Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>CO>[NH:1]1[C:9]2=[CH:8][N:7]=[CH:6][CH:5]=[C:4]2[C:3]([C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1cc2cc[nH]c2cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cnccc23)CC1
Temperature: 70 °C
Yield: 99.6 %

Procedure:
6-Azaindole (4.48 g, 37.9 mmol) was dissolved in MeOH (70 mL) and KOH (4.68 g, 83.4 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (8.31 g, 41.7 mmol) were added. The reaction mixture was heated at 70° C. for 18 h. The residue was partitioned between water (250 mL) and DCM (250 mL) and the aq phase was extracted with DCM (2×250 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow foam (11.3 g, 99%). LCMS (ES+): 300.1 [MH]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([NH:12][C:13](=[O:23])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Li+].Cl>O1CCCC1>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][C:13]([NH:12][CH:4]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]([OH:24])=[O:2])=[O:23])=[CH:21][CH:20]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)CCc1ccc(O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCc1ccc(O)cc1)NC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.4 %

Procedure:
2-[3-(4-hydroxyphenyl)propionylamino]-3-phenyl propionic acid methyl ester (200 mg), prepared in Example 4, was dissolved in tetrahydrofuran (10 mL) and treated with 2M lithium hydroxide (1 mL). The resulting mixture was stirred for 18 hours at room temperature. The reaction was neutralized with aqueous hydrochloric acid, extracted with ethylacetate (EtOAc) (100 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: EtOAc) to obtain 150 mg of the title compound. The yield was 78%. The results of analyses of the compound are as follows:
Reaction SMILES: C([Li])CCC.Br[C:7](Br)=[CH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CO.C(OCC)(=O)C>C1COCC1>[C:8]([C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[CH:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=C(Br)Br
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88.3 %

Procedure:
Butyl lithium (48 mL, 0.08 mol) was added at -78° C. to a stirred solution of (R)-t-butyl 2-(2,2-dibromoethenyl)-1-pyrrolidinecarboxylate (14.2 g, 0.04 mol) in dry THF (300 mL). The color turned to dark yellow. After 15 min. methanol (10 mL) and ethyl acetate (10 mL) were added and the solution was allowed to warm to room temperature. The solvent was removed and the residue was partitioned between ethyl acetate and water. The ethyl acetate phase was concentrated and applied to a silica gel column. Elution with ethyl acetate:Skellysolve B (1:10) gave 6.9 g (88%) of product as a yellow oil.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26](N)[CH2:27][CH2:28][CH2:29][CH3:30].S>C(O)C>[CH2:26]([NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CCCCCN
Agent: S
Solvent: CCO
Product: CCCCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 100 °C

Procedure:
A suspension of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2 g and pentylamine (3 cc) in absolute ethanol (30 cc) is saturated with hydrogen sulphide and then heated for 2 hours to a temperature in the region of 100° C. After being cooled, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The pasty residue is taken up with ethyl ether (50 cc) and distilled water (15 cc). The organic phase is separated, dried over potassium carbonate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual viscous yellow oil is purified by chromatography on a column (height: 35 cm; diameter: 2.6 cm) of silica gel (0.2-0.063 mm), eluting with ethyl acetate (300 cc) and collecting 25-cc fractions Fractions 3 to 9 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-Pentyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2.25 g) is thereby obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]([O:43][CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:75])[C@H:49]([N:57]([C:59](=[O:74])[C@H:60]([NH:72][CH3:73])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:42])[CH3:41]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:40]([O:43][CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:75])[C@H:49]([N:57]([C:59](=[O:74])[C@H:60]([N:72]([C:13](=[O:15])/[CH:12]=[CH:11]/[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:17])[CH3:16])[CH3:73])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)(=[O:42])[CH3:41]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
(2E)-5-tert-Butoxycarbonylamino-5-methylhex-2-enoic acid (277 mg, 1.14 mmol) and 1-hydroxy-7-azabenzotriazole (155 mg, 1,14 mmol) were dissolved in dichloromethane (3 mL) and N,N-dimethylformamide (3 mL). The solution was cooled to 0° C. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (254 mg, 1.32 mmol) was added. The solution for stirred for 10 min at 0° C., before a solution of 3-((2R)-2-(N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate in dichloromethane (3 mL) was added. The solution was stirred for 18 hours, while it was warming up slowly to room temperature. It was diluted with ethyl acetate (100 mL) and extracted with 10% sodium hydrogensulfate solution. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatogrpahy on silica (45 g) with ethyl acetate/heptane (2:1) to give 427 mg of 3-((2R)-2-(N-((2R)-2-(N-((2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:16]
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccc(Cl)cc2)cc1)c1cc(Cl)cc(Br)c1
Temperature: 25 °C

Procedure:
Neat i-Pr2NEt (0.21 mL, 1.19 mmol) was added to a DCM mixture (5 mL) of 3-bromo-5-chlorobenzoic acid (140 mg, 0.60 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (145 mg, 0.71 mmol), HOBt (92 mg, 0.60 mmol) and EDCI (114 mg, 0.60 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting precipitate was filtered off, washed with water and MeOH, and dried in vacuo to yield the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[S:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>CN(C)C=O>[S:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]1=[O:12]
Reactant: BrCCCCCCOc1nc2ccccc2s1
Reactant: O=C1NCCN1c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCOc2nc3ccccc3s2)CCN1c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-pyridyl)-2-imidazolidinone (0.11 g, 0.65 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 31.2 mg, 0.78 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath again. 2-[(6-Bromohexyl)oxy]-1,3-benzothiazole (0.20 g, 0.65 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvent was removed under vacuum. A saturated aqueous NH4Cl solution (5 mL) and dichloromethane (10 mL) were successively added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 4) as a white solid (0.14 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[NH2:32][CH2:33][CH2:34][OH:35]>C(#N)C>[OH:35][CH2:34][CH2:33][NH:32][C@H:14]1[CH2:15][CH2:16][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[C:3]=3[NH:22][C:23](=[O:31])[CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:8]=2)[CH2:13]1
Reactant: Cc1ccc2nc(N3CC[C@@H](OS(C)(=O)=O)C3)ccc2c1NC(=O)CC1CCCCC1
Reactant: NCCO
Solvent: CC#N
Product: Cc1ccc2nc(N3CC[C@H](NCCO)C3)ccc2c1NC(=O)CC1CCCCC1

Procedure:
Prepared according to the method of example 33(b), using N-[6-methyl-2-[(3R)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 86(a)) (0.16 g), 2-amino-ethanol (0.065 mL), and acetonitrile (4 mL). Purification (SiO2, 7M ammonia in methanol:methanol:dichloromethane 1:2:99 as eluant) gave the title compound (0.06 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(=O)([O-])O.[NH4+]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1([C:15](=[O:17])[NH2:19])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
To a solution of 1-benzyloxycarbonylamino-cyclopropanecarboxylic acid (7.0 g, 29.8 mmol) in DMF (30 mL) was added HATU (11.3 g, 29.8 mmol) and Et3N (4.3 mL, 29.8 mmol). The mixture was allowed to stir at room temperature for 20 min, then ammonium hydrogen carbonate (7.06 g, 89.3 mmol) was added in one portion. The reaction was heated at 60° C. for 12 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (2×100 mL). The combined extracts were washed with satd NaHCO3, water, brine and dried with MgSO4. The mixture was filtered and the solvent removed to give (1-carbamoyl-cyclopropyl)-carbamic acid benzyl ester (5.5 g, 24.5 mmol) as a white solid.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH:11]([OH:43])[CH2:12][N:13]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:14]([C:16]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([O:22]CC1C=CC=CC=1)=[O:21])=[O:17])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[C:1]([NH:9][C@@H:10]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH:11]([OH:43])[CH2:12][N:13]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:14]([C:16]([N:18]1[CH2:32][CH2:31][CH2:30][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)N(CC(O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](C(=O)N1CCC[C@H]1C(=O)O)N(CC(O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)OCc1ccccc1

Procedure:
(3S)-1-[N-[3-(Benzoylamino)-2-hydroxy-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline, phenylmethyl ester from Example 1 (g) is treated with sodium hydroxide to give (3S)-1-[N-[3-(benzoylamino)-2-hydroxy-4-phenylbutyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline. Treatment with the reagent listed below in Col. I gives the N-protected product shown in Col. II. Removal of the N-protecting group by hydrogenolysis with palladium on carbon catalyst in the presence of hydrochloric acid gives the product shown in Col. III. ##STR183##
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([OH:10])=[O:9])[C@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:16]OS(OC)(=O)=O.CCOCC>CC(C)=O.O>[O:1]=[C:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]([O:10][CH3:16])=[O:9])[C@H:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COS(=O)(=O)OC
Reactant: CCCCC[C@H]1C(=O)CC[C@H]1CC(=O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCCCC[C@H]1C(=O)CC[C@H]1CC(=O)OC
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To 104 mg (0.49 mmole) of (±)cis-3-oxo-2-pentyl-1-cyclopentaneacetic acid (93:7 cis/trans ratio) in 1 ml of (CH3)2CO there were added, first 56 μl of (CH3)2SO4 (74 ml, 0.59 mmole, 1.2 eq.) and then 81 mg (0.59 mmole, 1.2 eq.) of anhydrous solid K2 CO3. The resulting suspension was heated at r.t. during 4 h and taken in water and with ether. The ether phase was separated and the aqueous phase once more extracted with ether. The combined organic phases were washed with water, dried over MgSO4, filtered and concentrated. The residue was distilled in a bulb-to-bulb apparatus (oven t.: 180°/7 Pa) to provide 93 mg (0.44 mmole, yield 84%) of methyl (±)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate (92/8 cis/trans ratio).
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][C:8]2(C)C)[CH2:3]1.[CH:12](OC)(OC)[O:13]C>>[O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6][O:7][CH:8]2[O:13][CH3:12])[CH2:3]1
Reactant: CC1(C)OCCC2CC(=O)N21
Reactant: COC(OC)OC
Product: COC1OCCC2CC(=O)N21

Procedure:
Following the procedure described for the preparation of 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane from 4-(2'.hydroxyethyl)-2-azetidinone and using trimethyl orthoformate instead of 2,2-dimethoxypropane one obtains 8-oxo-2-methoxy-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:22])[CH3:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]([N:10]1[CH2:11][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:9]1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CNCC1c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(NC(=O)OC(C)(C)C)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cooled stirred solution of tert-butyl (4-phenylpyrrolidin-3-yl)carbamate (prepared as described in J. Med. Chem. 1993, 36, 4139 starting from (2E)-3-phenylprop-2-enoic acid) (1.0 eq.) in dry DCM (0.1M) were slowly added acetyl chloride (4.0 eq.) and DIPEA (4.0 eq.). The reaction mixture was stirred for 1 h at RT, then diluted with DCM, washed with sat. aq. NaHCO3 sol., water and brine. The solution was dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography eluting with 5-100% EtOAc/petroleum ether, then eluting with 0-10% MeOH/EtOAc affording the titled compound as yellow oil. MS (ES) C17H24N2O3 requires: 304, found: 305 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([CH:9]1[CH:14]2[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]2)[CH:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].[OH-].[Na+].O>CCOCC>[OH:8][CH2:7][C:9]1[CH:14]2[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]2)[C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CC1C2CCC(CC2)C1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCC1=C(c2ccccc2)C2CCC1CC2
Reaction time: 1 h

Procedure:
To lithium aluminium hydride (1 g; 0.03 m) in ether (50 ml) was added 3-formyl-2-phenylbicyclo[2,2,2]octane (4.2 g; 0.02 m) in ether (40 ml) dropwise at 0° C. After 1 hour, 5N sodium hydroxide (1 ml) followed by water (5 ml) was added cautiously. After filtering, the filtrate was evaporated to give an oil which was used directly in (e) below.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][CH:3]=1.[CH3:26][NH2:27]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH3:26])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)n1
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)ccc3F)c2c1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(6-Amino-3-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (45 mg) and a 40% aqueous solution (50 mg) of methylamine were added to pyridine (200 mg), and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and ethanol (0.5 ml) was added to the residue. Deposits were collected by filtration and washed successively with methanol and diisopropyl ether to obtain the title compound (182 mg) as a yellow powder.
Reaction SMILES: [O:1]=[C:2]([CH2:14][CH2:15][C:16]#[C:17][CH3:18])/[CH:3]=[CH:4]/[C@H:5]1[CH2:12][CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:13])[O:9]2.[CH3:19][Mg]Br>>[OH:1][C:2]([CH3:19])([CH2:14][CH2:15][C:16]#[C:17][CH3:18])/[CH:3]=[CH:4]/[C@H:5]1[CH2:12][CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:13])[O:9]2
Reactant: C[Mg]Br
Reactant: CC#CCCC(=O)/C=C/[C@H]1CC[C@@H]2OC(=O)C[C@@H]21
Product: CC#CCCC(C)(O)/C=C/[C@H]1CC[C@@H]2OC(=O)C[C@@H]21

Procedure:
Analogously to Example 7(a), 8 g. of (1S,5R,6R)-6-[(E)-3-oxo-1-octen-6-ynyl]-2-oxabicyclo[3,3,0]octan-3-one [preparation see Example 13(a)] is reacted with methylmagnesium bromide, thus obtaining 6.8 g. of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:10][CH2:11][CH:12]([CH2:14][OH:15])[OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:10][CH2:11][CH:12]([CH2:14][O:15][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCC(=O)OCC(O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.2 %

Procedure:
1-Octanoyl-rac-glycerol (10.00 g, 45.81 mmol) and DMAP were placed in a flame-dried round bottom flask, followed by triethylamine (13.0 ml, 93.27 mmol) and CH2Cl2 (200 ml). When the solid dissolved, trityl chloride (14.07 g, 50.47 mmol) was added and the mixture was stirred at room temperature for two days. The mixture was poured into ice water and the two phases were separated. The organic layer was washed three times with 1 N HCL and twice with water, dried over MgSO4, and evaporated. The product was purified by chromatography in two batches, (150 g silica gel each with hexanes:ethyl acetate (8:1) solvent) to yield compound 43, 1-octanoyl-3-O-trityl-rac-glycerol (9.96 g, 47% yield).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:64])([C:60]([F:63])([F:62])[F:61])[C:24]([F:59])([F:58])[C:25]([F:57])([F:56])[O:26][C:27]([F:55])([F:54])[C:28]([F:53])([F:52])[O:29][C:30]([F:51])([F:50])[C:31]([F:49])([F:48])[C:32]([F:47])([F:46])[C:33]([F:45])([F:44])[C:34]([F:43])([F:42])[CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40]Br>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH2:35][C:34]([F:42])([F:43])[C:33]([F:44])([F:45])[C:32]([F:46])([F:47])[C:31]([F:48])([F:49])[C:30]([O:29][C:28]([F:52])([F:53])[C:27]([F:54])([F:55])[O:26][C:25]([F:56])([F:57])[C:24]([F:58])([F:59])[C:23]([F:64])([F:22])[C:60]([F:61])([F:63])[F:62])([F:51])[F:50])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)COCCCCBr
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.01 g, 3.56 mmol) and 4-(6-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2,3,3,4,4,5,5,6,6-decafluorohexyloxy)-1-bromobutane (3.07 g, 4.0 mmol; prepared by combining 1,4-dibromobutane and 2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2,3,3,4,4,5,5,6,6-decafluorohexanol). The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with 15 volume percent ethyl acetate/hexane, to yield 2.3 g of purified product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Reactant: COCc1cccc(B(O)O)c1
Product: COCc1cccc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Yield: 82 %

Procedure:
Prepared in a similar manner to Example 1 starting from 3-(methoxymethyl)phenylboronic acid and 2-(4-bromophenyl)-2-methylpropanoic acid. Yield: 82%. 1H NMR (400 MHz, DMSO): δ 1.48 (s, 6H), 4.46 (s, 2H), 7.27-7.29 (d, 1H), 7.40-7.44 (m, 3H), 7.54-7.56 (d, 2H), 7.60-7.62 (d, 2H), 12.40 (s, 1H).