. First crop-Anal. Calcd. for C23H33N3O6 (mp 120°-121°): C=61.71%, H=7.45%, N=9.39%. Found: C=61.74%, H=7.56%, and N=9.46%.
Reaction SMILES: [N:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[CH:3][C:2]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=O.C1([SiH3])C=CC=CC=1>C1COCC1.C([Sn](Cl)(Cl)CCCC)CCC>[N:1]1[C:6]([NH:7][CH2:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)=[CH:5][CH:4]=[CH:3][C:2]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1cccc(-c2cccnc2)n1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNc2cccc(-c3cccnc3)n2)cc1
Reaction time: 108 h
Yield: 98.3 %

Procedure:
To a stirred suspension of a mixture of 11 (3.00 g, 17.52 mmol), methyl 4-formylbenzoate (4.62 g, 28.11 mmol, 1.5-2.0 equiv.) and dibutyl tin dichloride 160 mg, 0.53 mmol) in anhydrous THF (15 mL) at room temperature was added phenylsilane (2.34 mL, 19.28 mmol) in three portions over two days. After stirring for 2 to 7 days the reaction mixture was filtered, filtrate was concentrated and purified by flash chromatography on silica gel (MeOH/CH2Cl2, 2/98→10/90) to afford the title compound 12 (5.50 g, 17.22 mmol, 98% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.11 (dd, J=2.3, 0.7 Hz, 1H), 8.55 (dd, J=4.7, 1.8 Hz 1H), 8.29-8.24 (m, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.57-7.40 (m, 5H), 7.18 (d, J=7.2 Hz, 1H), 6.59 (d, J=8.2 Hz 1H), 4.69 (d, J=6.1 Hz, 2H), 3.85 (s, 3H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>COCCOC>[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C=C1CCN(C(=O)OCC)CC1
Reaction time: 1 h
Yield: 106.6 %

Procedure:
To a suspension of 4 g oily sodium hydride (60%) in 200 ml of anhydrous 1,2-dimethoxyethane, was added dropwise 23.6 g ethyl diethylphosphonoacetate at about 20° C., and the mixture was stirred at that temperature for about one hour. To the solution thus obtained, was added dropwise 17.1 g N-ethoxycarbonyl-4-piperidone at temperatures below 30° C., the mixture was stirred for an additional two hours, and the solvent was distilled off under reduced pressure. Ice water (100 ml) and ethyl acetate (100 ml) were added to the residue, the mixture was shaken, and the layers were separated. The aqueous layer was extracted twice with 100 ml ethyl acetate, and all the organic solutions were combined, washed with water and dried over anhydrous magnesium sulfate. Distilling off the solvent from the dried solution gave 25.7 g of ethyl N-ethoxycarbonyl-4-piperidylideneacetate as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A10) (4.67 g, 16.6 mmol) and morpholine (7.21 ml, 82.8 mmol) in DMSO (30 mL) at RT according to the general procedure B. Obtained as a yellow solid (5.01 g, 87%).
Reaction SMILES: NC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC#N)C=CC=1OC.[CH3:24][O:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1.[Mg].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][C:45]=1[N+:46]([O-:48])=[O:47])[CH:41]=[O:42]>>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:41]([C:28]2[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=2)[OH:42])[CH:43]=[CH:44][C:45]=1[N+:46]([O-:48])=[O:47]
Reactant: COc1cc(C=O)ccc1[N+](=O)[O-]
Reactant: COc1cc(Br)cc(OC)c1
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1N
Agent: [Mg]
Product: COc1cc(OC)cc(C(O)c2ccc([N+](=O)[O-])c(OC)c2)c1
Yield: 72.7 %

Procedure:
(3-Methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol was prepared analogously to 3-(3-amino-4-methoxy-phenyl)-3-(3,4-dimethoxy-phenyl)-acrylonitrile using 3,5-dimethoxy-bromobenzene (4.4 g, 20.1 mmol), magnesium turning (1.0 g, 20.1 mmol) and 3-methoxy-4-nitro-benzaldehyde (3.0 g, 16.8 mmol) to afford (3-methoxy-4-nitro-phenyl)-(3,5-dimethoxy-phenyl)-methanol (3.9 g, 73%): 1H NMR (CDCl3) δ 7.79 (d, J=8 Hz, 1H), 7.22 (s, 1H), 7.00-6.99 (dd, J=2, 9.1 Hz, 1H), 6.48 (d, J=2 Hz, 2H), 6.40 (d, J=2 Hz, 1H), 5.75 (d, J=3 Hz, 1H), 3.96 (s, 3H), 3.77 (s, 6H), 2.45 (d, J=2 Hz, 1H).
Reaction SMILES: [K].[CH2:2]([O:4][C:5](=[O:23])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=[O:8])[CH3:3].[CH:24]1([CH2:30][CH2:31]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[K+]>CN(C)C=O>[CH2:2]([O:4][C:5](=[O:23])[CH:6]([C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:31][CH2:30][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:3]
Reactant: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: BrCCC1CCCCC1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCC1CCCCC1)C(=O)c1ccc(OCc2ccccc2)cc1
Yield: 69.4 %

Procedure:
A mixture 100 mg (0.3 mmol) of 3-(4-benzyloxy-phenyl)-3-oxo-propionic acid ethyl ester potassium salt, 86 mg (0.45 mmol) of 2-cyclohexylethyl bromide, and 17 mg (0.1 mmol) of potassium iodide (KI) in 1 mL of dimethylformamide (DMF) in a 4 mL vial was shaken in a sand bath at 80° C. overnight. The mixture was then concentrated to give a residue which was purified via reverse-phase chromatography (Gilson) to afford (after lyophilization) 85 mg (70% yield) of 2-(4-benzyloxy-benzoyl)-4-cyclohexyl-butyric acid ethyl ester as a solid as indicated by LC-MS—calcd for C26H32O2 [M++H]+: 409.23, found: 409.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[C:10]([O:12]C)=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:14])[C:10]([OH:12])=[O:11])=[C:2]([F:1])[CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)C(C)c1ccc(O)cc1F
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(OC2CCCC2)cc1F
Temperature: 60 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
To a solution of compound (8) (0.50 g, 2.5 mmol) in dry DMF (5 mL), potassium carbonate (1.2 g, 8.8 mmol), and bromocyclopentane (0.32 g, 3.0 mmol) were added and stirred at 60° C. for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate (300 mL) followed by washing with water and drying (over sodium sulfate). The solvent was distilled off, and the residue was dissolved in dichloromethane and washed with a 1 M-aqueous solution (30 mL) of sodium hydroxide. The organic layer was dried (over sodium sulfate) and distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution followed by conventional hydrolysis to give 0.56 g (84%) of compound (14) of interest as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[C:6](Cl)[N:5]=[C:4]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1.C(N(CC)C(C)C)(C)C>C(O)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:7]1[C:6]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[N:5][C:4]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:3][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Clc1nc(C2CCOCC2)nc(Cl)c1-c1nc2ccccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCOCC3)nc(Cl)c2-c2nc3ccccc3s2)C1
Yield: 78.6 %

Procedure:
Following the same procedure as in step 4 of Example 21 using 2-[4,6-dichloro-2-(oxan-4-yl)pyrimidin-5-yl]-1,3-benzothiazole (90 mg, 0.25 mmol, 1.00 equiv), tert-butyl (3R)-3-aminopiperidine-1-carboxylate (49 mg, 0.24 mmol, 1.00 equiv), and N,N-Diisopropylethylamine (63 mg, 0.49 mmol, 1.98 equiv) in ethanol (2 mL). The reaction mixture was concentrated under reducing pressure to afford 100 mg of the title compound as a yellow solid, which was used directly for next step without further purification. 1H-NMR (CDCl3, 400 MHz,): δ ppm 1.29 (s, 9H), 1.73 (s, 1H), 1.90-2.08 (m, 8H), 2.98 (m, 8H), 3.00 (m, 1H), 3.30-4.48 (m, 10H), 7.33-7.50 (m, 2H), 7.46-8.06 (m, 4H), 11.09 (d, J=6.8, 1H).
Reaction SMILES: CP(Cl)(=O)OC.[C:7]([O:10][CH:11]([C:27]1[CH:31]([OH:32])[O:30][C:29](=[O:33])[CH:28]=1)[CH2:12][O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:9])[CH3:8]>>[C:7]([O:10][CH:11]([C:27]1[CH:31]([OH:32])[O:30][C:29](=[O:33])[CH:28]=1)[CH2:12][O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:9])[CH2:8][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCC(=O)OCC(OC(C)=O)C1=CC(=O)OC1O
Agent: COP(C)(=O)Cl
Product: CCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCC)C1=CC(=O)OC1O

Procedure:
Using methyl methylphosphonochloridate in place of dodecanoyl chloride in the above-described procedure for making 4-(1-acetoxy-2-dodecanoyloxyethyl)-5-hydroxy-2(5H)-furanone, the product obtained is 4-[1-acetoxy-2-OP(0)(CCH3)(CH3) ethyl]-5-hydroxy-2(5H)-furanone.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH:14]1[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)#[N:9]>ClCCl>[NH:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:11]=[C:10]([CH:27]=[CH:26][CH:25]=2)[C:8]#[N:9])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cccc(C#N)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(OC2CNC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (10 ml) is added to a solution of tert-butyl 3-(3-cyanophenoxy)azetidine-1-carboxylate a1-43 (260 mg, 0.95 mmol, 1 eq) in dichloromethane (10 ml). The reaction mixture is stirred for 2 hours at room temperature, then concentrated to dryness to afford 262.3 mg of crude 3-(azetidin-3-yloxy)benzonitrile a1-45 as an oil. This oil is used in the next step without any further purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([OH:18])=O)=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:56][C:57]1[C:58]([OH:68])=[N:59][C:60]([N:63]2[CH:67]=[CH:66][CH:65]=[N:64]2)=[N:61][CH:62]=1>CC#N>[OH:68][C:58]1[C:57]([NH:56][C:16](=[O:18])[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2])=[CH:14][CH:13]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:62][N:61]=[C:60]([N:63]2[CH:67]=[CH:66][CH:65]=[N:64]2)[N:59]=1
Reactant: CCOP(=O)(OCC)c1ccc(C(C(=O)O)c2ccccc2)cc1
Reactant: Nc1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)Nc2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-(Diethoxyphosphoryl)phenyl)-2-phenylacetic acid, 14-f, (1.18 g, 3.4 mmol), HATU (1.86 g, 4.9 mmol) and triethylamine (989 mg, 9.8 mmol) in CH3CN (20 mL) was added 5-amino-2-(1H-pyrazol-1-yl)pyrimidin-4-ol (11-e, 577 mg, 3.30 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was taken up in EA and water. The aqueous layer was extracted with EA. The combined layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product of 14-1 which was purified by pre-HPLC (766 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ1.18-1.23 (m, 6H), 3.92-4.03 (m, 4H), 6.64 (s, 1H), 7.25-7.35 (m, 6H), 7.47-7.51 (m, 2H), 7.64-7.71 (m, 2H), 7.97 (s, 1H), 8.61-8.52 (m, 1H), 8.63 (br s, 1H); LC-MS: (M+H)+ 508.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Br:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1>>[Br:44][C:45]1[CH:46]=[CH:47][C:48]([OH:51])=[C:49]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])[CH:50]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(Br)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-bromophenol, the title compound was obtained (41%): 1H NMR (300 MHz, CDCl3) δ 9.46-9.25 (br, 1H), 7.51-6.80 (m, 7H), 4.73-4.51 (br, 1H), 3.79-3.56 (m, 2H), 1.76-1.60 (m, 2H), 1.41-1.22 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 377 (M−17), 379 (M−17), 412 (M+23), 414 (M+23).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.F[B-](F)(F)F.C[O+](C)C.[Cl-].[NH4+:27]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2([CH3:15])[CH2:9][O:10][CH2:11][C:12]([NH2:27])=[N:13]2)[CH:7]=1
Reactant: [NH4+]
Reactant: CC1(c2cc(Br)ccc2F)COCC(=O)N1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Product: CC1(c2cc(Br)ccc2F)COCC(N)=N1

Procedure:
In analogy to step a) in the synthesis of building block D, the treatment of (RS)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-morpholin-3-one with trimethyloxonium tetrafluoroborate followed by the nucleophilic substitution with ammonium chloride yielded the title compound; its hydrochloride was obtained as a white solid. Mass (calculated) C11H12BrFN2O [287.13]; (found) [M+H]+=287, [M+2+H]+=289.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]([Cl:21])([Cl:20])[C@@H:11]1[N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13](=[O:19])[O:12]1.[CH3:22][O:23][CH2:24]Cl.O>C1COCC1>[CH3:22][O:23][CH2:24][C@@:14]12[CH2:18][CH2:17][CH2:16][N:15]1[C@@H:11]([C:10]([Cl:9])([Cl:20])[Cl:21])[O:12][C:13]2=[O:19]
Reactant: COCCl
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Temperature: -30 °C

Procedure:
A 1M of solution of lithium diisopropylamide in a 3:5 mixture of hexanes/THF (8.25 ml) is added dropwise to (3R,7aS)-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1-one (1.51 g, prepared as described by Wang and Germanas Synlett 1999, 33-36.) in THF (5 ml) at −78° C. After stirring 30 minutes at −78° C. methoxymethylchloride (1.14 ml) is added. The reaction mixture is then allowed to warm to −30° C. over 3 hours and water is added. The aqueous layer is extracted with dichloromethane, the combined organic layers evaporated and the residue is then purified by normal phase chromatography, eluting with dichloromethane, to give the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.[C:19]([SiH2:23][O:24][C:25]([CH3:39])([CH3:38])[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[C:34]([CH:36]=O)=[CH:33][CH:32]=[CH:31]2)([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:19]([SiH2:23][O:24][C:25]([CH3:39])([CH3:38])[C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[C:34]([CH2:36][N:15]1[CH2:14][CH2:13][C:12]3([N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][NH:10][C:11]3=[O:18])[CH2:17][CH2:16]1)=[CH:33][CH:32]=[CH:31]2)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc2cccc(C=O)c12
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc2cccc(CN3CCC4(CC3)C(=O)NCN4c3ccc(F)cc3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (0.056 g, 0.22 mmol) and 8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalene-1-carbaldehyde (0.067 g, 0.22 mmol) were dissolved in dry 1,2-dichloroethane (5 mL). To the reaction mixture was added crashed 4A Molecular Sieve (0.028 g), a catalytic amount of glacial acetic acid. The reaction mixture was stirred at room temperature for 1 hr and it was then added at room temperature sodium triacetoxyborohydride (0.071 g, 0.33 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with water and dichloromethane. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via semi-preparative HPLC (aqueous 0.5% TFA/acetonitrile) to yield crude 8-[8-(tert-butyl-dimethyl-silanyloxymethyl)-naphthalen-1-ylmethyl]-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one which was directly used to the next step.
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[CH3:12][CH:13]1[CH2:18][C@H:17]([OH:19])[C@@H:16]([CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:14]1.C(OC=C)(=O)C>CCCCCCC>[C:17]([O:10][CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2]1)(=[O:19])[CH3:16].[CH:13]1([CH3:12])[CH2:14][CH2:15][CH:16]([CH:20]([CH3:21])[CH3:22])[CH:17]([OH:19])[CH2:18]1
Reactant: CC1CC[C@H](C(C)C)[C@@H](O)C1
Agent: CC1CCC(C(C)C)C(O)C1
Solvent: C=COC(C)=O
Solvent: CCCCCCC
Product: CC(=O)OC1CC(C)CCC1C(C)C
Reaction time: 24 h

Procedure:
Lyophilised “AMANO AK” (a Pseudomonas fluorescens lipase enzyme) was obtained from Amano Pharmaceutical Co. (Japan). Concentrated liquid menthol was produced by the hydrogenation of thymol. The menthol contained four diastereomeric pairs of menthols, namely (+)-menthol (51%), (±)-isomenthol (14%), (±)-neomenthol (29%) and (±)-neoisomenthol (2%). A volume of 1 ml was added to sealed batch reactors. Vinyl acetate (54 μl) was added at a 2:1 molar ratio to (−)-menthol. Heptane was added as solvent to a final reaction volume of 5 ml. These reactors were incubated in silicon oil baths at 50° C. and stirred on a stirring hot plate. Batch times, unless otherwise stated were 24 hours. The reaction mixture was then centrifuged to separate the products from the enzyme. The supernatant was analysed by GC (% m/m analysis). Of the available (−)-menthol, 100% was converted to (−)-menthyl acetate, at an ee of 98%. The enzyme was recycled a total of 150 times by washing with heptane and adding fresh substrate (liquid menthol, vinyl acetate and heptane) after every recycle. An amount of menthyl acetate equivalent to 185 g of (−)-menthol was produced by this process.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=2)=[CH:5][CH:4]=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CC(=O)CC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:31][CH2:30][CH2:29][CH2:28][Br:27])[CH:21]=2)=[CH:5][CH:4]=1
Reactant: BrCCCCBr
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(O)c2)cc1
Solvent: CCC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(CCCCBr)c2)cc1

Procedure:
A slurry of 4.04 g (11 mmol) of 2-(4-Methoxyphenyl)-3-(3-hydroxyphenyl)-6-methoxybenzo[b]thiophene, 1,4-dibromobutane 26.3 mL (220 mmol), and 3.5 g (25.3 mmol) of K2 CO3 in 200 mL of 2-butanone was preapared. The reaction mixture was heated to reflux for two hours, then filtered, and evaporated to dryness. The resulting oil was chromatographed on a silica gel column eluted with a linear gradient begining with EtOAc-hexane (1:9) (v/v) and ending with EtOAc-hexane (1:4) (v/v). The desired fractions were combined and evaporated to a yellow oil. This yielded 5 g of the title compound.