Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][O:7]/[N:8]=[CH:9]/[C:10]1[C:11]([F:33])=[C:12]([F:32])[C:13]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:14]([CH:22]=1)[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16])(=[O:3])[CH3:2].ClCCl.ClC(Cl)C(O)=O.C(=O)(O)[O-].[Na+]>O>[C:1]([NH:4][CH2:5][CH2:6][O:7][NH:8][CH2:9][C:10]1[C:11]([F:33])=[C:12]([F:32])[C:13]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:14]([CH:22]=1)[C:15]([NH:17][O:18][CH2:19][CH2:20][OH:21])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To (E)-5-[(2-acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (57.6 mg, 99.3 μmol) obtained in Step D was added dichloromethane (2.5 ml). The mixture was stirred at room temperature, and borane-pyridine complex (80 μl, 0.79 mmol) and dichloroacetic acid (67 μl, 0.80 mmol) were added thereto. After stirring for 3 hours, water (10 ml) and saturated aqueous sodium bicarbonate (2 ml) were added to the reaction mixture, which was then extracted with methylene chloride (15 ml and 2×8 ml). The combined organic layers were washed with aqueous sodium bicarbonate (8 ml) and saturated aqueous sodium chloride (8 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol (10:1)) to give 5-[(2-acetylamino-ethoxyamino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (Compound C-7, 44.0 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[CH:5]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH3:11])[CH:5]=1)=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Product: COC(=O)c1ccc(-c2ccccc2)c(C)c1
Yield: 10.1 %

Procedure:
A solution of 4-bromo-3-methyl-benzoic acid methyl ester (1.0 g, 4.36 mmol) and phenylboronic acid (0.64 g, 5.24 mmol) in n-PrOH (15 mL) is treated with 2 M Na2CO3 (4.4 mL), and purged with N2 for 10 min, and Pd(PPb3)4 (25 mg, 0.22 mmol) is then added. The reaction is refluxed overnight. Organic solvent is removed in vacuo, the residue is extracted with CH2Cl2 (30 mL), washed with 10% Na2CO3 (30 mL), H2O (30 mL); dried with Na2SO4 and concentrated. Purification of the crude material by chromatography affords the title compound (0.10 g, 10%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C@H:11]3[CH2:27][C@H:15]4[O:16][C:17]5[C:22]([F:23])=[C:21]([O:24][CH2:25][CH3:26])[CH:20]=[CH:19][C:18]=5[C@@H:14]4[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C(O)=O.O>C1(C)C=CC=CC=1>[CH2:25]([O:24][C:21]1[CH:20]=[CH:19][C:18]2[C@@H:14]3[CH2:13][CH2:12][C@@H:11]([CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)[CH2:27][C@H:15]3[O:16][C:17]=2[C:22]=1[F:23])[CH3:26]
Reactant: CCOc1ccc2c(c1F)O[C@@H]1C[C@H](C3CCC4(CC3)OCCO4)CC[C@@H]21
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCOc1ccc2c(c1F)O[C@@H]1C[C@H](C3CCC(=O)CC3)CC[C@@H]21
Reaction time: 18 h

Procedure:
13.3 g (35.3 mmol) of (±)-(3R*,4aR*,9bS*)-3-(1,4-dioxaspiro[4.5]dec-8-yl)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran are dissolved in 200 ml of toluene and stirred vigorously together with 40 ml (1.06 mol) of formic acid with addition of 1.0 ml (55.6 mmol) of water. After 18 h, the organic phase is separated off, and the formic acid is extracted with toluene. The combined organic phases are washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvent is purified by column chromatography (SiO2, toluene:ethyl acetate=4:1), giving (±)-4-((3R*,4aR*,9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-yl)cyclohexanone as colourless solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].[BH4-].[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[C:11]1[CH:12]=[C:13]([CH2:14][OH:15])[CH:16]=[CH:17][CH:18]=1
Reactant: CN1CCC(OC(c2cccc(C=O)c2)c2nc3ccccc3[nH]2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(OC(c2cccc(CO)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzaldehyde (example 505B, 310 mg) in methanol (4 mL) is added portionwise sodium borohydride (50 mg). The reaction mixture is stirred at room temperature for 15 minutes then heated at reflux for 3 h. Methanol is removed under reduced pressure. Water is added and the aqueous phase is extracted by ethyl acetate. The organic phase is washed by water, then dried over magnesium sulfate and concentrated to give {3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}methanol. 1H NMR: 9.85 (sl, 1H), 7.78-7.65 (m, 1H), 7.50-7.12 (m, 7H), 5.87 (s, 1H), 4.64 (s, 2H), 3.62-3.45 (m, 1H), 2.78-2.58 (m, 2H), 2.22 (s, 3H), 2.15-1.50 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[N:17]=[N:16][C:15]([CH:18]2[CH2:20][CH2:19]2)=[C:14]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[CH:13]=1>C1COCC1>[CH:28]1([O:27][C:24]2[CH:25]=[CH:26][C:21]([C:14]3[CH:13]=[C:12]([O:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[N:17]=[N:16][C:15]=3[CH:18]3[CH2:19][CH2:20]3)=[CH:22][CH:23]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CC2)nn1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CC3)nn2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-methyl-piperidin-4-ol (0.50 mmol, 0.06 g) in THF (1 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.75 mmol, 0.03 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 6-chloro-4-(4-cyclohexyloxy-phenyl)-3-cyclopropyl-pyridazine (0.25 mmol, 0.082 g) in THF (0.5 mL). After completion of addition, the reaction mixture was warmed to 50° C. and stirred for 2 hours. After cooling the reaction to room temperature, the reaction was quenched with water (1 mL) and extracted with ethyl acetate (1×5 mL). The ethyl acetate layer was washed with brine (2 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 4 g SiO2 cartridge 4-6% (2N NH3 in MeOH) in DCM to give 4-(4-cyclohexyloxy-phenyl)-3-cyclopropyl-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.030 g). LCMS: m/z 409 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.48-7.58 (2H, m), 7.30-7.48 (1H, m), 7.04-7.14 (2H, m), 5.30-5.54 (1H, m), 4.37-4.48 (1H, m), 3.60-3.70 (1H, m), 3.14-3.51 (3H, m), 2.93 (3H, s), 2.54 (1H, d), 2.41 (1H, d), 2.16-2.31 (2H, m), 1.96-2.10 (3H, m), 1.76-1.89 (2H, m), 1.27-1.67 (6H, m), 1.09-1.24 (4H, m).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][CH2:11][C:12](=O)[CH2:13][CH3:14].N1C=CC=CC=1.ClCCl>O1CCCC1.Cl[Ti](Cl)(Cl)Cl.O>[CH3:6][O:5][C:3](=[O:4])[C:2](=[C:12]([CH2:13][CH3:14])[CH2:11][CH3:10])[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: CCC(=O)CC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC(CC)=C(C(=O)OC)C(=O)OC
Reaction time: 18 h
Yield: 46.6 %

Procedure:
Step A To a solution of dimethyl malonate (10 g, 75 mmol), 3-pentanone (6.5 g, 75 mmol) and pyridine (7.9 g, 100 mmol) in anhydrous tetrahydrofuran (300 mL) at 0° C. was added a dichloromethane solution (1 M) of TiCl4 (100 mL, 100 mmol) during a period of 1 h. After the addition was finished, the reaction mixture was gradually warmed room temperature and stirred for 18 h. Water was added to quench the reaction. The mixture was extracted with ethyl ether. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20) to give 2-(1-ethyl-propylidene)-malonic acid dimethyl ester as a light yellow oil (7 g, 46%).
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1>C(O)C.C(O)COCCO.NN.[Na].[OH-].[K+]>[CH:7]1[C:6]2[CH2:5][C:6]3[C:5](=[CH:4][CH:3]=[CH:2][CH:7]=3)[C:8]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)cc1
Agent: NN
Agent: [K+]
Agent: [Na]
Solvent: CCO
Solvent: OCCOCCO
Product: c1ccc2c(c1)Cc1ccccc1-2

Procedure:
The 2,7-bis-basic alkanes (IX) are prepared from the corresponding 2,7-bis-basic ketones (II) via the general reaction conditions of the Wolff-Kishner reduction, utilizing hydrazine and a base catalyst in an organic solvent. The desired product can be obtained by the direct reduction of the corresponding ketone, or the reduction may proceed in a stepwise fashion by the isolation of the hydrazone intermediate which is then subsequently reduced. In general the 2,7-bis-basic ketones are dissolved in an organic solvent such as ethanol, diethylene glycol or p-xylene to which hydrazine and sodium or potassium hydroxide or alkoxide is added. The reaction mixture is heated from about 140° to about 180°C for a period of from 12 to 48 hours to form the desired 2,7-bis-basic alkanes of fluorene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:27])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([N:19]([CH3:27])[CH3:18])[CH2:21][CH2:22]1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (870 mg, 2.80 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine (400 mg, 2.80 mmol) to afford the desired product (398 mg, 36%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.12 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 7.85 (dd, J=8.9, 2.0 Hz, 1H), 7.76 (d, J=8.9 Hz, 1H), 4.10-3.84 (m, 1H), 2.93-2.70 (m, 1H), 2.56-2.40 (m, 1H), 2.37 (s, 6H), 2.25 (d, J=12.0 Hz, 2H), 2.05 (d, J=11.4 Hz, 2H), 1.62-1.31 (m, 4H), 1.31-1.01 (m, 4H).
Reaction SMILES: [N:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[C@@H:3]([C:8]([O:10]CC)=[O:9])[CH2:2]2>Cl>[N:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[C@@H:3]([C:8]([OH:10])=[O:9])[CH2:2]2
Reactant: CCOC(=O)[C@H]1CN2CC[C@@H]1C2
Agent: Cl
Product: O=C(O)[C@H]1CN2CC[C@@H]1C2
Yield: 71.9 %

Procedure:
Ethyl (3R,4S)-1-azabicyclo[2.2.1]heptane-3-carboxylate (2.0 g, I. F. Cottrell, D. Hands, D. J. Kennedy, K. J. Paul, S. H. B. Wright and K. Hoogsteen, J. Chem. Soc. Perkin Trans. 1, 1991, 1091-1097) was dissolved in concentrated hydrochloric acid and heated under reflux for 5 hours. After cooling the solution was evaporated under reduced pressure and the residue re-evaporated from toluene (×3). Drying over phosphorous pentoxide and trituration with cold ethyl acetate/methanol gave the hydrochloride salt of (3R,4S)-1-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.2g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:12](=O)[NH:13][C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:31](O)(=O)C>>[C:1]([O:5][C:6](=[O:30])[NH:7][CH:8]([C:12]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]2[CH:16]=[CH:17][C:18]([CH3:31])=[CH:19][C:14]=2[N:13]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Br)ccc1NCc1ccccc1
Product: Cc1ccc2c(c1)nc(C(NC(=O)OC(C)(C)C)C(C)C)n2Cc1ccccc1
Yield: 66 %

Procedure:
A solution of [1-(2-benzylamino-5-bromo-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (400 mg, 0.84 mmol) in acetic acid (4 ml) was heated at 100° C. for 2 hours. The solvent was removed in vacuo and the resulting solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography to give of [1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-carbamic acid tert-butyl ester (300 mg, yield 66%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])[CH:5]=[CH:4][C:3]=1N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N([O-])=O.[Na+].[I-:48].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[F:18][C:16]([F:17])([F:19])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][C:3]([I:48])=[C:2]([CH3:1])[CH:7]=2)=[C:10]([CH2:28][CH2:29][CH3:30])[CH:11]=1)([O:24][CH2:25][O:26][CH3:27])[C:20]([F:22])([F:21])[F:23]
Reactant: [I-]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(N)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=N[O-]
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Solvent: O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(I)c(C)c1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 2-methyl-4-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-phenylamine (271 mg, 0.600 mmol) in acetonitrile (3.0 mL), p-toluene sulfonic acid monohydrate (342 mg, 1.80 mmol) was added. The resultant mixture was added with a mixed aqueous solution (water 400 μL) of sodium nitrite (83 mg, 1.20 mmol) and potassium iodide (249 mg, 1.50 mmol) at 10° C., stirred at the same temperature for 10 minutes, and then stirred at room temperature overnight. The reaction solution was added with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-1-(4-iodo-3-methylphenoxy)-2-propylbenzene (226 mg, yield 67%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[N:16][C:15]=3[CH3:29])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[H-].[Na+]>>[C:35]([O:34][C:32](=[O:33])[CH2:31][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=4)=[N:16][C:15]=3[CH3:29])[CH:6]=2)[C:2]([CH3:1])=[CH:3]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(C)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(C)cn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 a], 3-methyl-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-1H-indole was reacted with tert-butyl bromoacetate in the presence of sodium hydride to obtain (3-methyl-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless gum.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CCCC(=O)Cl
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (300 mg, 1.2 mmol) and triethylamine (260 μL, 1.8 mmol) in methylene chloride (50 mL) was added dropwise butyryl chloride (140 μL, 1.3 mmol) in methylene chloride (10 mL). After the addition the reaction was allowed to stir at ambient temperature for 1 h and then washed with a dilute aqueous sodium hydrogen carbonate solution. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:4:0.5) as the eluent. Yield: 330 mg (86%) of the title compound as white crystals: mp 131-132° C.; [α]21D +24° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 315 (39, M+).
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.[C:10]([NH2:16])(=[O:15])[CH2:11][C:12]([NH2:14])=[O:13].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=O>C(O)CCC>[OH:13][C:12]1[CH:11]=[C:10]([OH:15])[N:16]=[C:19]([C:18]([F:25])([F:24])[F:17])[N:14]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC(=O)CC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: Oc1cc(O)nc(C(F)(F)F)n1
Reaction time: 16 h
Yield: 44.5 %

Procedure:
Sodium hydride (900 g, 57.5% dispersion in mineral oil; 518 g active NaH; 22.5M) was stirred with 7.5 L toluene in a 22 L round-bottomed flask. Butanol was added over 5 hr. so that the pot temperature was maintained at 40°. The mixture was stirred an additional 16 hr. Malonamide (765 g; 7.5 M) was added, followed by ethyl trifluoroacetate (1065 g; 7.5 M). The ensuing reaction was exothermic; the mixture was then heated on a steam-bath for 3.5 hrs. It was then stirred at 23°-25° for an additional 16 hrs. The mixture was extracted with water (1×4 L and 1×2 L). The combined aqueous extracts were treated with activated charcoal and filtered. The filtrate was maintained at 10°-15° as it was acidified to pH 1-2 with 37% hydrochloric acid. The mixture was chilled to 5°. The solid was isolated by filtration and dried at 50° in vacuo to give 600 g (44.4% yield) VI m.p. 255°-256° (Lit. 265°).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.[Cu]I>[CH2:13]([NH:12][C:10]([C:6]1[S:5][C:4]([N:1]2[CH:36]=[C:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:3]=[N:2]2)=[N:8][C:7]=1[CH3:9])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1nc(N=[N+]=[N-])sc1C(=O)NCc1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(-n2cc(-c3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of 2-azido-N-benzyl-4-methylthiazole-5-carboxamide (0.65 g, 2.38 mmol) in tetrahydrofuran (10 mL) was added copper(I) iodide (0.45 g, 2.38 mmol), N,N-diisopropylethylamine (1.24 mL, 7.14 mmol) and phenylacetylene (0.37 g, 3.57 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:1) to afford the title compound as a white solid in 70% yield: mp 175-178° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.47-7.37 (m, 8H), 6.11 (br s, 1H), 4.64 (d, J=6.0 Hz, 2H), 2.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.9, 155.4, 153.3, 148.7, 137.4, 129.2, 129.0, 128.9, 128.8, 127.8, 126.0, 124.4, 116.7, 44.3, 17.4; MS (ES+) m/z 376.3 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C@H:6]([NH:20][C:21]([C:23]1[N:27](CC2C=CC=CC=2)[N:26]=[N:25][N:24]=1)=[O:22])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)C.C(OC(=O)C[C@H](NC(C1N=NN(CC2C=CC=CC=2)N=1)=O)CC1C=CC(C2C=CC=CC=2)=CC=1)C.[Li+].[OH-].Cl>CCO.C1COCC1>[C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]([CH2:7][C@@H:6]([NH:20][C:21]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)=[O:22])[CH2:5][C:4]([OH:35])=[O:3])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnnn1Cc1ccccc1
Agent: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnn(Cc2ccccc2)n1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1nnn[nH]1
Reaction time: 0.5 h

Procedure:
To a mixture of (R)-3-[(1-benzyl-1H-tetrazole-5-carbonyl)-amino]-4-biphenyl-4-yl-butyric acid ethyl ester and (R)-3-[(2-benzyl-2H-tetrazole-5-carbonyl)-amino]-4-biphenyl-4-yl-butyric acid ethyl ester (180 mg, 0.383 mmol) in EtOH (1 mL) and THF (1 mL) is added aqueous 1M LiOH (2 mL). After stirring for 0.5 hour, the reaction mixture is acidified with aqueous 1M HCl. The mixture is extracted with ethyl acetate, dried over Na2SO4, and concentrated under reduced pressure. The residue is dissolved in MeOH and hydrogenated with 10% Pd/C at room temperature for 3 hours and at 40° C. for 2 hours. The reaction mixture is concentrated and purified by reverse phase HPLC to give (R)-4-biphenyl-4-yl-3-[(1H-tetrazole-5-carbonyl)-amino]-butyric acid. HPLC retention time=1.18 minutes (condition D); MS (m+1)=352; 1H NMR (400 MHz, DMSO-d6) ppm 2.56 (dd, J=5.81, 15.92 Hz, 1H), 2.67 (dd, J=7.58, 15.92 Hz, 1H), 2.85-2.99 (m, 2H), 4.55-4.64 (m, 1H), 7.26-7.35 (m, 3H), 7.43 (dd, J=7.83, 7.83 Hz, 2H), 7.56 (d, J=8.08 Hz, 2H), 7.62 (d, J=7.07 Hz, 2H), 9.28 (d, 8.84 Hz, 1H), 12.28 (s, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([CH:14]=[C:15]([NH:17]C(=O)C)[N:16]=1)[C:8](N(OC)C)=[O:9])(=O)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.Cl>C1COCC1>[NH2:17][C:15]1[CH:14]=[C:7]([C:8]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:9])[CH:6]=[C:5]([NH2:4])[N:16]=1
Reactant: CON(C)C(=O)c1cc(NC(C)=O)nc(NC(C)=O)c1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cc(C(=O)c2ccc(F)cc2)cc(N)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a solution of 0.5 g (1.78 mmol) 2,6-bis-acetylamino-N-methoxy-N-methyl-isonicotinamide in 8 ml THF was added at room temperature 7.14 ml (7.14 mmol) of a 1M solution of 4-fluorophenylmagnesium bromide in THF and stirred for 80 min at room temperature and subsequently for 2 h at 40° C. After cooling to room temperature 0.8 ml 37% HCl was added and the mixture was evaporated to dryness. The residue was taken up in ethyl acetate and 2M Na2CO3. The aqueous phase was extracted with ethyl acetate and the combined organic fraction were dried with MgSO4 and evaporated to dryness. The residue was taken up in 3 ml MeOH and 1 ml 37% HCl and heated to reflux for 4 h. After evaporation to dryness the residue was taken up in ethyl acetate and 2M Na2CO3. The aqueous phase was extracted with ethyl acetate and the combined organic fraction were dried with MgSO4 and evaporated to dryness. The title compound was further purified by reversed phase HPLC eluting with an acetonitrile/water gradient and yielded 131 mg (32%) yellow crystals.