Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6](=[NH:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[N+:9](=[C:11]1[N:15]=[CH:14][N:13]=[C:12]1[C:16]([NH2:18])=[O:17])=[N-:10]>C(O)C>[CH2:1]([N:5]([C:6](=[NH:8])[CH3:7])[N:10]=[N:9][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[C:16]([NH2:18])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: CCCCNC(C)=N
Solvent: CCO
Product: CCCCN(N=Nc1[nH]cnc1C(N)=O)C(C)=N
Reaction time: 0.17 h

Procedure:
1.2 g. of N-butyl-acetamidine (Bp.: 76°-78° C./0.4 torr) are dissolved in 50 ml of anhydrous ethanol, whereafter 1.4 g. of 5-diazo-imidazole-4-carboxamide are added at 25° C. under stirring within 10 minutes. After 2.5 hours the orange-colored solution is clarified with activated characoal and evaporated in vacuo. 2.6 g. of a slowly crystallizing resin are obtained, which is twice crystallized from an ethanol-acetone mixture. Thus, a colorless, crystalline product, the 5-[3-n-butyl-3-(alpha-iminoethyl)-1-triazeno]-imidazole-4-carboxamide, melting at 191° C., is obtained (decomposition)
Reaction SMILES: Cl([O-])(=O)(=O)=O.[C:6]([O-])(=O)[CH3:7].[C:10]1([CH3:17])[CH:15]=[CH:14][C:13]([Tl+2])=[CH:12][CH:11]=1.O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC=CC=1>[CH3:17][C:10]1[CH:15]=[CH:14][C:13]([C:10]2[CH:15]=[CH:14][C:6]([CH3:7])=[CH:12][CH:11]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc([Tl+2])cc1
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc(C)cc2)cc1

Procedure:
A solution of 1000 parts by weight of p-tolyl thallium acetate perchlorate (p-CH3C6H4TlClO4CH3COO) in 6000 parts by weight of water and a solution of 2 parts by weight of palladium (II)-acetate [Pd(OAc)2 ] in 1500 parts by weight of benzene were stirred together vigorously for 2 hours at 60° C. Then the organic phase was separated and the benzene was distilled off under reduced pressure. 310 parts by weight of a residue remained which contained 297 parts by weight of p-tolyl acetate and 11 parts by weight of 4,4-dimethyl biphenyl in addition to palladium compounds. The reaction rate was 99% with a selectivity of 95%. The mixture was rectified over a short column at 10 m bar with the fraction passing over between 79° and 85° C. consisting of pure p-tolyl acetate. The distillation residue was taken up in acetone, and 4,4'-dimethyl biphenyl in pure form was obtained by addition of water.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15](OCC)=[O:16])=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.CCOCC>[CH2:1]([C:5]1[NH:6][C:7]([CH2:15][OH:16])=[C:8]([N:10]2[CH:11]=[CH:12][CH:13]=[CH:14]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-n2cccc2)c(C(=O)OCC)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nc(-n2cccc2)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 2-butyl-4-(1H-pyrrol-1-yl)imidazole-5-carboxylate (Example 21, 0.5 g) in tetrahydrofuran (15 mL) was treated with a 1 M solution of LiAlH4 in ether (2.1 mL). The reaction was stirred overnight at room temperature then quenched by addition of saturated aqueous (NH4)2SO4. The resulting suspension was extracted three times with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate and evaporated to afford the title compound as an off-white solid. MS (DEI) 205 (m).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13](O)(=O)[CH3:14]>CO>[CH2:5]([NH:12][N:2]1[CH2:1][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [BH3-]C#N
Reactant: NCc1ccccc1
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNN2CCC2)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 97.3 %

Procedure:
Sodium cyanoborohydride (1.15 g, 18.3 mmol) was added to a solution of benzylamine (1.04 ml, 9.5 mmol) and glacial acetic acid (2.10 ml, 36.7 mmol), in dry methanol (150 ml), at room temperature. The solution was cooled to 0° C. and a solution of the-preceding aldehyde (1.35 g, 7.3 mmol), in methanol (50 ml), was added. The mixture was warmed to room temperature and stirred for 20 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc/aq. K2CO3. The aqueous was extracted with EtOAc (×3) and the combined extracts dried and evaporated. The crude product was chromatographed on silica gel eluting with CH2Cl2 /MeOH (95:5→92:8) to give the desired N-benzylaminoazetidine (1.5 g, 73%). A mixture of formic acid (99%, 18 ml) and H2O(2 ml) was added to N-tert-butyloxycarbonyl-3-(benzylamino)methyl azetidine (1.5 g, 5.3 mmol) at 0° C. The mixture was warmed to room temperature, stirred for 16 h, and the solvent then removed under vacuum. Saturated aqueous K2 CO3 (25 ml) was added to the residue and extracted with nBuOH (5×25 ml). The combined extracts were evaporated and the residue treated with CH2Cl2 (50 ml) and filtered to remove inorganics. The filtrate was dried (Na2SO4) and evaporated to give the title compound (0.512 g, 55%). δ (360 MHz, CDCl3) 2.85 (2H, s, CH2Ph), 3.36-3.39 (1H, m, CH), 3.57-3.72 (4H, m, 2 of CH2), 3.79 (2H, s, CH2), 7.23-7.34 (5H, m, Ar--H).
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.C(N(CC)CC)C.[CH3:32][Si:33]([CH3:48])([CH3:47])[CH2:34][CH2:35][O:36][C:37](ON1C(=O)CCC1=O)=[O:38].S([O-])(O)(=O)=O.[K+]>CS(C)=O.O>[CH3:32][Si:33]([CH2:34][CH2:35][O:36][C:37]([NH:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)=[O:38])([CH3:48])[CH3:47]
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: C[Si](C)(C)CCOC(=O)N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of thyroxine (1.66 g, 2.14 mmol) in DMSO (15 mL) was added triethylamine (3.21 mmol) followed by solid Teoc-0Su (610 mg, 2.35 mmol). The mixture was stirred at room temperature overnight then diluted with water (22 mL), acidified with saturated potassium hydrogen sulfate solution and extracted with ether (3×45 mL). The combined organic extracts were washed with water (4×45 mL), dried with magnesium sulfate, and evaporated to dryness. (Yield: 1.87 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40]([C@@H:42]1[CH2:47][NH:46][CH2:45][CH2:44][N:43]1[CH3:48])=[O:41]>>[CH3:38][O:39][C:40]([C@@H:42]1[CH2:47][N:46]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:45][CH2:44][N:43]1[CH3:48])=[O:41]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COC(=O)[C@@H]1CNCCN1C
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)[C@H](C(=O)OC)C1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with (S)-1-methyl-piperazine-2-carboxylic acid methyl ester (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H45N4O4Cl2 [(M+H)+] 679.2813, observed 679.2805.
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CN)CCCCC1.BrCC(N(C)C)=O.Br[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28]>>[CH:1]1([CH2:7][NH:9][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CBr)N1CCOCC1
Reactant: C[C@H](N)c1ccccc1
Agent: CN(C)C(=O)CBr
Agent: NCC1CCCCC1
Product: O=C(CNCC1CCCCC1)N1CCOCC1

Procedure:
By following the procedure of section (a) of this example but replacing (S)-1-phenylethylamine with twice the equivalent amount of (cyclohexylmethyl)amine and replacing 2-bromo-N,N-dimethylacetamide with an equivalent amount of 4-(2-bromo-1-oxoethyl)morpholine, 4-{2-[(cyclohexylmethyl)amino]-1-oxoethyl}morpholine [1H NMR(CDCl3) δ 3.76-3.54 (m,3H), 3.43-3.33 (m,4H), 2.45 (d, J=6.6 Hz,2H), 2.41 (broad s,1H), 1.84-0.84 (m, 11H)] was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:20]([F:34])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.C(#N)C.Cl.[OH-].[Na+]>C(OCC)(=O)C.O>[NH2:1][C:2]1[C:3]([C:18]2[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:20]([F:34])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(C2CCC3(CC2)OCCO3)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ncc(C2CCC(=O)CC2)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-(3-amino-6-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide (170 mg, 0.368 mmol) was added acetonitrile (3 mL), water (2 mL) and then HCl 3M aqueous solution (0.613 mL, 1.838 mmol). The reaction was stirred at room temperature for 30 min followed by LCMS. To the reaction was added 200 mL of ethyl acetate, basified with excess 1M NaOH. The aqueous layer was extracted and the organic layer was washed with water (3×), filtered and concentrated to residue to give the desired product as free base. Assume quantitative yield (0.368 mmol). LCMS (m/z): 419.3 (MH+), 0.75 min.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]=1[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:34])[N:26]([CH3:33])[CH2:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[CH:21][C:20]=2[CH:35]([CH3:37])[CH3:36])[N:17]=[C:16]([C:38]([NH:40][C:41]2([C:51]([OH:53])=[O:52])[CH:48]3[CH2:49][CH:44]4[CH2:45][CH:46]([CH2:50][CH:42]2[CH2:43]4)[CH2:47]3)=[O:39])[CH:15]=1.[OH-].[OH:55][CH2:56][CH2:57][N+:58]([CH3:61])([CH3:60])[CH3:59]>CO>[OH:55][CH2:56][CH2:57][N+:58]([CH3:61])([CH3:60])[CH3:59].[CH3:13][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH3:4])[C:7]=1[C:14]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:34])[N:26]([CH3:33])[CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])=[CH:21][C:20]=2[CH:35]([CH3:37])[CH3:36])[N:17]=[C:16]([C:38]([NH:40][C:41]2([C:51]([O-:53])=[O:52])[CH:42]3[CH2:43][CH:44]4[CH2:45][CH:46]([CH2:47][CH:48]2[CH2:49]4)[CH2:50]3)=[O:39])[CH:15]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)[O-])C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
A solution of 1 ml of DCM containing 0.05 g of the compound obtained in EXAMPLE 1' and 0.025 ml of a 45% solution of choline hydroxide in MeOH are left stirring for 15 minutes at 35° C., and the mixture is then concentrated under vacuum. The residue is triturated in 5 ml of ether and the precipitate formed is drained. 0.03 g of the expected product is obtained, m.p.=150° C.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][C@@H:8]([NH:16]S(C1C=CC(C)=CC=1)=O)[C@H:9]([CH3:15])[C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])(C)(C)C.FC(F)(F)C(O)=O>CO>[NH2:16][C@@H:8]([C@H:9]([CH3:15])[C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])[CH2:7][C:6]([OH:26])=[O:5]
Reactant: CCC[C@@H](C)[C@@H](C)[C@@H](CC(=O)OC(C)(C)C)NS(=O)c1ccc(C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCC[C@@H](C)[C@@H](C)[C@H](N)CC(=O)O
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To the solution of (4R,5R)-4,5-dimethyl-(R)-3-(toluene-4-sulfinylamino)-octanoic acid tert-butyl ester (1.8 g, 4.71 mmol) in dry methanol (30 mL) at 0° C. under nitrogen was added excess trifluoroacetic acid (25 mL) and stirred for 2 hours at that temperature. The solution was concentrated to dryness followed by the addition of dry dichloromethane (20 mL) and trifluoroacetic acid (20 mL). The resulting mixture was stirred for 2 hours under nitrogen and concentrated to dryness. The residue was applied to BondElute SCX ion exchange resin and eluted with water until the eluent was at constant pH of 6.5. The resin was then eluted with a 1:1 solution of methanol and with 10% ammonium hydroxide solution. The ammonium hydroxide solution was evaporated and the residue was crystallized with methanol-acetonitrile mixture to afford the titled compound (0.717 g, 81.2% yield) as a white solid: 1H NMR (400 MHz, CD3OD-D) δ ppm 0.9 (m, 11 H) 1.1 (m, 2 H) 1.3 (m, 1 H) 1.4 (m, 1 H) 1.6 (m, 1 H) 1.7 (m, 2 H) 2.3 (dd, J=16.6, 10.0 Hz, 1 H) 2.5 (dd, J=16.7, 3.5 Hz, 1 H) 3.3 (m, 1 H). MS, m/z (relative intensity): 188 [M+1H, 100%], 186 [M−1H, 100%].
Reaction SMILES: Cl[C:2]1[C:3]([C:20]([NH2:22])=[O:21])=[N:4][C:5]([CH2:18][CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)[CH2:26][CH2:25]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[CH2:18]([C:5]1[N:4]=[C:3]([C:20]([NH2:22])=[O:21])[C:2]([NH:40][C:39]2[CH:41]=[CH:42][C:36]([N:33]3[CH2:34][CH2:35][CH:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH2:31][CH2:32]3)=[CH:37][CH:38]=2)=[N:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH3:19]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 55.1 %

Procedure:
A mixture of 3-chloro-6-ethyl-5-(3-nitrophenoxy)pyrazine-2-carboxamide (400 mg), 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (374 mg), trifluoroacetic acid (209 μL), and N-methylpyrrolidone (2.8 mL) was heated at 150° C. for 16 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the precipitated solid was collected by filtration, and then dried. The obtained solid was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-200:10:1) to obtain 6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(3-nitrophenoxy)pyrazine-2-carboxamide (383 mg) as a brown solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])N1C=CN=C1.[Br:10][C:11]1[CH:12]=[C:13]([C:17]([OH:22])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:14]=[CH:15][CH:16]=1>O1CCCC1>[Br:10][C:11]1[CH:12]=[C:13]([C:17]([CH2:18][CH3:19])([O:22][Si:2]([CH3:1])([CH3:8])[CH3:9])[CH2:20][CH3:21])[CH:14]=[CH:15][CH:16]=1
Reactant: CCC(O)(CC)c1cccc(Br)c1
Reactant: C[Si](C)(C)n1ccnc1
Solvent: C1CCOC1
Product: CCC(CC)(O[Si](C)(C)C)c1cccc(Br)c1
Reaction time: 8 h
Yield: 59 %

Procedure:
N-trimethylsilylimidazole (8.2 mL, 55.81 mol) was added to a solution of the crude 3-(3-bromo-phenyl)-pentan-3-ol in tetrahydrofuran (100 mL) in a nitrogen atmosphere at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into distilled water, followed by extraction with dichloromethane. The extract was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane:ethyl acetate=40:1) to give the title compound as a colorless oil (8.7 g, 59% in two steps).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:23]1([C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)O)[OH:24].CC1C=CC(S(O)(=O)=O)=CC=1.O.C1(C)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:22][C:30]3[CH:29]=[CH:28][CH:27]=[CH:25][C:23]=3[O:24]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: Clc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 50.3 %

Procedure:
The above ketone (450 mg, 1.39 mmol), catechol (614 mg, 5.58 mmol), p-TsOH.H2O (529 mg, 2.78 mmol), toluene (5 mL) and xylene (15 mL) were heated at 185° C. overnight using a Dean-Stark apparatus to remove water. Work-up and purification afforded 4-[2-(4-chloro-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a pink oil (221 mg, 50%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]([F:71])([F:70])[C:25]1[CH:26]=[C:27]([C@H:35]2[O:39][C:38](=[O:40])[N:37]([CH2:41][C:42]3[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[CH:44][C:43]=3[C:52]3[C:57]([Cl:58])=[CH:56][CH:55]=[C:54]([C:59]4[CH:64]=[CH:63][C:62]([CH:65]([OH:67])[CH3:66])=[CH:61][C:60]=4[CH3:68])[CH:53]=3)[C@H:36]2[CH3:69])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[C:65]([C:62]1[CH:63]=[CH:64][C:59]([C:54]2[CH:53]=[C:52]([C:43]3[CH:44]=[CH:45][C:46]([C:48]([F:49])([F:50])[F:51])=[CH:47][C:42]=3[CH2:41][N:37]3[C@@H:36]([CH3:69])[C@@H:35]([C:27]4[CH:26]=[C:25]([C:24]([F:71])([F:70])[F:23])[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=4)[O:39][C:38]3=[O:40])[C:57]([Cl:58])=[CH:56][CH:55]=2)=[C:60]([CH3:68])[CH:61]=1)(=[O:67])[CH3:66]
Reactant: Cc1cc(C(C)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccc(Cl)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin Periodinane (58.3 mg, 0.137 mmol) was added to a solution of alcohol from Example 51 (82 mg, 0.115 mmol) in methylene chloride (5 ml) at room temperature. The resulting slurry was stirred at room temperature for 1 h. No starting material was seen by TLC (EtOAc/hexane 2:8). The solid was filtered. The filtrate was concentrated. The residue was purified by flash column on silica gel, eluting with EtOAc/hexane (20:80) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz): δ a mixture of 1:1 atopoisomers 7.90 (s, 1H), 7.89 (s, 1H), 7.84 (d, J=8 Hz, 1H), 7.72 (m, 4H), 7.62 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 0.5H), 7.46 (d, J=8.0 Hz, 0.5H), 7.40-7.34 (m, 2H), 7.26 (d, J=2.5 Hz, 0.5H), 7.21 (d, J=2.5 Hz, 0.5H), 5.62 (d, J=8.0 Hz, 1H), 5.02 (d, J=15.5 Hz, 0.5H), 4.83 (d, J=16.0 Hz, 0.5H), 4.08 (d, J=16.0 Hz, 0.5H), 4.01 (d, J=15.5 Hz, 0.5H), 3.99 (m, 0.5H), 3.90 (m, 0.5H), 2.64 (s, 3H), 2.40 (s, 1.5M), 2.39 (s, 1.5H), 0.64 (d, J=6.5 Hz, 1.5H), 0.62 (d, J=6.5 Hz, 1.5H). LC/MS M+714.01.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18]([CH3:24])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].IC.[H-].[Na+].Cl.[C:31]([O-])(O)=O.[Na+]>C1COCC1>[CH3:24][C:18]1[C:17]([CH2:16][O:15][C:13]2[CH:12]=[CH:11][C:10]3[C:6]([CH:5]([CH3:31])[C:4]([O:3][CH2:1][CH3:2])=[O:25])=[CH:7][S:8][C:9]=3[CH:14]=2)=[CH:22][CH:21]=[C:20]([CH3:23])[N:19]=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1csc2cc(OCc3ccc(C)nc3C)ccc12
Reaction time: 8 h

Procedure:
To a mixture of ethyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-1-benzothiophen-3-yl)acetate (710 mg) and iodomethane (0.373 ml) and THF (10 mL) was added sodium hydride (60% in oil, 160 mg) at 0° C. The mixture was stirred 0° C. to room temperature under argon atmosphere overnight. To the mixture was added 1N HCl at room temperature, and the mixture was adjusted to pH 6-7 with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed successively with brine and water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (230 mg).
Reaction SMILES: C([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH2:24][CH2:25][Cl:26])[CH2:21][CH2:22][Cl:23])=[C:16]([CH3:27])[CH:15]=2)=[CH:9][CH:8]=1)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[Cl:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][Cl:26])[C:17]1[CH:18]=[CH:19][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][CH:9]=2)=[CH:15][C:16]=1[CH3:27].[F:29][C:30]([F:35])([F:34])[C:31]([O-:33])=[O:32]
Reactant: Cc1cc(Oc2ccc(C(=O)OC(C)(C)C)cc2)ccc1N(CCCl)CCCl
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Oc2ccc(C(=O)O)cc2)ccc1N(CCCl)CCCl
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of compound 5 in dichloromethane (5 ml) and trifluoroacetic acid (10 mL) was allowed to stir at ambient temperature for 2 hours. The mixture was evaporated to dryness, azeotroped twice with ethyl acetate to give 4-{4-[bis(2-chloroethyl)-amino]-3-methyl-phenoxy)-benzoic acid (compound 6) as a solid trifluoroacetate salt (1.0 g, 73% yield). Melting point, 91-3° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH:18][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)CCN
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(C(=O)NCCC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4.94 g of 4-butylbenzoylchloride in 20 ml of methylene chloride was added dropwise a solution of 2.53 g of 3,3-dimethylbutylamine and 5.1 g of triethylamine in 80.0 ml of methylene chloride. The resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with water, and the organic layer was washed with 6N hydrochloric acid, water, 2N sodium hydroxide, brine, dried, and evaporated to dryness to yield an oil which solidified on standing. The solid was triturated with hexane, collected by filtration, and dried to yield N-[3,3-dimethylbutyl]-4-n-butylbenzamide as a white solid, mp 70°-71° C.
Reaction SMILES: [CH:1](=[O:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C1(=O)[O:13][C:11](=[O:12])[CH2:10][CH2:9]1>CC(C)=O>[O:7]=[C:1]([C:2]1[O:6][C:5]([CH:4]=[CH:3][C:2](=[O:6])[CH3:1])=[CH:4][CH:3]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12].[O:7]=[C:1]([C:2]1[O:6][C:5]([CH2:4][CH2:3][C:2](=[O:6])[CH3:1])=[CH:4][CH:3]=1)[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C1CCC(=O)O1
Reactant: O=Cc1ccco1
Solvent: CC(C)=O
Product: CC(=O)C=Cc1ccc(C(=O)CCC(=O)O)o1
Product: CC(=O)CCc1ccc(C(=O)CCC(=O)O)o1

Procedure:
Furfural, acetone, and succinic anhydride are reacted to form the starting compounds of either 4-oxo-4-(5-(3-oxobut-1-en-1-yl)furan-2-yl)butanoic acid or 4-oxo-4-(5-(3-oxobutyl)furan-2-yl)butanoic acid, according to a method described in U.S. Provisional Application No. 61/669,775, filed Jul. 10, 2012, entitled “Compounds and Methods for the Production of Long Chain Hydrocarbons From Biological Sources,” the entire disclosure of which is incorporated herein by reference. These species are then esterified with ethanol in the usual way to form ethyl 4-oxo-4-(5-(3-oxobut-1-en-1-yl)furan-2-yl)butanoate and ethyl 4-oxo-4-(5-(3-oxobutyl)furan-2-yl)butanoate.