Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].C(#N)C.C1(C)C=CC=CC=1.[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>O>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([N:3]=[C:2]=[O:1])=[O:18]
Reactant: N#C[O-]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: Cc1ccccc1
Product: O=C=NC(=O)C(Cl)(Cl)Cl

Procedure:
To a 500 ml three neck flask equipped with a reflux condenser, thermometer, 250 ml addition funnel, magnetic stirrer, and water bath was charged 43.9 grams (0.675 mole) sodium cyanate, 75 ml acetonitrile, and 125 ml toluene. To the addition funnel was added 123 grams (0.675 mole) trichloroacetyl chloride. The trichloroacetyl chloride was added under nitrogen atmosphere at a rate to maintain the reaction temperature between 30°-40° C. After the addition was complete (30 min) the water bath was replaced with an electric heating mantle and the mixture was maintained at 65°-70° C. for 1.5 hour and then cooled to room temperature with the water bath, giving a solution of trichloroacetyl isocyanate containing slurried sodium chloride.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=NC=1CC.[CH3:32][N:33]([CH3:62])[C:34]1[N:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]([CH2:59][CH3:60])[C:43]([NH:48][C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=[N:44][C:45]=2[CH2:46][CH3:47])=[C:36]([CH3:61])[CH:35]=1>>[CH3:62][N:33]([CH3:32])[C:34]1[N:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]([CH2:59][CH3:60])[C:43]([NH:48][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])=[N:44][C:45]=2[CH2:46][CH3:47])=[C:36]([CH3:61])[CH:35]=1
Reactant: CCc1nc(-c2cnc(N(C)C)cc2C)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a light golden amorphous solid. IR (diffuse reflectance) 3446, 2969, 2931, 2893, 2874, 1604, 1562, 1517, 1487, 1392, 1372, 1208, 1174, 1123, 1089 cm−1; OAMS supporting ions at: ESI+ 446.3; MS (EI) m/z 445 (M+); HRMS (FAB) calcd for C27H35N5O+H1 446.2920, found 446.2915. [α]25D=−89 (c 0.47, methylene chloride); Anal. Calcd for C27H35N5O: C, 72.78; H, 7.92; N, 15.72. Found: C, 72.58; H, 7.94; N, 15.59.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[CH3:28])(=[O:19])=[O:18])[CH2:13][C@@H:12]2[CH3:29])=[O:10])=[CH:4][CH:3]=1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>C(O)(C)C>[ClH:1].[N:30]1([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([S:17]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=4[CH3:28])(=[O:19])=[O:18])[CH2:13][C@@H:12]3[CH3:29])=[O:10])=[CH:4][CH:3]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)c2ccc(Cl)nc2C)[C@@H](C)C1
Reactant: C1CNC1
Solvent: CC(C)O
Product: Cc1cc(C#N)ccc1S(=O)(=O)N1CCN(C(=O)c2ccc(N3CCC3)nc2C)[C@@H](C)C1
Product: Cl
Temperature: 120 °C
Yield: 43.5 %

Procedure:
4-({(3S)-4-[(6-Chloro-2-methyl-3-pyridinyl)carbonyl]-3-methyl-1-piperazinyl}sulfonyl)-3-methylbenzonitrile (may be prepared as described in Example 25) (65 mg, 0.15 mmol) was weighed into a microwave vial and suspended in isopropanol (1.5 ml). Azetidine (0.203 ml, 3.01 mmol) was added and the mixture was heated in the microwave to 120° C. for 18 h with stirring. LCMS analysis showed >80% conversion. The reaction mixture was concentrated to give the crude material as a colourless gum (273 mg). This was purified by MDAP to give the free base of the title compound as a colourless gum (32 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)=[CH:16][CH:15]=1.Cl>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)=[CH:18][CH:19]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.61-6.92 (m, 11H), 5.24-5.16 (m, 1H), 3.70-3.58 (m, 2H), 3.02-2.91 (br, 2H), 2.80-2.64 (m, br, 3H), 2.64-2.50 (m, 3H), 2.18-1.94 (m, br, 6H), 1.62-1.44 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz); ESMS m/e: 605.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N-]=C=O>CN(C=O)C.C(O)(=O)C>[O:34]1[CH:38]=[CH:37][C:36]([CH2:39][N:11]2[CH2:12][CH2:13][CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:9]([CH2:8][N:7]([C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[C:6](=[O:33])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)=[CH:35]1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(Cc2ccoc2)CCC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a mixture of 13.3 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate, 3.4 mg of 3-furaldehyde, 0.050 mL of acetic acid, and 0.5 mL of DMF was added 75 mg of MP-Triacetoxyborohydride (Argonaut Technologies, USA) at room temperature, followed by stirring overnight. To the reaction mixture was added 50 mg of PS-Isocyanate (Argonaut Technologies, USA) at room temperature, followed by stirring for 2 hours, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl {[1-(3-furylmethyl)-4-phenylpiperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product. To 0.5 mL of a methanol solution of the obtained crude product was added 0.5 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: registered trademark SunFire, Waters, particle diameter of 5 μm, inner diameter of 19 mm, and length of 100 mm), flow rate: 25 ml/min., column temperature: 20° C., methanol—a 0.1% aqueous formic acid solution) to obtain 4.9 mg of (1R)—N-{[1-(3-furylmethyl)-4-phenylpiperidin-3-yl]methyl}-1-(1-naphthyl)ethaneamine.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[N+:12]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(N(C(C)C)CC)(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Clc1nc(Cl)c2occc2n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(Oc2nc(Cl)nc3ccoc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
6.4 g (33.9 mmol) of 2,4-dichlorofuro[3,2-d]pyrimidine (see: International Publication Number WO 2008073785 and WO 2008152394) was dissolved in 32 mL of methanol, and 5.7 g (40.6 mmol) of 3-nitrophenol and 12 mL (67.7 mmol) of diisopropylethylamine were added thereto, and stirred for 24 hours at room temperature. Upon the completion of the reaction, the resulting solid was filtered and dried over under a reduced pressure to obtain 6.3 g of the title compound (yield: 64%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)c(Cl)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3Cl)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (0.89 g), 2-chloro-4-methylphenol (1.0 g), and 4-dimethylaminopyridine (1 g) were suspended in o-dichlorobenzene (10 ml), and the mixture was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, and water was then added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (0.92 g, yield 70%).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[O:17](C)[S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[S:18]([O-:20])(=[O:19])=[O:17].[CH3:21][N+:8]1[CH:9]=[CH:10][N:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:1])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CN(c1ccccc1)S(=O)(=O)n1ccnc1
Solvent: ClCCl
Product: CN(c1ccccc1)S(=O)(=O)n1cc[n+](C)c1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of N-methyl-N-phenyl-1H-imidazole-1-sulfonamide (700 mg, 2.95 mmol) in dry DCM (5 mL) was added methyl triflate (725 mg, 4.4 mmol) under nitrogen at 0° C. The mixture was stirred at 0° C. for 3 h and at a temperature below 10° C. for 12 h. After the solvent was removed, the residue was used in next step without further purification. LCMS (ESI): m/z 237.9 [M+H+].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)(=O)[CH3:2].[N:14]1[NH:15][C:16](=[O:20])[CH:17]=CC=1>>[O:20]=[C:16]1[NH:15][N:14]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=2)[CH:2]=[CH:17]1
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1ccc(CC(=O)O)cc1
Product: O=C(O)Cc1ccc(-c2ccc(=O)[nH]n2)cc1

Procedure:
15 g of 4-acetylphenylacetic acid (preparation described in Can. J. Chem.; 82; 12; 2004; 1760-1768) are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([OH:14])=[O:13].CC1C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:24][S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]([OH:14])=[O:13])=[CH:20][CH:19]=2)(=[O:22])=[O:23])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: O=C(O)c1ccc(C=NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
In the same manner as Example 2, 0.60 g (4 mmol) of 4-carboxybenzaldehyde, 0.80 g (4 mmol) of 4-carboxybenzenesulfonamide and 15 mg of TsOH in 80 mL of chlorobenzene under nitrogen were heated to provide 80% of SULF-5 as a light tan powder: IR (Nujol) 3400-2600 (br), 3082, 1688, 1614, 1160 cm-1 ; 1H NMR (DMSO-d6, TMS ext std) δ9.17 (s, 1), 8.2-7.8 (m, 8).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([P:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:24][O:25][K].C(O)=O.C(OCC)(=O)C>C(O)C>[OH:25][NH:24][C:3](=[O:2])[CH2:4][N:5]([P:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CN(CCc1ccccc1)P(C)(=O)c1ccccc1
Reactant: NO[K]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CP(=O)(c1ccccc1)N(CCc1ccccc1)CC(=O)NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(Methylphenylphosphinyl)-N-(2-phenylethyl)glycine methyl ester (300 mg, 0.905 mmol) is treated with 0.77 mL of NH2OK (1.76M in methanol, solution prepared as described in Fieser and Fieser, Vol. 1, p. 478). The mixture is stirred for 3 hours at room temperature, neutralized with formic acid and concentrated. The crude product is purified by silica gel flash chromatography (85:15 ethyl acetate:ethanol) giving the product with slight impurities. Preparative TLC (90:10 ethyl acetate:ethanol) gives N-hydroxy-2-[[methyl phenylphosphinyl](2-phenylethyl)-amino]-acetamide as a colorless solid: MS-IS m/z 333 [M+H]+, 350 [M+NH4 ]+, 355 [M+Na]+, 371 [M+K]+. (R1 =phenyl ethyl, R2 =H, R3 =methyl, R4 =phenyl).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH:13]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]1.Br[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[CH3:21]>C1COCC1>[Cl:28][C:24]1[CH:23]=[C:22]([CH:20]([C:13]2([C:17]#[N:18])[CH2:16][CH2:15][CH2:14]2)[CH3:21])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(Br)c1cccc(Cl)c1
Reactant: N#CC1CCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(c1cccc(Cl)c1)C1(C#N)CCC1
Reaction time: 0.08 h

Procedure:
n-BuLi (4.7 mL, 11.8 mmol, 2.5 M in hexane) was added to a solution of diisopropylamine (1.13 g, 11.2 mmol) in THF (20 mL) at −78° C. After stirring for 5 min, neat cyclobutanecarbonitrile (0.8 g, 9.87 mmol) was added and the mixture was stirred at −78° C. for 1 hour. Then a solution of Example 44A (2.6 g, 11.8 mmol) in THF (10 mL) was added and the mixture was stirred at −78° C. for 1 h. The mixture was quenched with water and extracted with EtOAc (40 mL). The solvent was evaporated and the residue was used directly in the next step without further purification. LC-MS: m/z 220 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:18]([CH3:20])[CH3:19])[CH:13]([OH:17])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:18]([CH3:20])[CH3:19])[CH:13]([O:17][C:27](=[O:29])[CH3:28])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C(=O)O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoic acid (1.70 g, 6.04 mmol) and pyridine (4.9 mL) was added acetic anhydride (5.7 mL, 6.17 g, 60.4 mmol) dropwise at room temperature. The reaction was allowed to stir overnight and was diluted with ethyl acetate and washed with water (2X). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a thick oil. The residue was purified by column chromatography on silica gel with 15% methanol/dichloromethane to afford 1.56 g (80%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-acetoxy-4-methyl pentanoic acid as a light yellow viscous oil. FAB MS [M+H] m/z; Calcd: 324, Found: 324.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[C:16]([F:26])[CH:15]=2)[CH:7]=1)([CH3:3])[CH3:2].[OH-].[Li+]>C(O)(C)C.O1CCCC1>[CH:1]([O:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[C:16]([F:26])[CH:15]=2)[CH:7]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(C#Cc2cccc(C(=O)OC(C)C)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cccc(C#Cc2ccc(CC(=O)O)c(F)c2)c1
Reaction time: 0.67 h
Yield: 97.9 %

Procedure:
A solution of 3-(4-ethoxycarbonylmethyl-3-fluoro-phenylethynyl)-benzoic acid isopropyl ester (Intermediate 138, 0.1 g, 0.27 mmol) in isopropanol (2 mL) and tetrahydrofuran (2 mL) was treated with a 2M solution of lithium hydroxide (1 mL, 2 mmol). After 40 min. at ambient temperature, the reaction mixture was concentrated in vacuo a bit, neutralized with 10% hydrochloric acid and the solid formed was filtered, washed with water and dried to afford the title compound (0.09 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:16]([O:18]C)=O)[C:8]([C:12]([O:14]C)=O)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].C(N(CC)CC)C.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[C:7]3[C:16]([OH:18])=[N:32][N:31]([C:28]4[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=4)[C:12](=[O:14])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: CC(C)c1ccc(NN)cc1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a stirred suspension of dimethyl 7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (2.01 g, 6.80 mM) and 4-isopropylphenyl hydrazine hydrochloride (8.90 g, 47.6 mM) in ethanol (72 mL) was added triethylamine (7.6 mL, 54.5 mM) to give a brown solution. This solution was refluxed for 16 hours, cooled to room temperature, and then added slowly to a mixture of hydrochloric acid (12N, 100 mL) and ice (100 mL) with vigorous stirring whereupon a pink suspension formed. The suspension was filtered, and the collected solids were washed with a cold solution made by mixing methanol (100 mL), hydrochloric acid (100 mL, 12N) and ice (100 g) to give the 4-isopropylphenyl hydrazine salt of the title compound as a purple powder (1.80 g). This material was refluxed in glacial acetic acid (15 mL) for 3 hours to give a tan suspension. The suspension was cooled to room temperature and filtered. The collected solids were washed with glacial acetic acid (10 mL) and ether to give the title compound (1.125 g, 43%) as a tan powder, mp 367-369° C.: MS(CI): 382 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([C:40](=[O:42])[NH2:41])=[CH:35][C:34]=1[CH3:43])[C:9](=[O:31])[N:10]1[CH:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][CH:8]([C:9](=[O:31])[N:10]1[CH:19]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[CH2:32][C:33]1[C:34]([CH3:43])=[CH:35][C:36]([C:40]([NH2:41])=[O:42])=[CH:37][C:38]=1[CH3:39]
Reactant: Cc1cc(C(N)=O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(N)=O)cc(C)c1CC(N)C(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Reaction time: 3 h
Yield: 28 %

Procedure:
To 0.8 mmol of {1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamic acid tert-butyl ester cooled in an ice bath under argon, was added 3 mL of trifluoroacetic acid. After stirring for 3 hours, the reaction mixture was concentrated and purified on a Gilson prep LC system. Obtained 79 mg (0.13 mmol) of the pure S,S isomer of 4-{2-amino-3-oxo-3-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3,5-dimethyl-benzamide and 58 mg (0.09 mmol) of a mix of diastereomers for a total of 137 mg (0.22 mmol, 28% yield). Data for “pure” isomer (may contain a trace of other isomer as evident by tlc): 1H NMR (300 MHz, CD3OD): δ 1.85 (0.5H, dd), 2.13–2.51 (6H, m), 2.91 (0.4H, dd), 3.18–3.52 (4H, m), 3.70 (0.5H, d), 4.28–4.47 (1H, m), 4.60–5.06 (2.5H, m), 5.62 (0.5H, t), 6.95–7.90 (13H, m).
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([C:16]([CH3:36])([CH3:35])[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])=[CH:24][CH:25]=1)=[O:18])C(=O)[O-])(C)C>ClCCl>[CH3:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:34])[C:27]=1[O:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C:16]([CH3:35])([CH3:36])[NH2:12])=[CH:25][CH:24]=1
Reactant: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C)c1Oc1ccc(NC(=O)C(C)(C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl[2-({6-[(2,6-dimethylphenyl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 79, 202.1 mg) was dissolved in dichloromethane (2 mL) to give a pale yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The solvent was evaporated under vacuum to afford a yellow oil which was charged on a 5 g SCX cartridge. It was then flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (144.4 mg).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](Cl)=[N:17][N:16]=[C:15]3Cl)=[O:11])[CH:4]=1.[CH3:26][O-:27].[Na+].Cl.CN([CH:33]=[O:34])C>>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([O:27][CH3:26])=[N:17][N:16]=[C:15]3[O:34][CH3:33])=[O:11])[CH:4]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccn1)c1ccc2c(Cl)nnc(Cl)c2c1
Reactant: C[O-]
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Product: COc1nnc(OC)c2cc(C(=O)Nc3cc(C(F)(F)F)ccn3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridin-2-yl)amide (0.487 g, 1.258 mmol), NaOMe (0.333 g, 6.164 mmol) and DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was poured onto water, neutralized with 2N HCl and extracted into EtOAc (×3). The combined organic layer was washed with water, brine and dried (Na2SO4). Chromatography (Hex/EtOAc) afforded 1,4-dimethoxy-phthalazine-6-carboxylic acid (4-trifluoromethyl-pyridin-2-yl)-amide (0.24 g), m/z (M+1) 379.11.