Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][NH:3]1.[BH4-].[Na+].Cl>C1COCC1>[OH:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([N:10]2[C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:8]([C:18]3[CH:19]=[C:20]([C:23]([NH2:25])=[O:24])[S:21][CH:22]=3)=[N:9]2)[CH2:12][CH2:13]1
Reactant: NC(=O)c1cc(-c2nn(C3CCC(=O)CC3)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2nn([C@H]3CC[C@H](O)CC3)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-oxo-1-(4-oxocyclohexyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (40.0 mg) obtained in Example 170 in THF was added sodium borohydride (8.49 mg) at 0° C., and the mixture was stirred overnight at room temperature under nitrogen atmosphere. To the reaction solution was added 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give a cis/trans mixture (30.9 mg) of the title compound. The obtained cis/trans mixture was purified by HPLC (column: L-column2 ODS (trade name) 20 mmID×150 mmL, 5 μm, manufactured by Daicel Chemical Industries, mobile phase: water/acetonitrile (containing 10 mM ammonium carbonate)) to give the title compound having a shorter retention time.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>CS(C)=O.C(N(CC)CC)C>[NH2:31][CH:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]3[NH:13][C:12]4[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=4[N:10]=3)=[O:6])=[CH:3][C:2]=2[Cl:1])=[O:24])[CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: NC1CCCN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)C1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl piperidin-3-ylcarbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17. HPLC-MS results: retention time: 2.91 minutes; C21H21Cl2N5O2 (446,34); mass spectrum: (M+H)+=446.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([N:21]([CH2:22][CH3:23])[C:16]([CH:13]1[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1)=[O:18])[CH3:20]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Reactant: CCNCC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCN(CC)C(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.1 %

Procedure:
Under an argon atmosphere, 1-[(benzyloxy)carbonyl]-3-pyrrolidinecarboxylic acid (500 mg) was dissolved in DMF (5 mL), added with N,N-diethylamine (0.293 g), further with EDC (769 mg) and HOBt (542 mg) and stirred at room temperature for 72 hours. The reaction solution was diluted with ethyl acetate, sequentially washed with 1 N hydrochloric acid, a 1 N sodium hydroxide aqueous solution, water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate before distillation of the solvent. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=95:5→0:1) to give the titled compound (556 mg) having the following physical properties.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:12]2([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH2:10][CH3:11])[C:5]([F:26])=[CH:4][C:3]=1[C:27]#[N:28].[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:27]([C:3]1[CH:4]=[C:5]([F:26])[C:6]([NH:8][C@H:9]([C:12]2([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)[CH2:10][CH3:11])=[N:7][C:2]=1[NH:29][C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1)#[N:28]
Reactant: CC[C@H](Nc1nc(Cl)c(C#N)cc1F)C1(NC(=O)OCc2ccccc2)CC1
Reactant: Cc1cccc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@H](Nc1nc(Nc2cccc(C)c2)c(C#N)cc1F)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Yield: 77.4 %

Procedure:
To a solution of (S)-benzyl 1-(1-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)propyl)cyclopropylcarbamate (60 mg, 0.15 mmol) in dioxane (1 mL) was added m-toluidine (19 mg, 0.18 mmol), BINAP (18.7 mg, 0.03 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol) and Cs2CO3 (146 mg, 0.45 mmol). After degassed with Argon, the mixture was heated at 80° C. for 15 h. The mixture was diluted with dioxane, precipitate was filtered off, filter cake was washed with ACN, the filtrate was concentrated and purified by column to give of (S)-benzyl 1-(1-(5-cyano-3-fluoro-6-(m-tolylamino)pyridin-2-ylamino)propyl)cyclopropylcarbamate (55 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH2:27][C@@H:28]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=1)[C:29]([NH:31][C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([C:10](=[O:12])[NH:27][C@H:28]([C:29](=[O:30])[NH:31][C:32]1[CH:33]=[N:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Reaction time: 8 h

Procedure:
To a solution of 2-{[(tert-butoxy)carbonyl]amino}-3-ethoxy-3-oxopropanoic acid XCVII (0.5 g; 2.02 mmol) and DIPEA (1.20 mL; 7.07 mM) in DCM (30 mL) was added (2S)-2-amino-N-(quinolin-3-yl)-3-[4-(trifluoromethyl)phenyl]propanamide LXXI (0.88 g; 2.02 mmol) and TBTU (0.68 g; 2.12 mmol). The reaction mixture was stirred overnight, diluted with DCM (30 mL), washed with 1 M aq NaOH (2×), 1 M aqueous HCl (2×), brine and dried over anhydrous MgSO4. The solvent was evaporated and the crude product was crystallized from DCM/hexane to give ethyl 2-{[(tert-butoxy)carbonyl]amino}-2-{[(1S)-1-[(quinolin-3-yl)carbamoyl]-2-[4-(trifluoromethyl)phenyl]ethyl]carbamoyl}acetate XCVIII as yellow crystals (0.90 g, 1.53 mmol, 76% yield). ESIMS found for C29H31F3N4O6 m/z 589 (M+H).
Reaction SMILES: [C-]1C2C(=CC=CC=2)C=CC=1.[Li+].C1(S[C:19]2([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:24]=3)[CH2:21][CH2:20]2)C=CC=CC=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][CH2:42][CH:43]=[O:44])[CH:36]=1>O1CCCC1>[C:26]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([O:22][C:19]2([CH:43]([OH:44])[CH2:42][CH2:41][C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: O=CCCc1cccnc1
Reactant: c1ccc(SC2(Oc3ccc(-c4ccccc4)cc3)CC2)cc1
Agent: [Li+]
Agent: [c-]1cccc2ccccc12
Solvent: C1CCOC1
Product: OC(CCc1cccnc1)C1(Oc2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Lithium naphthalenide (0.625M, 7.4 ml; prepared by adding equimolar quantities of naphthalene and lithium metal to tetrahydrofuran, under nitrogen, and stirring at room temperature overnight) was added slowly to a stirred solution of 4-(1-phenylsulfanyl-cyclopropoxy)biphenyl (0.7 g) in dry tetrahydrofuran at −78° C., under nitrogen, and then stirred at this temperature for 15 minutes. To this was added a solution of 3-pyridinepropanal (0.3 g, prepared according to the method of Example 3 of International Patent Application No. WO-A-92/19593) in dry tetrahydrofuran (15 ml), and the stirring was continued at −78° C. for 5 minutes, then allowed to warm up to room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution, and extracted into diethyl ether (3×30 ml). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a pale yellow gum, which was further purified by reverse phase HPLC to give the title compound as a pale yellow gum (0.11 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10])[CH3:2].[S:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[CH:23]1.[BH4-].[Na+].C(Cl)Cl.CO>CO>[CH2:1]([N:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:24]3[CH:25]=[CH:26][S:22][CH:23]=3)[CH:28]=2)[CH:16]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([O:12][CH3:13])([CH3:11])[CH3:10])[CH3:2]
Reactant: O=Cc1cccc(-c2ccsc2)c1
Reactant: CCN(C/C=C/C#CC(C)(C)OC)Cc1cccc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN(C/C=C/C#CC(C)(C)OC)Cc1cccc(NCc2cccc(-c3ccsc3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
65 mg of (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-aminobenzylamine and 43 mg of 3-(3thienyl)benzaldehyde were dissolved in 2 ml of methanol, and the solution was stirred overnight at room temperature. With stirring under ice cooling, 12.9 mg of sodium borohydride was added, and stirred for 1 hour at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and water. The organic layer was separated, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated. The residue was purified by silica gel column chromatography Wakogel C-200, 5 g; eluting solvent: methylene chloride/ methanol=60/1] to give 87 mg (yield 84%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].Br[CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13].[C:15]([O-:27])(=[O:26])[CH2:16][C:17]([CH2:22][C:23]([O-:25])=[O:24])([C:19]([O-:21])=[O:20])[OH:18].[Na+].[Na+].[Na+]>C(#N)C>[C:15]([O-:27])(=[O:26])[CH2:16][C:17]([CH2:22][C:23]([O-:25])=[O:24])([C:19]([O-:21])=[O:20])[OH:18].[CH3:13][C:12]([CH3:14])=[CH:11][CH2:10][N+:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1.[CH3:13][C:12]([CH3:14])=[CH:11][CH2:10][N+:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1.[CH3:13][C:12]([CH3:14])=[CH:11][CH2:10][N+:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: CC(C)=CCBr
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)=CC[n+]1cccc(C#N)c1

Procedure:
3-Cyanopyridine is reacted with 1-bromo-3-methyl-2-butene in acetonitrile; and the halide intermediate is reacted with sodium citrate.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]>>[O:29]=[C:24]1[NH:25][C:26](=[O:28])[C:27](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=3)=[CH:5][CH:4]=2)[S:23]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C=O)cc2)c1
Reactant: O=C1CSC(=O)N1
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 100.1 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 9.5 g (32 mmol) of tert-butyl (4′-formyl-biphenyl-3-yl)carbamate with 3.8 g (32 mmol) of 2,4-thiazolidine dione, 12.7 g (91%) of the expected product are obtained.
Reaction SMILES: [OH-].[K+].[CH3:3]N(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[N+](=C)=[N-].[C:20]([OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O.CN(C=O)C>[C:20]([O:28][CH3:3])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COC(=O)c1ccccc1

Procedure:
In a 1.5 l double-walled glass reactor 531 g of aqueous 30% KOH solution are submitted and are heated, respectively, to 40° C., 55° C. and 70° C. By controlled dropwise addition of 405.8 g of 26.4% N-methyl-N-nitroso-p-toluenesulfonamide (MNTSA) solution in DMSO into this KOH solution, diazomethane (DAM) is generated and is aspirated in gaseous form into a glass reactor via a frit by means of vacuum at 500 mbar. The metered addition is effected in such a way that the diazomethane concentration in the gas phase does not exceed a partial pressure of 120 mbar. With a view to determining the DAM quantity and yield, this glass reactor is charged with an acid, for example with a solution of benzoic acid in DMF, so that the DAM aspirated via the frit reacts to completion immediately to form methyl benzoate, and the content thereof is determined analytically and can be utilized as an equivalent for DAM. The following table reproduces the results:
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:10].C(C1C=C(C=C(C)C=1O)[C:16]#[N:17])C>>[OH:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([C:16]#[N:17])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: COc1cccc(C)c1O
Product: COc1cc(C#N)cc(C)c1O

Procedure:
The title compound is prepared from commercially available 2-hydroxy-3-methoxy-toluene in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile); LC-MS: tR=0.84 min. 1H NMR (CDCl3): δ 2.27 (s, 3H), 3.93 (s, 3H), 6.24 (s, 1H), 6.97 (d, J=1.3 Hz, 1H), 7.12 (s, 1H).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[CH:37]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)([CH3:39])[CH3:38]>>[CH:37]([C:40]1[CH:47]=[CH:46][C:43](/[CH:44]=[C:15](/[C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[C:3]([CH3:36])([CH3:2])[CH2:12][CH2:11][C:10]3([CH3:13])[CH3:14])\[CH3:16])=[CH:42][CH:41]=1)([CH3:39])[CH3:38]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C/C(=C\c1ccc(C(C)C)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
In a manner analogous to that described in Example 1, from [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]-triphenylphosphonium bromide and 4-isopropyl-benzaldehyde there can be obtained 6-[(E)-p-isopropyl-α-methylstyryl]-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene of melting point 86°-87° C.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][N:39]=[N+:40]=[N-:41])[NH:13]2)=[O:11])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:42])([CH3:43])[CH2:37][CH2:38][N:39]=[N+:40]=[N-:41])[NH:13]1)=[O:11]
Reactant: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CCN=[N+]=[N-])CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 120d (40 mg, 0.06 mmol) was reacted with aqueous HCl solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-azido-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (29 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[CH:11]=[C:10](N3CCCC3)[CH:9]2[C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:16](=[O:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[CH2:11][C:10]([OH:33])=[C:9]2[C:26]([O:28][CH3:29])=[O:27])=[CH:4][CH:3]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COC(=O)C1C(N2CCCC2)=CC2=C(C(=O)CC(C)(C)C2)C1c1ccc(F)cc1
Product: COC(=O)C1=C(O)CC2=C(C(=O)CC(C)(C)C2)C1c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A suspension of 13.0 g (32.7 mmol) of the compound of Example XII in 1100 ml of a sat. solution of citric acid is stirred at 60° C. for 16 h. The mixture is allowed to cool and extracted with ethyl acetate (3×600 ml). The combined organic phases are washed with sat. NaCl solution and dried over Na2SO4, giving a yellow residue which is purified by flash filtration over 450 g silica gel 60 using EtOAc/cyclohexane 1:20 to 20:1.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4](F)[C:3]=1[F:15].CN1CCCC1=O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>C(OC)(C)(C)C.C1(C)C=CC=CC=1>[CH2:23]([NH:30][C:4]1[C:5]([F:13])=[C:6]([F:12])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]([F:1])[C:3]=1[F:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: COC(=O)c1c(F)c(F)c(NCc2ccccc2)c(F)c1F
Temperature: 5 °C
Yield: 85.8 %

Procedure:
Methyl pentafluorobenzoate (41.4 g, 183 mmol) was treated with N-methylpyrrolidinone (36.0 g) and the solution stirred and cooled to 5° C. under a N2 atmosphere. Benzylamine (19.8 g, 185 mmol) was added dropwise over 27 min. at 5° C.–20° C. The resulting thick yellow slurry was cooled to 2° C. over 25 min. and N,N-diisopropyl ethylamine (27.0 g, 209 mmol) was added over 30 min. at 3° C.–10° C. The mixture was allowed to warm to 18° C. and stirred for 2 hrs. It was then heated to 60° C. and stirred another 2 hs at 58° C.–67° C. The resulting solution was cooled to room temperature and stirred overnight. The mixture was treated with toluene (200 mL) and methyl tert-butyl ether (120 mL) and extracted with water (150 mL) followed by 10% aqueous acetic acid (2×50 mL). The organic layer was concentrated to a solid, which was recrystallized from toluene (45 mL) and heptane (50 mL). After cooling to −20° C., the crystals were collected, washed with heptane (2×25 mL) and vacuum dried at 35° C. to give methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate (49.3 g, 157 mmol): mp 96–97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([O:39]CC)=[O:38].[OH-].[Na+].C1COCC1.Cl>C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:36])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:24]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:37]([OH:39])=[O:38]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cccc(Oc5ccccc5)c4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCCc1cccc(Oc2ccccc2)c1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Yield: 83.2 %

Procedure:
Ethyl 6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl) phenoxy)chroman-4-carboxylate (71.6 mg, 0.125 mmol) was reacted with 1.0 molar sodium hydroxide (501 μl, 0.501 mmol) in a 3:1 THF:Ethanol solution (0.05 M). After 2 hours the reaction was diluted with ethyl acetate, neutralized with 1.0 molar hydrochloric acid (526 μl, 0.526 mmol) and partitioned between saturated aqueous sodium chloride. The organic layer was dried with sodium sulfate, filtered, concentrated, and dried under high vacuum to provide the title compound (56.4 mg, 0.104 mmol, 82.8% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][NH:28][C:29]2=[O:34]>CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][NH:28][C:29]3=[O:34])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cccc2c(=O)[nH]ncc12
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2c(=O)[nH]ncc12)C(F)(F)F)c1ccc(F)c(F)c1OC

Procedure:
In the same way as in Example 29, 372 mg (1.14 mmol) of (2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 200 mg (1.14 mmol) of 5-aminophthalazin-1-one and 0.36 ml of titanium tetra-tert-butoxide are reacted to give 5-{[(2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}phthalazin-1-one. 560 mg of crude imine are cyclized in the same way as in Example 29 at −30° C. with 11.8 ml (11.8 mmol) of 1 M boron tribromide solution to give the desired product. Preparative thin-layer chromatography on silica gel (hexane/2-propanol 17%) yields 249 mg of the desired product
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].N(C(C1C=CC2C(=CC=C(C(C)(N=C=O)C)C=2)C=1)(C)C)=C=O.[O-]C#N.[Na+].N1C=CC=CC=1.C(Cl)[Cl:43]>[Cl-].[Zn+2].[Cl-].O>[CH3:3][C:2]([Cl:43])([CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=C(C)c1ccccc1
Reactant: ClCCl
Agent: CC(C)(N=C=O)c1ccc2cc(C(C)(C)N=C=O)ccc2c1
Agent: N#C[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(Cl)c1ccccc1
Temperature: 4 °C

Procedure:
α,α-Dimethylbenzylchloride was prepared by passing a stream of dry halogen chloride gas through a solution of methylene dichloride (750 ml) and α-methylstyrene (500 g, 4.2 moles) at 4° C. The reaction and work-up were the same as employed for the preparation of 2,6-Bis(1-isocyanato-1-methylethyl)naphthalene described in Example 8. The resulting monochloride was dissolved in 750 ml. methylene dichloride and was added to a cooled (4° C.) catalyst solution previously prepared from anhydrous, 90% sodium cyanate (389 g, 5.39 moles), pyridine (50 ml, 0.633 mole), zinc chloride (39.15 g, 0.28 mole) and 1 ml H2O in 1075 ml. methylene dichloride. At this point the reaction mixture contained 0.04% by weight of water.