Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)[CH2:4][CH2:5]I)[CH3:2].[Li].[CH3:21][CH2:22][C:23](=[O:29])[CH2:24][C:25](=[O:28])[CH2:26][CH3:27]>CN(C)C=O>[CH2:1]([C:3](=[CH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH:24]([C:23](=[O:29])[CH2:22][CH3:21])[C:25](=[O:28])[CH2:26][CH3:27])[CH3:2]
Reactant: CCC(=CCCc1ccc(C(=O)OC)cc1)CCI
Reactant: CCC(=O)CC(=O)CC
Agent: [Li]
Solvent: CN(C)C=O
Product: CCC(=O)C(CCC(=CCCc1ccc(C(=O)OC)cc1)CC)C(=O)CC

Procedure:
[I; Ar is 4-CH3O2CC6H4, R0 is H, R' and R" are CH3CH2CO, Y is C(C2H5)=CHCH2CH2 ] was prepared from 14 g. of 3-ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl iodide (Preparation D10) and 14 g. of the lithium salt of 3,5-heptanedione in 200 ml. of dimethylformamide according to the procedure described above in Example 2. The product was chromatographed on silica gel and eluted with the pentane-benzene-ether solvent series. Benzene containing 2% ether brought out the desired product, 2.6 g. of 4-[3-ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl]-3,5-heptanedione as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]>C(#N)C1C=CC=CC=1>[C:11]1([C:10]([C:3]2[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=2[NH2:1])=[O:12])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: CC(=O)c1cc(C)cc(C)c1N
Solvent: N#Cc1ccccc1
Product: Cc1cc(C)c(N)c(C(=O)c2ccccc2)c1

Procedure:
2-Amino-3,5-dimethylphenyl phenyl ketone was synthesized in the same fashion as for 2′-amino-3′,5′-dimethylacetophenone (Example 39) except that benzonitrile was used instead of acetonitrile.
Reaction SMILES: C[Al](C)C.CCCCCCC.[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH2:17])[CH3:13].[I:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]([C:31](OCC)=[O:32])[C:24]2=[O:36].NC(C1C=CC2C(=CC=CC=2)N=1)=O>ClCCl.O>[CH2:12]([N:14]([CH2:18][CH3:19])[CH2:15][CH2:16][NH:17][C:31]([C:25]1[C:24](=[O:36])[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([I:20])[CH:22]=2)[NH:27][CH:26]=1)=[O:32])[CH3:13]
Reactant: CCOC(=O)c1c[nH]c2ccc(I)cc2c1=O
Reactant: CCN(CC)CCN
Agent: C[Al](C)C
Agent: NC(=O)c1ccc2ccccc2n1
Solvent: CCCCCCC
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCNC(=O)c1c[nH]c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a stirred solution of a 2.0 M trimethylaluminium solution in heptane (20.8 mL, 41.6 mmol) in anhydrous dichloromethane (350 mL) was added at 0° C., under argon, N,N-diethylethylenediamine (5.78 mL, 41.1 mmol) dropwise. After 10 min, ethyl 6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (93) (10.0 g, 31.4 mmol) (Edlin, C.; Eldred, C. D.; Lunniss, C. J.; Redgrave, A. J.; Robinson, J. E.; Woodrow, M. Preparation of aminocarbonylquinoline derivatives as phosphodiesterase type IV (PDE4) inhibitors. Patent WO2005030725, 2005) was added. The mixture was refluxed for 12 h. After cooling to room temperature, water (500 mL) was added and the precipitate was filtered and washed with ethanol (2×100 mL). The filtrate was evaporated under vacuum. The residue was chromatographed (Al2O3, CH2Cl2/EtOH, 94/6, v/v) to give amide 94 (9.70 g, 23.5 mmol) as a beige solid. Yield 81%; Rf (Al2O3, CH2Cl2/EtOH, 94/6, v/v) 0.32; mp 243-245° C.; IR (KBr) ν 1466, 1507, 1551, 1633, 2800-3000, 3062 cm−1; 1H NMR (200 MHz, DMSO-d6) δ 1.23 (t, 6H, J=7.1 Hz), 3.17 (q, 4H, J=7.1 Hz), 3.23 (t, 2H, J=6.8 Hz), 3.71 (q, 2H, J=6.4 Hz), 7.59 (d, 1H, J=8.6 Hz), 8.05 (dd, 1H, J=2.0, 8.6 Hz), 8.51 (d, 1H, J=2.0 Hz), 8.72 (s, 1H), 10.04 (t, 1H, J=5.8 Hz), 10.13 (se, 1H); ESI-MS m/z 413.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11]C23C=CC=CC2C(NC3=O)=O)=[CH:4][CH:3]=1.O.[NH2:29]N>C1COCC1.CCO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[CH2:11][NH2:29])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C2(Cc3cccc(COc4ccc(Cl)cc4)c3)C=CC=CC12
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1cccc(COc2ccc(Cl)cc2)c1
Temperature: 25 °C

Procedure:
2-[3-(4-Chloro-phenoxymethyl)-benzyl]-phthalimide (345 mg, 0.91 mmol) and hydrazine hydrate (0.27 mL, 4.5 mmol) were dissolved in THF (2.5 mL) and EtOH (2.5 mL). The mixture was heated to reflux for 17 h, cooled to r.t. and evaporated to dryness. The residue was suspended in THF (6 mL). The precipitate was filtered and washed with THF (4×3 mL). The filtrate was evaporated to dryness to give the title compound, pure enough for further reactions.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Br.CCCCCC.C(OCC)(=O)C>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:36][C:35]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:34]=2[F:33])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)C(=O)O1
Temperature: -60 °C

Procedure:
In analogy with Example 1h), 5.0 g (16.37 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] dissolved in 100 ml of THF are deprotonated, at -75° C., with 32.7 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated with 2.51 ml (19.6 mmol) of 2,4-difluorobenzyl bromide (Aldrich; Milwaukee/U.S.A.) at -75° C. initially (heating to a maximum of -60° C. over a period of 2 h). Column chromatography (SiO2, hexane/ethyl acetate, 2:1) affords the title compound: TLC Rf (D)=0.5; tRet (II)=17.2 min.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])O.[Na+].C>C(O)(CC)C.O>[OH:1][C:2]1[CH:16]=[C:15]([O:17][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=[O:5]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Yield: 64.5 %

Procedure:
A mixture of 20 g (80 mmol) of 2,4-dihydroxy-4'-chlorobenzophenone, 21.9 g (88 mmol) of 1-bromododecane and 8.4 g (100 mmol) of sodium hydrogen carbonate in 77.6 g of sec-butyl alcohol and 25.6 g of H2O is heated with stirring and maintained at reflux for 20 h. The reaction mixture is stirred for an additional 15 min in the presence of 0.8 g of activated charcoal and is then filtered while hot. After the filtrate has cooled, the product crystallizes. It is recrystallized from sec-butyl alcohol to give 21.5 g of pale yellow crystals having a melting point of 61°-63° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:5][C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:38][S:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:32]([N+:46]([O-:48])=[O:47])[CH:31]=2)(=[O:29])=[O:28])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH3:56][N:57]([CH3:61])[C:58](Cl)=[O:59]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([C:58]([N:57]([CH3:61])[CH3:56])=[O:59])[CH2:16][CH2:17]2)[CH:6]=[CH:5][C:4]=1[C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:38][S:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[C:32]([N+:46]([O-:48])=[O:47])[CH:31]=2)(=[O:28])=[O:29])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1cc(CCCN2CCNCC2)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCCSc3ccccc3)c([N+](=O)[O-])c2)cc1
Reactant: CN(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CCCN2CCN(C(=O)N(C)C)CC2)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(NCCSc3ccccc3)c([N+](=O)[O-])c2)cc1
Reaction time: 0.5 h

Procedure:
A solution of Example 183D (108 mg, 0.157 mmol) and triethylamine (45 μL, 0.32 mmol) in THF (2 mL) at room temperature was treated with dimethylcarbamic chloride (14 uL, 0.157 mmol), and stirred for 30 minutes. The mixture was purified by flash column chromatography on silica gel with 10:10:80 methanol/acetonitrile/ethyl acetate to provide the desired product. MS (ESI(−)) m/e 759 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 1.93 (m, 2H), 2.65 (t, 2H), 2.74 (s, 6H), 2.89 (m, 2H), 3.08 (m, 4H), 3.34 (m, 6H), 3.61 (m, 2H), 3.75 (s, 3H), 6.88 (d, 1H), 6.96 (s, 1H), 7.01 (d, 1H), 7.21 (m, 2H), 7.30 (t, 2H), 7.41 (m, 3H), 7.88 (d, 1H), 7.89 (d, 2H), 8.51 (d, 1H), 8.54 (t, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][C:17]=1[Cl:24].Cl>C1COCC1.CCOCC.C(Cl)Cl>[Cl:24][C:17]1[CH:18]=[C:19]([CH2:22][C:5]2[N:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:8][C:3](=[O:2])[CH:4]=2)[CH:20]=[CH:21][C:16]=1[Cl:15]
Reactant: CCOC(=O)Cl
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: COc1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)N1CCC(=O)C=C1Cc1ccc(Cl)c(Cl)c1
Yield: 44 %

Procedure:
A mixture of 4-methoxypyridine (0.4 mol) in THF (1000 ml) was stirred and cooled in a 2-propanol/CO2 bath. Ethyl chloroformate (0.4 mol) was added dropwise and the mixture was stirred for 3 hours while cooling (mixture I). In another round-bottom flask, the Grignard-reagent was prepared: Mg (0.44 mol) was stirred in a small amount of (C2H5)2O. Some 12 was added. A small amount of 1,2-dichloro-4-(chloromethyl)-benzene was added. Then, 1,2-dichloro-4-(chloromethyl)benzene (0.4 mol) in (C2H5)2O (600 ml) was added dropwise at reflux temperature. The mixture was stirred for one hour (mixture II). The Grignard-reagent was decanted off, added to mixture I at <−40° C., and the resulting reaction mixture was stirred, allowing the temperature to reach RT. The reaction mixture was stirred for one hour at RT. HCl (10%, 800 ml) was added and the mixture was stirred for 30 minutes, then CH2Cl2 was added. The organic layer was separated, dried, filtered and the solvent evaporated, yielding 57.8 g (44%) of (±)-ethyl 6-[(3,4-dichlorophenyl)methyl]-1,2,3,4-tetrahydro-4-oxo-1-pyridinecarboxylate (intermediate 9).
Reaction SMILES: BrC1C=C(F)C2OC(C3CCNCC3)CC=2C=1.ClC1N=CC(CCC)=CN=1.[Br:28][C:29]1[CH:30]=[C:31]([F:54])[C:32]2[O:36][CH:35]([C:37]3(O)[CH2:42][CH2:41][N:40]([C:43]4[N:48]=[CH:47][C:46]([CH2:49][CH2:50][CH3:51])=[CH:45][N:44]=4)[CH2:39][CH2:38]3)[CH2:34][C:33]=2[CH:53]=1>>[Br:28][C:29]1[CH:30]=[C:31]([F:54])[C:32]2[O:36][CH:35]([CH:37]3[CH2:38][CH2:39][N:40]([C:43]4[N:44]=[CH:45][C:46]([CH2:49][CH2:50][CH3:51])=[CH:47][N:48]=4)[CH2:41][CH2:42]3)[CH2:34][C:33]=2[CH:53]=1
Reactant: CCCc1cnc(N2CCC(O)(C3Cc4cc(Br)cc(F)c4O3)CC2)nc1
Agent: CCCc1cnc(Cl)nc1
Agent: Fc1cc(Br)cc2c1OC(C1CCNCC1)C2
Product: CCCc1cnc(N2CCC(C3Cc4cc(Br)cc(F)c4O3)CC2)nc1

Procedure:
Compound 3F was prepared from Compound 3E and 2-chloro-5-propylpyrimidine in a similar manner to the procedure described in Compound 1H, Example 1. LC/MS (m/z)=421 (M+H)+.
Reaction SMILES: CC(C)(O[N:5]([C@H:9]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]#[CH:31])[C:25]([Br:32])=[CH:24][N:23]=2)[CH:14]=1)=[O:11])C(=O)[O-])C.S(=O)(=O)(O)O.O>O1CCOCC1>[NH2:5][C@H:9]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:10]([NH:12][C:13]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[C:15]([NH:21][C:22]2[N:27]=[C:26]([O:28][CH2:29][C:30]#[CH:31])[C:25]([Br:32])=[CH:24][N:23]=2)[CH:14]=1)=[O:11]
Reactant: C#CCOc1nc(Nc2cc(CO)cc(NC(=O)[C@@H](Cc3ccccc3)N(OC(C)(C)C)C(=O)[O-])c2)ncc1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: C#CCOc1nc(Nc2cc(CO)cc(NC(=O)[C@H](N)Cc3ccccc3)c2)ncc1Br
Yield: 56 %

Procedure:
1,1-Dimethylethoxy[(1R)-2-[[3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-5-(hydroxymethyl)phenyl]amino]-2-oxo-1-(phenylmethyl)ethyl]carbamate (22 mg) and sulfuric acid (0.3 ml; 2 n) were stirred in dioxane (3 ml) at 100° C. for 2.5 h. After cooling and dilution with water saturated NaHCO3-solution was added and the resulting preticipate collected by filtration yielding the title compound (10 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[C:20]([C:22]1[C:27](F)=[CH:26][CH:25]=[CH:24][N:23]=1)#[N:21]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:27]1[C:22]([C:20]#[N:21])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: N#Cc1ncccc1F
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cccnc2C#N)c(OC)c1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
2,4-Dimethoxybenzylamine (3.29 g, 19.7 mmol) and triethylamine (1.99 g, 19.7 mmol) were added sequentially to a solution of 2-cyano-3-fluoropyridine (2.0 g, 16.4 mmol) (Sakamoto et. al., Chem. Pharm. Bull., 1985, 33, 565-71) in N,N-dimethylacetamide (29 mL). The reaction was heated at 80° C. for 4 h, quenched with water and extracted with diethyl ether (3×). The combined organic extracts were washed water, saturated brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 0-12% ethyl acetate (with 0.1 triethylamine) in dichloromethane gradient elution) to produce the title compound (3.25 g). MS 270.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[CH:12]([CH2:13][C@H:14]([OH:28])[C@@H:15]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:16]1)[CH2:11][CH2:10]3.[C:29]1([C:39]([N:41]2[CH2:48][CH2:47][CH2:46][C@H:42]2[C:43]([OH:45])=O)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:28][C@@H:14]1[C@@H:15]([N:22]2[CH2:23][CH2:24][N:25]([C:43]([C@@H:42]3[CH2:46][CH2:47][CH2:48][N:41]3[C:39]([C:29]3[CH:30]=[CH:31][C:32]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:38]=3)=[O:40])=[O:45])[CH2:26][CH2:27]2)[CH2:16][C@@:17]2([CH3:18])[CH:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13]1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)c1cccc2ccccc12
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)[C@@H](N5CCNCC5)C[C@]4(C)[C@H]3CC[C@]12C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CO[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](O)[C@@H](N5CCN(C(=O)[C@@H]6CCCN6C(=O)c6ccc7ccccc7c6)CC5)C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h
Yield: 23.7 %

Procedure:
To a solution of compound 36 (90 mg, 0.23 mmol) in anhydrous DMF (5 mL) at room temperature under an atmosphere of argon were added carboxylic acid 20 (68 mg, 0.25 mmol), PyBOP (132 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), and DIPEA (128 μL, 0.74 mmol). The solution was subsequently stirred overnight at room temperature. The resulting solution was then poured into water and extracted with EtOAc (2×30 mL), washed with brine, dried with MgSO4 and evaporated to dryness. Purification by two successive flash chromatography procedures using (DCM/MeOH: 95:5) and (Hexanes/Acetone: 1:1) respectively and trituration with diethyl ether yielded 35 mg (23%) of compound 37. 1H NMR (CDCl3) δ: 0.73 (s, 18-CH3), 0.84 (s, 19-CH3), 0.65-2.25 (residual CH and CH2), 2.40-2.75 (broad m, 2×CH2N and 2α-CH), 3.19 (t, J=8.3 Hz, 17α-CH), 3.32 (s, OCH3), 3.45-3.95 (broad m, 2×CH2NCO, CH2N of proline and 3β-CH), 5.14 (t, J=7.6 Hz, NCHCO of proline), 7.52 (m, 2×CH of naphthalene), 7.67 (d, J=8.4 Hz, CH of naphthalene), 7.85 (m, 3×CH of naphthalene), 8.09 (s, CH of naphthalene). 13C NMR (CDCl3) δ: 11.7, 17.1, 21.0, 23.2, 27.6, 28.1, 29.4, 33.0, 35.2, 35.8, 38.4, 43.0, 48.0, 49.0, 50.3, 51.1, 55.7, 56.0, 56.2, 57.8, 59.3, 63.6, 63.8, 64.1, 64.7, 65.0, 66.9, 90.7, 126.6, 127.2, 127.4, 127.7, 127.8, 128.0, 128.6, 132.5, 133.6, 133.9, 169.5, 170.4 HRMS: calcd for C40H55N3O4: 642.4265, found [M+H]+ 642.4274.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[C:32]([CH:39]([CH3:41])[CH3:40])[C:31]=3[O:42][CH2:43][CH:44]([F:46])[F:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)(=O)[CH3:19].O>CN(C=O)C>[CH2:4]([O:5][C:6](=[O:7])[C:8]([F:9])=[C:18]([C:21]1[O:25][C:24]2[C:26]([C:30]3[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[CH:33]=[C:32]([CH:39]([CH3:41])[CH3:40])[C:31]=3[O:42][CH2:43][CH:44]([F:46])[F:45])=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)[CH3:19])[CH3:3]
Reactant: CC(=O)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)=C(C)c1cc2cccc(-c3cc(C(C)C)cc(C(C)C)c3OCC(F)F)c2o1
Temperature: 40 °C

Procedure:
To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil) in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents) of triethyl 2-fluoro-2-phosphonoacetate (diluted in 1 mL of dry DMF) at 0° C. After the gas evolution has ceased, 0.51 mmol of 2-acetyl-7-[3,5-diisopropyl-2-(2,2-difluoroethoxy)phenyl]-benzo[b]furan (see Example 9, step A) diluted in 3 mL of dry DMF was added dropwise. The red mixture was slowly heated to 40° C. until complexion. After cooling, water was added and the solution was extracted 2 times with ethyl acetate. The organic layers were combined, washed with water and brine and dried over MgSO4. After evaporation of the solvents, the crude oil is purified over a short plug of silica gel (eluent: 95/5 hexane/ethyl acetate) to afford 2-fluoro-3-{7-[2-(2,2-difluoroethoxy)-3,5-diisopropylphenyl]-benzo[b]furan-2-yl}-but-2-enoic acid ethyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][NH2:2].C[O:4][C:5](=O)[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1>CO>[CH:8]1([CH2:7][CH2:6][C:5]([NH:2][CH3:1])=[O:4])[CH2:13][CH2:12][CH:11]=[CH:10][CH2:9]1
Reactant: COC(=O)CCC1CC=CCC1
Reactant: CN
Solvent: CO
Product: CNC(=O)CCC1CC=CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
Methyl amine (8 M in EtOH, 75 ml, 600 mmol) was added to a mixture of 3-cyclohex-3-enyl-propionic acid methyl ester (German patent DE 4023848 A1 19920130) (20.0 g, 119 mmol) in 75 mL of methanol. The mixture was stirred at room temperature for one day. Additional Methyl amine (8 M in EtOH, 40 ml, 320 mmol) was added to the mixture and stirring continued for one more day. The mixture was concentrated and the residue was taken up in ethyl acetate, washed with 0.5 M aqueous HCl, dried and stripped of the solvent to give the title compound (19.50 g, 98% yield, uncorrected) as a pale orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][CH:15]=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([I:24])C(=O)C1>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([I:24])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]cnc2C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(I)nc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
To a solution of 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (Preparation 20, 18 g, 80.62 mmol) in THF (300 mL) was added NIS (27.2 g, 121 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc (800 mL), washed with sodium thiosulfate aqueous solution (3×700 mL) and brine (500 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow solid (18.25 g) in a 64.8% yield.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[N:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][OH:11])=[CH:14][CH:15]=1
Reactant: Clc1nc2cccnc2s1
Reactant: OCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCc1ccc(Oc2nc3cccnc3s2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-chloro[1,3]thiazolo[5,4-b]pyridine (103 mg, 0.604 mmol) in DMF (2.0 mL) was added 4-hydroxymethyl-phenol (75 mg, 0.604 mmol, 1.0 equiv.) and Cs2CO3 (221 mg, 0.628 mmol, 1.04 equiv.). The reaction was allowed to stir at rt for 14 h. The reaction mixture was then filtered through diatomaceous earth, diluted with EtOAc (15 mL), washed with water (4×50 mL) and dried. After filtration and concentration, the desired product was obtained as a cream-colored solid (140 mg, 90%). MS (ESI): mass calcd. for C13H10N2O2S, 258.1; m/z found, 259.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 8.46-8.44 (m, 1H), 8.11-8.08 (m, 1H), 7.51 (dd, J=8.2, 4.7, 1H), 7.48-7.42 (m, 4H), 5.32 (t, J=5.8, 1H), 4.55 (d, J=5.8, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].C1OCCOCCOCCOCCOCCOC1.[H-].[Na+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(OCC)(=O)C.ClCCl.O1CCCC1>[CH2:41]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCOP(=O)(CCCCCCCCCCCO)OCC
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOP(=O)(CCCCCCCCCCCOCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
Diethyl 11-hydroxyundecylphosphonate (4.0 g, 13.0 mmol) and 18-crown-6 (spatula tip) were added to anhydrous tetrahydrofuran under inert atmosphere. Sodium hydride (312 mg, 13.0 mmol) was added and the solution allowed to stir for 10 minutes. Benzyl bromide (2.4 mL, 19.5 mmol) was then added and the reaction stirred at reflux for 4 hours. After cooling to room temperature, dichloromethane was added and the mixture washed with water and brine. The organic layer was collected, dried over magnesium sulfate, and concentrated under reduced pressure to yield a liquid. Column chromatography (stationary phase:silica, mobile phase:ethyl acetate) was used to isolate the desired product (Rf=0.70, ethyl acetate) as a clear oil (2.173 g, 42% yield). 1H NMR (500.13 MHz, CD2Cl2) δ 7.36-7.29 (m, 4H), 7.29-7.23 (m), 4.47 (2H), 4.10-3.97 (m, 4H), 3.45 (t, J=6.62 Hz, 2H), 1.72-1.62 (m, 2H), 1.62-1.48 (m, 4H), 1.40-1.20 (m, 20H). 13C{1H} NMR (100.62 MHz, CD2Cl2) δ 139.4, 128.6 (2C), 127.9 (2C), 127.7, 73.03, 70.88, 61.57 (d, J=6.4 Hz, 2C), 30.95 (d, J=16.8 Hz), 30.17, 29.94, 29.91, 29.85, 29.75, 29.48, 26.58, 25.91 (d, J=139.8 Hz), 22.78 (d, J=5.3 Hz), 16.68 (d, J=5.9 Hz, 2C). 31P{1H} NMR (202.45 MHz, CD2Cl2): δ 32.83. Analysis calculated (found) %: C 66.30 (65.66), H 9.86 (9.95). MS (ESI, m/z): 399 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 399.2659 (399.2671).