Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[CH:14]1([Zn+])[CH2:16][CH2:15]1.CN1CCN(C)C1=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:14]2[CH2:16][CH2:15]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: [Zn+]C1CC1
Reactant: COC(=O)c1cc(Cl)cc(I)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc(C2CC2)c1
Temperature: 50 °C
Reaction time: 2.25 h
Yield: 63.2 %

Procedure:
To a solution of methyl 3-chloro-5-iodobenzoate (0.5 g, 1.69 mmol) in THF (5 mL) were added cyclopropylzinc(II)bromide (3.71 mL, 1.86 mmol), PEPPSI-IPr (22.9 mg, 33.7 μmol, CAS RN 905459-27-0) and 1,3-dimethyl-2-imidazolidinone (DMI) (1 mL) and the turbid light brown solution was stirred at 50° C. for 2.25 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 50 g column using an MPLC (Flasmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 70:30). The obtained fraction (light yellow oil, 315 mg) was dissolved in THF (5 mL), to the clear solution were added cyclopropylzinc(II) bromide (3.71 mL, 1.86 mmol), PEPPSI-IPr (22.9 mg, 33.7 μmol, CAS RN 905459-27-0) and 1,3-dimethyl-2-imidazolidinone (DMI) (1 mL) and the reaction mixture was heated at 50° C. for 2.25 hours. The reaction mixture was poured on 10% aqueous citric acid solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 40:60) to give the title compound as a light brown oil (0.225 g; 63%) containing 3,5-dicyclopropyl-benzoic acid methyl ester.
Reaction SMILES: C([O+](CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:20])[C:17]([NH2:19])=O.Cl.[C:22]1([C:28]2([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C@H:36]3[C@H:32]([CH2:33][NH:34][CH2:35]3)[C:31](=[O:37])[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[NH:19]=[C:17]([N:34]1[CH2:33][C@H:32]2[C@H:36]([C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30][C:31]2=[O:37])[CH2:35]1)[CH:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH3:8])[CH3:20]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: COc1ccccc1C(C)C(N)=O
Agent: CC[O+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C(C)C(=N)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 20 h

Procedure:
Triethyloxonium tetrafluoborate (6.34 g) is added to a stirred suspension of (RS)-2-(2-methoxyphenyl)propionamide (5.4 g) in anhydrous dichloromethane (60 cc). The reaction mixture is stirred for 20 hours. A solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (6.65 g) and triethylamine (2.8 cc) in dichloromethane (30 cc) is added. The reaction mixture is refluxed for 5 hours. It is then cooled to +5° C. and is then treated with a 10% aqueous potassium carbonate solution (20 cc). After filtering, the organic phase is washed with distilled water (20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a neutral alumina column (0.05 mm-0.160 mm, diameter 5 cm, height 20 cm), eluting with a mixture of cyclohexane and ethyl acetate (50/50) and collecting 250 cc fractions. The first fraction is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04 mm-0.06 mm, diameter 2 cm, height 35 cm), eluting with a mixture of n-butanol/acetic acid/pyridine/water (90/4/4/2 by volume) and collecting 20 cc fractions. Fractions 14 to 19 are concentrated to dryness under reduced pressure (0.13 kPa). The residue is taken up in dichloromethane (40 cc) and washed with aqueous potassium carbonate solution (10 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from diisopropyl ether. The crystals are drained and dried under reduced pressure (0.13 kPa). (3aR,7aR)-2-[1-imino-2-(2-methoxyphenyl)-2-methylethyl]-7,7-diphenyl-4-perhydroisoindolone, form A, (0.12 g) is obtained in the form of a white meringue.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15]C(C)C)=[O:14])[CH:6]=[N:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[CH:6]=[N:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CC(C)OC(=O)c1cnc(OC(C)C)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ncc(C(=O)O)cc1C#N
Temperature: 25 °C
Yield: 100.8 %

Procedure:
1-Methylethyl 5-cyano-6-[(1-methylethyl)oxy]-3-pyridinecarboxylate (Preparation 93) (1.28 g, 5.15 mmol) in ethanol (20 ml) was treated with sodium hydroxide (5.15 ml, 10.30 mmol) and the mixture stirred at room temperature to give a homogeneous solution, until LC/MS showed no starting material. The mixture was concentrated to remove ethanol. The residue was diluted with water, then acidfied with 2M HCl to give a thick white precipitate. The solid was filtered off, washed with water and dried overnight in vacuo at 60° C., to give the title compound (1.07 g),
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH:26]=[CH:25][CH:24]=[C:23]2C=O)[CH:19]=[CH:20][CH:21]=1>C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH:26]=[CH:25][CH:24]=[C:23]2[CH:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=3)[NH:10][C:9]2=[O:14])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cccn1-c1cccc(Cl)c1
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)C(c1cccn1-c1cccc(Cl)c1)C(=O)N2
Yield: 17 %

Procedure:
By carrying out the procedure as in Example 1, but starting with 1.05 g (5 mmol) of 5-acetylaminoindolin-2-one in 150 ml of ethanol and 0.95 g (10 mmol) of 3-[N-(3-chlorophenyl)pyrrole-2-carboxaldehyde, 0.32 g (17%) of 3-[N-(3-chlorophenyl)pyrrol-2-yl]-5-acetylaminoindolin-2-one is obtained in the form of an orange solid whose characteristic is the following: melting point=251° C.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[N+:12]([O-])([OH:14])=[O:13].C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O>[ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[NH:3])[NH2:4]
Reactant: O=[N+]([O-])O
Reactant: N=C(N)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Product: N=C(N)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Amidinophenol hydrochloride (1.0 g, 5.8 mmol) was dissolved in concentrated sulfuric acid (2.5 mL), and concentrated nitric acid (0.38 mL) was added at −15° C. The reaction mixture was stirred for 1 hour while maintaining the temperature of the reaction mixture at −15° C. to −2° C., and slowly added to ice water. The mixture was neutralized by slowly adding sodium hydrogen carbonate, and the precipitated orange solid was collected by filtration. The solid was washed with water and acetone, and suspended in methanol. 4N Hydrochloric acid/dioxane was added to dissolve the solid. Diisopropyl ether was added to the solution, and the precipitated solid was collected by filtration. The solid was washed with diisopropyl ether and dried to give the title compound (0.98 g) as a pale-yellow powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.C[N+]1([O-])CCOCC1.ClCCCl>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(O)C2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(=O)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
A mixture of alcohol 266 (2.75 g, 10.45 mmol), NMO (5.8 g, 49 mmol) and 4 Å molecular sieves (8.34 g) was suspended in dry DCM (100 mL) and dry 1,2-dichloroethane (100 mL), stirred at room temperature for 45 min, and then cooled to 0° C. for the addition of solid TPAP (0.36 g, 1.03 mmol). The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 5 h, filtered through Celite®/silica gel using 50% AcOEt in hexanes as an eluent, then concentrated. The residue was purified by flash chromatography (eluent: 30% to 50% AcOEt in hexane) to provide title compound 267 (0.78 g, 29% yield).
Reaction SMILES: [C:1]([CH:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]=[C:8]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([OH:3])=O.[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[N:37]1([CH2:36][CH2:35][CH2:34][NH:33][C:1]([CH:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:5][CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=[C:8]2[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[O:3])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NCCCN1CCCCC1
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(Cc1ccccc1)C(=O)NCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 107.1 %

Procedure:
To a stirring solution of 1-[3-carboxy-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (1.0 g, 2.2 mmol) in N,N-dimethylformamide (75 ml) were added sequentially 1-amino-3-(piperidin-1-yl)propane (345 mg, 1.1 eq), 1-hydroxybenzotriazole (327 mg, 1.1 eq), and dicyclohexylcarbodiimide (500 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concentrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.35 grams of an orange foam.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH:19]=[C:18]([C:30]([NH2:32])=[O:31])[C:14]=3[NH:15][C:16]=2[CH:17]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)[CH:19]=[C:18]([C:30]([NH2:32])=[O:31])[C:14]=3[NH:15][C:16]=2[CH:17]=1
Reactant: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(OCc5ccccc5)ccc4c3n2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(O)ccc4c3n2)cc1
Yield: 89.3 %

Procedure:
A mixture of 7-(benzyloxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (Example 206, 155 mg, 0.366 mmol), 10% palladium on activated carbon (75 mg) and ammonium formate (115 mg, 1.83 mmol) was heated at reflux for 2 hr. Filtration followed by removal of the solvent form the filtrate. The residue was suspended in methylene chloride and filtration afforded 7-hydroxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (109 mg) as a yellow solid. MS (ESI) m/z 334.1 (M+H). 1H NMR (DMSO-d6) δ ppm 11.23 (1H, br. s.), 9.75 (1H, br. s.), 8.52 (1H, br. s.), 8.17-8.26 (3H, m), 8.01 (1H, d, J=8.24 Hz), 7.79 (1H, br. s.), 7.04-7.13 (3H, m), 6.74 (1H, dd, J=8.39, 1.98 Hz), 3.85 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]1[CH2:25][CH:24]1[N:26]([CH3:34])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=1.C(OC(N1CCN(C2C=CC(C(=O)NC3C=CC=C(C(C)(C)C)C=3)=CC=2)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:21])[NH:33][C:30]3[CH:29]=[N:28][C:27]([N:26]([CH:24]4[CH2:23][CH2:25]4)[CH3:34])=[CH:32][CH:31]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(c1ccc(N)cn1)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Product: CN(c1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cn1)C1CC1

Procedure:
4-{4-[6-(Cyclopropyl-methyl-amino)-pyridin-3-ylcarbamoyl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was synthesized from 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and N-2-cyclopropyl-N2-methyl-pyridine-2,5-diamine in a manner similar to the one described in the synthesis of 4-[4-(3-tert-butyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, above. LCMS calcd for C25H33N5O3 (m/e) 451, obsd 452 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]2[O:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.[ClH:33]>C(OCC)(=O)C>[ClH:33].[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:19]2[O:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CSc1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CSc1ccccc1-c1cccc2c1OCCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A mixture of tert-butyl 9-[2-(methylthio)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (170 mg, 0.458 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (133 mg, 94.3%) as a solid.
Reaction SMILES: [Cl-].[Cl-].C([Al+2])C.[C:6]([O:10][CH3:11])(=[O:9])[CH:7]=[CH2:8].[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH2:24]/[C:25]/2=[CH:26]/[CH3:27])[CH2:17]1)(=[O:14])[CH3:13].O>C(Cl)Cl>[C:12]([O:15][C@@H:16]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@H:18]([CH2:19][CH2:20][C@@H:21]3[C:31]2=[CH:30][CH2:29][C@@:28]2([CH3:36])[C@H:22]3[CH2:23][CH:24]=[C:25]2[C@H:26]([CH3:27])[CH2:8][CH2:7][C:6]([O:10][CH3:11])=[O:9])[CH2:17]1)(=[O:14])[CH3:13]
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Reactant: C=CC(=O)OC
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CC[C@@H](C)C1=CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.7 %

Procedure:
Ethyl aluminum dichloride (14.2 mL, 25 mmol, 1.8M in toluene) was added to a solution of methyl acrylate (1.89 mL, 20 mmol) in DCM (60 mL) at 0° C. under inert atmosphere. The resulting solution was stirred for 15 min and then compound 1.6a (3 g, 8.7 mmol) was added. After stirring for an additional 20 min at 0° C., the temperature was raised to 25° C. and held there for a further 18 h. At this point the reaction was determined to be complete by TLC, then the mixture was poured into cold (0° C.) water (60 mL). The phases were separated and the aqueous layer was extracted with DCM (60 mL). The organic layers were combined and washed sequentially with water (50 mL) and saturated brine solution (100 mL). It was then dried over anhydrous Na2SO4 (5 g) and filtered. The filtrate was concentrated under vacuum, providing compound 1.7b (2.6 g, 70%).
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N+](C=C(SC)SC)([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27]CCCC1N=CNC=1Br)([O-:23])=[O:22].CN>>[N+:21]([CH:24]=[C:25]([NH:26][CH3:27])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[Br:1])([O-:23])=[O:22]
Reactant: NCCCCc1nc[nH]c1Br
Reactant: CSC(=C[N+](=O)[O-])NCCCCc1nc[nH]c1Br
Agent: CN
Agent: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCCCc1nc[nH]c1Br

Procedure:
When 5-bromo-4-(4-aminobutyl)imidazole is reacted with 1-nitro-2,2-bis-methylthioethylene according to the procedure of Example 8(i) and the resultant 1-nitro-2-methylthio-2-[4-(5-bromo-4-imidazolyl)butylamino]ethylene, m.p. 157°-158° treated with methylamine by the procedure of Example 8(ii), the title compound, m.p. 145°-148° is produced.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.CN(C)P(N(C)C)(N(C)C)=O>C(OCC)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: Cc1c(O)cccc1Br
Reactant: BrC12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1c(Br)cccc1OC12CC3CC(CC(C3)C1)C2
Temperature: 250 °C

Procedure:
3-Bromo-2-methylphenol (1000 mg) and 1-bromoadamantane (2013 mg) were added to hexamethylphosphoramide (8 mL) and the mixture was heated in a microwave reactor (Biotage) at 250° C. for 35 minutes. The solution was taken up in diethyl ether, washed with water two times, washed with brine, dried on anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel using 2% ethyl acetate (hexanes) increasing to 5% ethyl acetate (hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][PH:4](=[O:6])[OH:5].[C:12]([OH:31])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OOC(CC)(C)C)(CC)(C)C>[OH:6][P:4]([CH2:3][CH:2]([CH3:1])[CH2:7][C:8]([CH3:10])([CH3:9])[CH3:11])([CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([OH:31])=[O:30])=[O:5]
Reactant: CC(C[PH](=O)O)CC(C)(C)C
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: CCC(C)(C)OOC(C)(C)CC
Product: CCCCCCCCC(CCCCCCCCC(=O)O)P(=O)(O)CC(C)CC(C)(C)C
Temperature: 140 °C
Yield: 82.8 %

Procedure:
6.31 g (0.0354 moles) of 2,4,4-trimethylpentyl phosphinic acid, 10 g (0.0354 moles) of oleic acid and 0.25 mL (0.0012 moles) of di-tert-amylperoxide are mixed in a 50 mL single neck flask. The mixture is purged with argon to remove oxygen and is heated under argon for 6 hours at 140° C. Tert-amyl alcohol is removed by distillation and 13.5 g (83% yield) of 10-[hydroxy-(2,4,4-trimethyl-pentyl)-phosphinoyl]-octadecanoic acid is obtained as a viscous oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].Cl.C(N=C=NCCCN(C)C)C.[F:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[O:43][CH2:42][CH2:41][CH:40]2[NH2:47]>ClCCl>[F:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[O:43][CH2:42][CH2:41][CH:40]2[NH:47][C:21](=[O:22])[CH2:20][N:3]1[CH2:4][CH2:5][CH2:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]1=[O:1]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NC1CCOc2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)NC1CCOc2ccc(F)cc21
Reaction time: 60 h

Procedure:
A solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.063 g, 0.204 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.059 g, 0.305 mmol) and 6-fluorochroman-4-amine (0.037 g, 0.224 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring for approximately 60 hours, the reaction was loaded directly onto a SF15-12 column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 75% ethyl acetate/hexanes over 25 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.22-7.31 (m, 2H), 7.15-7.22 (m, 5H), 7.05-7.10 (m, 2H), 6.85-6.94 (m, 3H), 6.75-6.81 (m, 1H), 5.13 (dt, J=8.5, 5.8 Hz, 2H), 4.18 (d, J=14.6 Hz, 1H), 4.10-4.21 (m, 1H), 3.97-4.09 (m, 1H), 4.01 (d, J=14.6 Hz, 1H), 3.54-3.62 (m, 2H), 2.54-2.64 (m, 2H), 2.12-2.25 (m, 1H), 1.91-2.02 (m, 1H), 1.81-1.90 (m, 2H); MS (ESI−) m/z 457 (M−H)−.
Reaction SMILES: [CH2:1]([N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13]>>[CH2:1]([N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:14])[CH3:13])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: c1coc(Cn2cccc2)c1
Product: CC(=O)c1cccn1Cc1ccco1

Procedure:
a. 1-Furfuryl-2-acetyl-pyrrole was prepared starting from 1-furfuryl-pyrrole described by Reichstein in Helv. 15, 1450 (1932) as well as Gianturco et al. in Tetrahedron 20, 1763 (1964). Acetylation by reaction of the Grignard intermediate with acetyl chloride [cf. Chem. Ber. 47, 1416 (1914)] led to the desired ketone. (A small amount of the 3-isomer was also obtained, separable by fractional distillation). The product boils at 100°-102° C./0.03 mm Hg. and crystallizes on standing. Recrystallization from a mixture of methylene dichloride and petroleum ether gave a white crystalline product with a m.p. of 42°-43° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH:14][C:15]([OH:17])=[O:16].Cl>CO.[Pd]>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)C=CCCCCCCCCCCCF
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(O)CCCCCCCCCCCCCF
Reaction time: 12 h
Yield: 75.1 %

Procedure:
The methyl ester of 14-fluoro-2-tetradecenoic acid (3.3 g) was dissolved in methanol (20 ml), in which 10% palladium/carbon (0.9 g) was suspended, and a 10% methanolic hydrochloric acid solution (2 ml) was added. The mixture was stirred under hydrogen atmosphere for 12 hours. The reaction mixture was filtered, and a large amount of chloroform was added to the filtrate. The chloroform layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water. The organic layer was dried and concentrated to give the methyl ester of 14-fluorotetradecanoic acid (2.5 g). The methyl ester (2.5 g) was dissolved in a solution of potassium hydroxide in ethanol-water (1:1), and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was acidified by adding citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give 14-fluorotetradecanoic acid (2.3 g).