Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[BH4-].[Na+]>CO>[OH:1][CH:2]1[CH2:7][O:6][CH2:5][CH:4]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3]1
Reactant: O=C1COCC(NC(=O)OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: O=C(NC1COCC(O)C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
Benzyl 5-oxotetrahydro-2H-pyran-3-ylcarbamate (4.35 g, 17.45 mmol) and cerium(III) chloride heptahydrate (6.50 g, 17.45 mmol) were dissolved in methanol (100 mL) before cooling to 0° C. Sodium borohydride (0.660 g, 17.45 mmol) was then added slowly. Intense bubbling was observed. The reaction was allowed to stir at 0° C. for 30 min before quenching by addition of acetone (˜3 mL) and stirring at room temperature for 30 additional min. The reaction was then evaporated to dryness. The material was partitioned between DCM and water and the aqueous layer was washed with DCM (5×). The organic layers were combined, dried over sodium sulfate, filtered, and condensed to give impure benzyl 5-hydroxytetrahydro-2H-pyran-3-ylcarbamate (2.5 g, 9.95 mmol, 57.0% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.39 (m, 5H), 5.90-6.06 (m, 1H), 5.10 (d, J=4.29 Hz, 2H), 3.59-3.97 (m, 6H), 1.77-2.06 (m, 3H; MS (ESI) m/z 252.1 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN.Cl.O1CCOCC1.[BH3-][C:25]#[N:26].[Na+].[OH-].[Na+]>CO.O>[CH3:25][NH:26][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CNC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 1-benzyl-4-piperidone (1.9 g, 10 mmol) in MeOH (10 ml) were added methylamine (8 ml, 16 mmol) and 3 Å molecular sieves. After stirring at RT for 1 h, the reaction was cooled in an ice-bath and 4 N HCl in dioxane (2.5 ml, 10 mmole) and NaCNBH3 (1.2 g, 20 mmol) were added. The reaction was stirred at RT overnight. After the reaction was complete, H2O was added the pH was adjusted to 10 with 50% NaOH solution. The product was extracted with EtOAc (100 ml, 3×) from aqueous solution and combined. The combined organic solution was washed with brine, dried over MgSO4, filtered and concentrated to give an oil which was purified by silica flash chromatography, eluting with 8% saturated NH3 /MeOH in CH2Cl2 to give 4-methylamino-1-benzyl piperidine (1.77 g, 8.66 mmol, 86%). FAB Mass [M+1]+35Cl 205.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]#[N:8].[OH-:9].[K+].OO>O>[NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:8])=[O:9]
Reactant: [OH-]
Reactant: N#Cc1cccn1N
Agent: OO
Agent: [K+]
Solvent: O
Product: NC(=O)c1cccn1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
1-Amino-1H-pyrrole-2-carbonitrile (2.52 g, 23.5 mmole) was suspended in 75 ml water, treated with potassium hydroxide (32 g, 0.57 mole), 30% hydrogen peroxide (2 ml) and stirred overnight at room temperature. The reaction mixture was cooled to 0° C. for 30 min and the product was isolated by filtration, washed with cold water and dried under vacuum to give 2.55 g of product (yield: 87%).
Reaction SMILES: [OH-].[Na+].[C:3]([S:6][CH2:7][C:8]1[NH:9][C:10](=[O:13])[S:11][CH:12]=1)(=O)N.C(O)C.[C:17](#[N:20])[CH:18]=C>O.C(O)(=O)C>[C:17]([CH2:18][CH2:3][S:6][CH2:7][C:8]1[NH:9][C:10](=[O:13])[S:11][CH:12]=1)#[N:20]
Reactant: C=CC#N
Reactant: NC(=O)SCc1csc(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: N#CCCSCc1csc(=O)[nH]1
Reaction time: 0.08 h
Yield: 76.2 %

Procedure:
60 ml (0.60 mol) of 10N sodium hydroxide solution are added dropwise to a suspension containing 57 g (0.30 mol) of 4-carbamoylmercaptomethyl-2(3H)-thiazolone [compound of the formula (Ib)] in 150 ml of water and 90 ml of ethanol under stirring while bubbling an inert gas through the mixture. After 5 minutes, 17.5 g (0.33 mol) of acrylnitrile are added dropwise to the resulting solution at 25° to 30° C. The mixture is stirred for an additional 4 hours, then filtered to obtain a sharply clear solution which is then acidified by adding 27 ml of glacial acetic acid. The crystalline precipitate is filtered off at 15° to 20° C., washed with water and then with isopropanol and dried to give 45.8 g (76.5%) of the named compound, m.p.: 108°-111° C. The active ingredient content of the substance is 99.6%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[Br:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][O:22][C:20]1[CH:19]=[CH:18][C:17]([S:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(OCc4cccc(Br)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (62 mg, 0.30 mmol) was reacted with 4-[2-Amino-4-(3-bromo-benzyloxy)-phenylsulfanyl]-phenol (120 mg, 0.30 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (86 mg, 41%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.73 Hz, 3 H) 1.85 (dt, J=7.73 Hz, 2 H) 3.00 (dd, J=7.72 Hz, 2 H) 5.15 (s, 2 H) 6.27 (d, J=7.35 Hz, 1 H) 6.66 (d, J=8.82 Hz, 2 H) 7.07-7.69 (m, 7 H) 7.65 (s, 1 H) 7.83 (d, J=8.82 Hz, 1 H) 8.41 (d, J=6.99 Hz, 1 H) 9.03 (d, J=8.82 Hz, 1 H) 9.81 (s, 1 H) 11.05 (br s, 1 H) 14.43 (br s, 1 H); MS (ESI+) m/z 572, 574 (M+H−TFA)+; (ESI−) m/z 570-572 (M−H−TFA)−.
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)=[N:12][CH:13]=2)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:38][O:39][C:40]([C@H:42]1[CH2:47][C@@H:46](O)[CH2:45][CH2:44][N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:41]>C1COCC1>[N:14]1([C:11]2[N:12]=[CH:13][C:8]([O:7][CH2:6][C:4]3[CH:5]=[N:1][N:2]([C@@H:46]4[CH2:45][CH2:44][N:43]([C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[C@@H:42]([C:40]([O:39][CH3:38])=[O:41])[CH2:47]4)[N:3]=3)=[CH:9][CH:10]=2)[CH:18]=[N:17][N:16]=[N:15]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Reactant: COC(=O)[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 5-((2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine (600 mg, 2.45 mmol), triphenylphosphine (1.5 eq.), and (2R,4S)-N-Boc-4-hydroxypiperidine-2-carboxylic acid methyl ester (1.5 eq.) dissolved in THF (20 mL) at 0° C. was added a solution of di-tertbutylazodicarboxylate (1.5 eq.) in THF (5 mL) drop wise. The reaction was allowed to warm to room temperature overnight and the solvents removed in vacuo The crude material was purified by flash column chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 9.44 (1H, s), 8.27 (1H, d), 8.03 (1H, d), 7.71 (1H, s), 7.58 (1H, dd), 5.27 (2H, s), 4.99-5.19 (1H, m), 4.57 (1H, m), 4.11-4.31 (1H, m), 3.79 (3H, s), 3.04-3.24 (1H, m), 2.75 (1H, m), 2.18-2.32 (2H, m), 2.05 (1H, m), 1.50 (9H, s). ES+-MS found: 486.1.
Reaction SMILES: C1(N)CCCCC1.C(N(CC)CC)C.C(=S)=S.C(N(CC)CC)C.[CH:25]1([NH:31][C:32](=S)[SH:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[CH:25]1([N:31]=[C:32]=[S:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: S=C(S)NC1CCCCC1
Solvent: CC#N
Solvent: NC1CCCCC1
Solvent: S=C=S
Product: S=C=NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Cyclohexylamine (99 mg, 0.001 mol) and 101 mg (0.001 mol) of triethylamine together with 76 mg (0.001 mol) of carbon disulfide were dissolved in 10 ml of acetonitrile to prepare a solution of cyclohexyldithiocarbamic acid triethylamine salt in acetonitrile. To this solution was added 256 mg (0.001 mol) of DSC and the admixture was stirred for 24 hours at room temperature. The reaction mixture is distilled to remove the acetonitrile and the residue was admixed with ethyl acetate, washed with 1 N-HCl, with aqueous 4% NaHCO3, with water and finally with saturated aqueous NaCl, followed by drying over anhydrous sodium sulfate. The resulting solution was distilled to remove the ethyl acetate and the residue was purified by column-chromatography on silica gel developed with hexane-benzene to give cyclohexylisothiocyanate in a yield of 85%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[Mg].[CH3:11][O:12][C:13]([C:15]12[CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:21][C:20](=[O:30])[CH:19]1[CH2:18][N:17]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16]2)=[O:14].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:11][O:12][C:13]([C:15]12[CH:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:21][C:20]([OH:30])([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=3)[CH:19]1[CH2:18][N:17]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16]2)=[O:14]
Reactant: Cc1ccc(Br)cc1C
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C)c(C)c1)CCC2c1ccccc1
Temperature: -7 °C
Reaction time: 4 h

Procedure:
2.3 cm3 of 4-bromo-ortho-xylene and 0.42 g of magnesium turnings in a mixture of 20 cm3 of diethyl ether and 20 cm3 of tetrahydrofuran were heated at reflux for one hour. After cooling to a temperature in the region of -7° C., a solution of 3.11 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 20 cm3 of diethyl ether was added over 25 minutes. The reaction mixture was stirred for four hours at a temperature in the region of 25° C. and then hydrolysed by 50 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase was separated by settling and extracted with 25 cm3 of ethyl acetate. The organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, 1.995 g of methyl(3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3,4-dimethylphenyl)-4-phenyl-octahydroisoindole-3a-carboxylate were obtained, the characteristic of which compound, used as it was in the following stage, was as follows:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[H-].[Na+].Cl[CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31].[Cl-].[NH4+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+].CO.ClCCl.CN(C)C=O.O1CCCC1>[O:32]=[C:30]([CH3:31])[CH2:29][CH2:28][CH2:27][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: CC(=O)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)CCCn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (3.5 mmol) and tetrahydrofuran (45 mL) and dimethylformamide (5 mL). Cool in an ice bath and add sodium hydride (0.21 g, 60% in oil, 5.22 mmol). After 1 hour, add 5-chloropentan-2-one, ethylene ketal (0.79 mL, 5.22 mmol) and tetra-n-butylammonium bromide (112 mg, 0.35 mmol) and warm to ambient temperature. Heat to reflux. After 18 hours, cool, add sodium hydride (0.1 g) and 5-chloropentan-2-one, ethylene ketal (0.50 mL) and again heat to reflux. After 24 hours, cool in a dry-ice/acetone bath and add a saturated aqueous solution of ammonium chloride. Warm to ambient temperature and dilute the reaction mixture with a saturated aqueous solution of sodium bicarbonate. Concentrate in vacuo to remove most to the tetrahydrofuran and extract three times with ethyl acetate. Extract the combined organic layers with water and then brine, dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.1% saturated aqueous ammonia solution to give (1-(4-oxopentyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine, ethylene ketal.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1>CO.[Pd]>[ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1ccc(C2CCNCC2)cc1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (10 g) in methanol (200 mL) was added 10% palladium on charcoal (0.5 g) and the mixture was hydrogenated at 50 psi for 3 h. The catalyst was removed by filtration and solvent was evaporated, leaving the product (10.0 g) as a white powder, which was used in the next step without purification. The product appeared to be pure based on 1H NMR and TLC analysis. 1H NMR δ 1.95-2.03 (br d, 2H), 2.14-2.29 (m, 2H), 2.70-2.80 (m, 1H), 2.91-3.07 (br q, 2H), 3.60-3.64 (br d, 2H), 6.96-7.03 (m, 2H), 7.19-7.22 (m, 2H), 9.60 (br s, 1H), 9.71 (br s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1cccs1
Product: CC(=O)NCCc1cccs1
Yield: 90 %

Procedure:
In close analogy to the procedure described above, 2-Thiophen-2-yl-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CC(C)=O>[O:27]=[C:20]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To an ice-cooled solution of 3-(trifluoromethyl)aniline (64.5 g, 0.40 mol) and triethylamine (60 ml) in acetone (700 ml) was added dropwise, ethyl 3-chloro-3-oxopropanoate (63.6 g, 0.42 mol) in acetone (50 ml). After the addition (approx. 30 minutes) stirring was continued at room temperature overnight. The solvents were removed and water (1200 ml) was added. The resulting precipitate was filtered off, thoroughly washed twice with water and then dried to afford the title compound as yellow powder (109 g, 99%).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][O:8][C@H:9]1[CH2:27][O:26][C:12]2=[CH:13][CH:14]=[C:15]3[C:19]([N:18]([CH2:20][C@@H:21]([N:23]=[N+]=[N-])[CH3:22])[N:17]=[CH:16]3)=[C:11]2[CH2:10]1)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.[ClH:37]>C1COCC1>[ClH:37].[ClH:37].[NH2:23][C@@H:21]([CH3:22])[CH2:20][N:18]1[C:19]2[C:15](=[CH:14][CH:13]=[C:12]3[O:26][CH2:27][C@H:9]([O:8][CH2:7][CH2:6][OH:5])[CH2:10][C:11]3=2)[CH:16]=[N:17]1
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)C[C@@H](OCC(=O)OC(C)(C)C)CO3)N=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](N)Cn1ncc2ccc3c(c21)C[C@@H](OCCO)CO3
Reaction time: 1 h
Yield: 59 %

Procedure:
To a mixture of the product from Step C (0.30 g, 0.78 mmol) in anhydrous THF (20 mL) under nitrogen was added a 1 M solution of lithium aluminum hydride in THF (2.0 mL, 2.6 mmol). The mixture was stirred for 1 h and cooled followed by the addition of methanol and 2 N HCl. The volatiles were evaporated and the residue was purified by reversed phase HPLC (gradient, 0% to 50% acetonitrile in water). The desired fractions were combined, concentrated, treated with 2 N HCl in ethanol (10 mL), and evaporated (in vacuo, 65° C.) to give a glass (0.17 g, 59%): mp>100° C.; LCMS (+APCI) m/z 292 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([Li])CCC.IC.O>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:26])=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCC1C=C(Cl)C=CN1C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCC1C=C(Cl)C=C(C)N1C(=O)OC(C)(C)C
Temperature: -42 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-2-n-undecyl-1,2-dihydropyridine (3.15, 8.51 mmol) in 115 ml of THF at −42° C. was added n-butyllithium (6.4 mL, 10.2 mmol, 1.6 M solution in hexanes) dropwise via syringe. After the mixture had stirred at −42° C. for 1 h, iodomethane (1.6 mL, 25.54 mmol) was added and stirring was continued at −42° C. for 1 h and then at room temperature for 1 h. Water (30 mL) and ether (60 mL) were added, the layers were separated, the aqueous phase was extracted with ether (2×15 mL), and the combined organic extracts were washed with brine. The organic phase was dried over K2CO3 filtered through silica gel/Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography gave with 5% EtOAc in hexanes afforded 2.5 g (77%) of the product as a clear orange oil which was homogeneous by TLC analysis. 1H NMR (250 MHz) d 5.62 (dd, 1 H), 5.30 (m, 1 H), 4.76 (dt 1 H), 2.16 (s, 3 H), 1.53 (s, 9 H), 1.48-1.40 (m, 2 H), 1.26 (br s, 18 H), 0.84 (t, 3 H); 13C NMR (62.7 MHz) 153.1 (s), 137.1 (s), 126.6 (s), 119.4 (s), 112.3 (s), 81.4 (s), 54.2 (s), 31.9 (s), 31.8 (s), 29.69 (s), 29.63 (s), 29.55 (s), 29.44 (s), 29.36 (s), 29.33 (s), 28.2 (s), 24.6 (s), 22.7 (s), 22.0 (s), 14.1 (s) ppm. FT-IR (neat) 2956, 2924, 2852, 1709, 1637, 1471, 1393, 1368, 1342, 1169, 1131 cm−1.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.C1C=NC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=1.Cl>CN(C=O)C.C(N(CC)CC)C>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1ccc(-c2nn[nH]n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(NC(=O)c2ccc(-c3nn[nH]n3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2H-tetrazol-5-yl)benzoic acid (example 412, 4 mmol) and HOAt (4.2 mmol) in DMF (6 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (4.2 mmol) and the resulting mixture was stirred at room temperature for 1 hour. An aliquot of this HOAt-ester solution (0.45 mL) was mixed with 0.25 mL of a solution of 4-aminobenzoic acid (1.2 mmol in 1 mL DMF). (Anilines as hydrochlorides can also be utilised, a slight excess of triethylamine was added to the hydrochloride suspension in DMF prior to mixing with the HOAt-ester.) The resulting mixture was shaken for 3 days at room temperature. 1N hydrochloric acid (2 mL) was added and the mixture was shaken for 16 hours at room temperature. The solid was isolated by centrifugation (alternatively by filtration or extraction) and was washed with water (3 mL). Drying in vacuo at 40° C. for 2 days afforded the title compound.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[C:11]([OH:14])([CH3:13])[CH3:12])(=[O:9])=[O:8].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([CH:10]([S:7]([NH2:6])(=[O:8])=[O:9])[C:11]([OH:14])([CH3:13])[CH3:12])=[CH:16][CH:17]=1
Reactant: COc1ccc(CNS(=O)(=O)C(c2ccc(Br)cc2)C(C)(C)O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(O)C(c1ccc(Br)cc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-1-(4-bromophenyl)-2-hydroxy-2-methylpropane-1-sulfonamide from the above reaction in 150 ml of dichloromethane was admixed with 50 ml of trifluoroacetic acid and stirred at room temperature for 17 hours. The starting solution was coevaporated twice with 100 ml of toluene and the crude product was purified using a Flashmaster with an n-heptane/ethyl acetate gradient by means of normal phase chromotography. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (16 g) with a molecular weight of 308.2 g/mol (C10H14BrNO3S).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:3]=1[CH3:30].[C:31]([O-])([O-])=[O:32].[K+].[K+].C([B-](F)(F)F)=C.[K+].C1(C)C=CC=CC=1>O.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]([O:25][CH:19]([C:4]1[C:3]([CH3:30])=[C:2]([CH:31]=[O:32])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(Br)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=C[B-](F)(F)F
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C=O)c2ccccc2c1-c1ccc(Cl)cc1
Temperature: 23 °C
Yield: 50.6 %

Procedure:
A solution of ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (75 mg, 0.153 mmol), K2CO3 (317 mg, 2.29 mmol), PdCl2(dppf) (11.2 mg, 15.3 μmol), and potassium vinyltrifluoroborate (103 mg, 0.766 mmol) in H2O (500 μL), EtOH (absolute, 500 μL), and PhMe (1.0 mL) was heated to 100° C. for 4 h in a sealed vessel. The reaction was cooled to 23° C., diluted with H2O (30 mL), and extracted with EtOAc (3×). Combined organic phases were dried (Na2SO4), filtered, concentrated, and evaporated from MeOH in vacuo (2×). The residue was treated with MeOH (3.0 mL), and DCM (3.0 mL), and cooled to −78° C. The solution was sparged with ozone in O2 for 5 min. After min past the end of the sparge, the reaction was treated with DMS (100 μL) and warmed to 0° C. 10% Na2S2O3 (2.0 mL) was added, and the reaction was stirred at 23° C. for several minutes. The reaction was diluted with H2O and DCM, then filtered over Celite. The filtrate was extracted with DCM (2×). Organic phases were combined, dried (Na2SO4), filtered, and concentrated. DCM was added, and the solution was wet-loaded onto a 12 g “gold” ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes 3:97 isocratic) giving the desired product (34 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.73 (d, J=8.2 Hz, 1H), 7.56-7.22 (m, 7H), 5.16 (s, 1H), 4.24-4.12 (m, 2H), 2.81 (s, 3H), 1.23 (t, J=7.0 Hz, 3H), 1.00 (s, 9H).