Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.Cl[C:31]1[C:40]2[C:35](=[CH:36][C:37]([O:41][CH3:42])=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[F:43].[F:44][C:45]([F:71])([F:70])[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]([NH:62][C:63]3[CH:68]=[CH:67][C:66]([OH:69])=[CH:65][CH:64]=3)=[N:54][N:53]=2)=[CH:48][CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O.C(Cl)Cl.CS(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:43][C:32]1[CH:33]=[N:34][C:35]2[C:40]([C:31]=1[O:69][C:66]1[CH:65]=[CH:64][C:63]([NH:62][C:55]3[C:56]4[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=4)[C:52]([C:49]4[CH:50]=[CH:51][C:46]([C:45]([F:71])([F:70])[F:44])=[CH:47][CH:48]=4)=[N:53][N:54]=3)=[CH:68][CH:67]=1)=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=2
Reactant: COc1ccc2c(Cl)c(F)cnc2c1
Reactant: Oc1ccc(Nc2nnc(-c3ccc(C(F)(F)F)cc3)c3ccccc23)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(Nc4nnc(-c5ccc(C(F)(F)F)cc5)c5ccccc45)cc3)c(F)cnc2c1
Temperature: 100 °C

Procedure:
Racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (84 mg, 210 μmol), 4-chloro-3-fluoro-7-methoxyquinoline (67 mg, 315 μmol), 4-(4-(4-(trifluoromethyl)phenyl)phthalazin-1-ylamino)phenol (80 mg, 210 μmol), cesium carbonate (137 mg, 420 μmol), and Pd2 dba3 (96 mg, 105 μmol) were combined in a resealable tube, and the tube was purged with nitrogen. Toluene (1049 μl, 210 μmol) was added and the tube was sealed and heated to 100° C. overnight. Analysis by LCMS showed incomplete conversion to product. The reaction mixture was diluted with water and DCM, and the water layer was separated and extracted first with DCM followed by ethyl acetate. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The dark residue was taken up in DCM and hexanes, and a precipitate formed. The solid was filtered and purified by preparative HPLC. The crude reaction mixture was taken up in minimal DMSO and methanol and purified on the Gilson {15-85% (0.1% TFA in CH3CN) in H2O over 20 min}. Clean product containing fractions were combined and neutralized with saturated aqueous NaHCO3 then extracted with ethyl acetate, dried over MgSO4, filtered and concentrated in vacuo to afford N-(4-(3-fluoro-7-methoxyquinolin-4-yloxy)phenyl)-4-(4-(trifluoromethyl)phenyl) phthalazin-1-amine as a tan solid. Further purification was accomplished by silica gel chromatography (90:10 CH2Cl2:MeOH). N-(4-(3-fluoro-7-methoxyquinolin-4-yloxy)phenyl)-4-(4-(trifluoromethyl)phenyl) phthalazin-1-amine was afforded as a tan solid. MS [M+H]=557.0. Calc'd for C19H21N5O: 556.15.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Br-:19].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:19][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccccc2)c2ccc(O)cc2o1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1cc(-c2ccccc2)c2ccc(Br)cc2o1

Procedure:
7-hydroxy-4-phenyl-2H-chromen-2-one, (5.07 g, 21.3 mmol) and triphenylphosphine dibromide (9.88 g, 23.4 mmol) were heated in a sand bath at 320-350° C. for 3 h. The cooled mixture was dissolved in dichloromethane, silica gel (150 g) was added and the mixture was evaporated. Column chromatography with hexane/EtOAc: 70:30, gave the title compound.
Reaction SMILES: [CH3:1][C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)(C(OCC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH-].[Na+].O>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCC.C(O)C>[CH3:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(Cc1cccc(C)c1)C(=O)OCC
Agent: CCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)Cc1cccc(C)c1

Procedure:
500 ml of toluene, 207 g of ground potassium carbonate, 8 g of potassium iodide, 7 g of 18-crown-6 and 209 g of diethyl methylmalonate were initially introduced into a 2 l four-necked flask. The mixture was heated to 85° C. with stirring. 141 g of 3-methylbenzyl chloride were added dropwise in the course of half an hour and the mixture was then stirred at 90° C. for 8 hours. After cooling, the salts were removed by repeatedly shaking with water and the organic layer was distilled. 184 g of diethyl 2-methyl-2-(3-methylbenzyl)-malonate were obtained at a boiling point of 120° C. and a pressure of about 0.02 mbar. For hydrolysis, the ester was boiled under reflux with stirring for 16 hours with 60 g of NaOH, 170 ml of water and a spatula tip-full of tetradecyltrimethylammonium bromide, ethanol which formed in the meantime being distilled off. The dicarboxylic acid was liberated by acidifying with hydrochloric acid, separated off and heated in xylene for 4 hours under reflux for decarboxylation. The monocarboxylic acid was then esterified with ethanol (p-toluenesulfonic acid as catalyst, cyclohexane as entraining agent for water). 115 g of ethyl 2-(3-methylbenzyl)-propionate (boiling point 70°-73° C. at 0.03 mbar) were obtained. For hydrogenation, 21 g of LiAlH4 were dissolved or suspended in 800 ml of tetrahydrofuran in a 2 l four-necked flask under nitrogen. A mixture of 110 g of ethyl 2-(3-methylbenzyl)-propionate and 100 ml of tetrahydrofuran were then added dropwise with ice cooling. The mixture was then decomposed with ice and hydrochloric acid, extracted with ether and dried over K2CO3, and 75 g of 2-methyl-3-(3-methylphenyl)propan-1-ol (boiling point 68°-70° C. at 0.1 mbar) were obtained by distillation.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:5][CH:6]=1.[NH2:14][CH2:15][CH2:16][OH:17].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.CC(=O)OCC.O>[Br:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:14][CH2:15][CH2:16][OH:17])[CH2:9][CH2:8]2)[S:5][CH:6]=1
Reactant: NCCO
Reactant: O=C1CCN(c2nc(Br)cs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCCNC1CCN(c2nc(Br)cs2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 mg (0.37 mmol) of 1-(4-bromothiazol-2-yl)piperidin-4-one from step a and 22 μl (0.37 mmol) of 2-aminoethanol were suspended in 7 ml of THF, stirred at room temperature for 1 h, 21 μl (0.37 mmol) of glacial acetic acid and 164 mg (0.74 mmol) of sodium triacetoxyborohydride were added. The mixture was stirred at room temperature overnight, water and EA were added, the mixture was adjusted to pH 12 using a concentrated NaOH solution and extracted by shaking with EA. The organic phase was dried over sodium sulfate, filtered and evaporated.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[Br:13][C:14]1[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=1>C1COCC1>[Br:13][C:14]1[C:15]([O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(CO)cc1
Reactant: Clc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ncccc2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
3-bromo-2-(4-methoxybenzyloxy)pyridine was prepared by the procedure described in J. Med. Chem., 2008, 51, 3065. A pressure vessel was charged with anhydrous THF (25 ml) and sodium hydride (1.44 g, 36.18 mmol, 60% dispersion). To this stirred mixture was added portionwise a solution of 4-methoxybenzyl alcohol (5.0 g, 36.18 mmol) in anhydrous THF (15 ml). After addition was complete, the mixture was stirred at room temperature for 30 minutes and a solution of 3-bromo-2-chloropyridine (4.64 g, 24.08 mmol) in anhydrous THF (15 ml) was added. The vessel was sealed and the reaction mixture was heated at 75° C. for 6 hours. Upon cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water, sat'd NaCl(aq.), dried over MgSO4, filtered, and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 4:1 hexanes: EtOAc) gave the title compound as a clear oil (6.51 g, 92%).
Reaction SMILES: ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=O)[CH:25]=2)[CH:20]=[CH:19]1.[NH:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31]1>CN(C=O)C.O>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([N:30]3[CH2:34][CH2:33][C@@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31]3)=[O:29])[CH:25]=2)[CH:20]=[CH:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)c2ccc3cc[nH]c3c2)C1
Reaction time: 16 h

Procedure:
EDCxHCl (17.7 g, 93.00 mmol, 1.5 eq), 1-hydroxy-7-azabenzotriazole (4.2 g, 31.01 mmol, 0.5 eq) followed by triethylamine (28.7 mL, 204 mmol, 3.3 eq) were added at room temperature to a stirred solution of 1H-indole-6-carboxylic acid (10 g, 62.03 mmol, 1.0 eq) in dry DMF (50 mL). (R)-tert-butyl pyrrolidin-3-ylcarbamate (13.86 g, 74.44 mmol, 1.2 eq) was added after 10 min and stirring was continued for 16 h at room temperature. The reaction mixture was diluted with icy water (100 mL), and the precipitating solid was filtered off, washed with water (50 mL) and pet ether (50 mL), and dried under vacuum. White solid. Yield: 11.0 g (55% of theory)
Reaction SMILES: [OH-].[Na+].[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[CH2:8][CH2:9][CH2:10][C:11](=[O:17])[C:12]([O:14]CC)=[O:13].S(=O)(=O)(O)[O-].[K+]>CO>[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[CH2:8][CH2:9][CH2:10][C:11](=[O:17])[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(=O)CCCC1OCCO1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(=O)CCCC1OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 3 L 3-necked round bottom flask was equipped with an overhead stirrer, thermocouple, and an addition funnel containing 1.5 N NaOH (460 mL). The flask was charged with MeOH (700 mL) and cooled to 0° C. The NaOH solution was added slowly to the methanol, maintaining the temperature below 10° C. and upon complete addition, the resulting solution was cooled to 0° C. A methanol solution of 5-(1,3-dioxolan-2-yl)-2-oxo-pentanoic acid, ethyl ester (350 mL) was added to the reaction via dropping funnel at a rate which maintained the temperature of the reaction mixture below 3° C. (addition time 1 hr). The reaction was stirred at 0° C. for 2 hours and the pH of the reaction was adjusted to 7.71 by the addition of 2 M potassium bisulfate (75 mL). The methanol was evaporated and the cloudy aqueous slurry was washed with MTBE (3×500 mL). The pH of the aqueous layer was adjusted to 4.5 by the addition of 2 M potassium bisulfate (100 mL) and extracted with ethyl acetate (500 mL). The pH of the aqueous layer was further adjusted to 2.0 by the addition of 2 M potassium bisulfate (50 mL), and extracted with ethyl acetate (2×500 mL). The combined ethyl acetate extracts were dried over magnesium sulfate and concentrated to afford 5-(1,3-dioxolan-2-yl)-2-oxo-pentanoic acid (60 g, 80 M % yield) as a thick liquid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2(N(C)C)CC=CC=C2C2C=CC=CC=2)CCCCC1.Br[Zn][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>O1CCCC1.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH2:55]([O:54][C:52](=[O:53])[CH2:51][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([O:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1)[CH3:56]
Reactant: CCOC(=O)C[Zn]Br
Reactant: Brc1ccc(OCCOC2CCCCO2)c2ccoc12
Agent: [Pd]
Agent: CN(C)C1(P(C2CCCCC2)C2CCCCC2)CC=CC=C1c1ccccc1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OCCOC2CCCCO2)c2ccoc12
Temperature: 25 °C
Yield: 54 %

Procedure:
Combine 7-Bromo-4-[2-(tetrahydropyran-2-yloxy)ethoxy]benzofuran (2.598 g, 7.61 mmol), bis(dibenzylideneacetone) palladium (0.461 g, 0.802 mmol), and 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl (0.308 g, 0.783 mmol) in tetrahydrofuran (15 ml) under nitrogen. Add bromo(2-ethoxy-2-oxoethyl)zinc (2 equiv.), and heat the mixture at 80° C. for 16 hours. (Knochel, P.; Honed, P.; Eds. Organozinc Reagents: A Practical Approach; Oxford University Press, Inc: London, 1999). Cool the mixture to room temperature, filter through a silica plug eluting with ethyl ether, and concentrate. Purify by flash chromatography and elute with hexane:ethyl acetate to give 1.422 g (54%) of the title compound as an oil. Mass spectrum: electrospray (m/z) 265 (M++1-85).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C[O:22][CH:23](OC)[C:24]1[C:25](F)=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27]([OH:29])=[O:28]>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:10][C:3]2[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=2[F:1])[C:24]=1[CH:23]=[O:22]
Reactant: CSc1ccc(N)c(F)c1
Reactant: COC(OC)c1c(F)ccc(C(=O)O)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(Nc2c(C(=O)O)ccc(F)c2C=O)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.8 %

Procedure:
To a cold (−78° C.) solution of 2-fluoro-4-methylsulfanyl-phenyl amine (1.55 g, 9.9 mmol) in THF (15 mL) was added LHMDS (9.9 mL, 1.0 M solution in hexanes 9.9 mmol) dropwise so as to maintain the temperature below −65° C. After stirring for 30 minutes a solution of 3-dimethoxymethyl-2,4-difluoro-benzoic acid (700 mg, 3.0 mmol) in THF (15 mL) was added dropwise, the resultant mixture stirred cold for 3 hours then allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride and the products partitioned between ethyl acetate and water. The aqueous layer was separated and acidified to pH 1 (concentrated HCl) and then extracted twice with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated with diethyl ether to give the title compound as a yellow solid (105 mg, 10% yield). 1H NMR (CDCl3, 400 MHz) 10.26-10.23 (2 H, m), 8.04 (1 H, dd, J=8.76, 6.31 Hz), 7.03-6.96 (2H, m), 6.91 (1 H, d, J=1.96 Hz), 6.65 (1 H, dd, J=10.02, 8.77 Hz), 2.42 (3 H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10]C(=O)C1C=CC=CC=1)=[S:9]>[OH-].[Na+]>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9]
Reactant: O=C(NC(=S)Nc1cnccn1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: NC(=S)Nc1cnccn1

Procedure:
A solution of N-[(pyrazin-2-ylamino) carbonothioyl]benzamide (25 g, 0.096 mol) in 10% NaOH solution (200 ml) is stirred at 80° C. for 20 min. The reaction mixture is cooled and the solvent is removed under vacuum. The residue is acidified with 2M HCl to pH=1 and then basified with ammonium hydroxide. The solid precipitated is collected by filtration and dried under suction affording N-Pyrazin-2-ylthiourea as a solid (12 g; 80%). 1H NMR (DMSO-d6, 300 MHz): δ 8.24 (br s, 2H), 8.54 (s, 1H), 9.10 (m, 1H), 9.95 (m, 1H), 10.66 (br s, 1H). M+ (ESI): 154.9. HPLC (Method B), Rt: 3.47 min (purity: 98.23%). TLC: Chloroform/methanol (9/1): Rf−0.25. Mp: 234° C.-235° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.[N:8]1[NH:9][C:10](=[O:14])[CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][C:4]([N:9]2[C:10](=[O:14])[CH:11]=[CH:12][CH:13]=[N:8]2)=[CH:5][CH:6]=1
Reactant: Brc1ccc(Br)s1
Reactant: O=c1cccn[nH]1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=c1cccnn1-c1ccc(Br)s1
Temperature: 110 °C

Procedure:
A mixture of 2,5-dibromothiophene (1.5 g, 6.2 mmol), pyridazin-3(2H)-one (0.4 g, 4.1 mmol), copper(I) iodide (0.24 g, 1.2 mmol), potassium carbonate (1.7 g, 12.4 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.2 mL, 1.2 mmol) and toluene (15 mL) was degassed for 15 minutes and then heated in a sealed tube at 110° C. for 18 hours. Cooled to room temperature, filtered through celite and washed with EtOAc. The filterate was washed with water (100 mL×2). The organic layer was dried over Na2SO4, filtered and concentrated give the desired product 2BZ (0.9 g, 90%). The residue was purified on silica gel eluting with 80% EtOAc/hexane to give the desired product 2BZ (0.7 g, 67%).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)cc3C)CC2)n(C(C)(C)C)n1

Procedure:
164 mg (84%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(2,4-dimethylphenyl)piperazine (86 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]([O:32]C)=[O:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:18]3[CH:26]=[CH:27][C:28]([C:30]([OH:32])=[O:31])=[CH:29][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Yield: 104.2 %

Procedure:
A solution of compound 48 (0.514 g, 1.17 mmol) in tetrahydrofuran (5 mL) and ethanol (5 mL) was treated with 4 M NaOH (5 mL). The reaction mixture was refluxed for 1 h, cooled to rt, and concentrated on a rotary evaporator. The residue was dissolved in a small amount of water and made acidic with concentrated hydrochloric acid. The solid precipitate was filtered, washed with water, and dried to afford 49 as a white solid (0.52 g, 100%). ESI-MS m/e 427.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]([C:15]2[S:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:18][C:19]=2I)[CH3:14])=[CH:8][C:7]=1[CH3:31].[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:13]([C:15]2[S:16][C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[CH:18][C:19]=2[CH:33]=[CH2:34])[CH3:14])=[CH:8][C:7]=1[CH3:31]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)CCc1ccc(SC(C)c2sc(-c3ccc(C(F)(F)F)cc3)cc2I)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Sc1ccc(CCC(=O)OC)c(C)c1
Temperature: 80 °C

Procedure:
The solution of 3-(4-{1-[3-Iodo-5-(4-trifluoromethyl-phenyl)-thiophen-2-yl]-ethylsulfanyl}-2-methyl-phenyl)-propionic acid methyl ester (0.195 g, 0.348 mmole) and tributyl(vinyl)tin (0.331 g, 1.04 mmole) in toluene (3 mL) is bubbled with nitrogen gas for 10 minutes. To it is added tetrakis(triphenylphosphine)palladium(0) (0.20 g). The reaction is heated under 80° C. overnight. The mixture is concentrated, loaded to a silica gel column, eluted with ethyl acetate in hexane (0-15%) and concentrated to provide the titled compound as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1([CH:47]([OH:53])[CH2:48][C:49]([NH:51][NH2:52])=[O:50])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:52][NH:51][C:49](=[O:50])[CH2:48][CH:47]([OH:53])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NNC(=O)CC(O)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NNC(=O)CC(O)c1ccccc1
Yield: 46.5 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (100 mg, 0.18 mmol) and 3-phenylhydracrylic acid hydrazide (39 mg, 0.22 mmol) according to Method C with HPLC purification to give the title compound (58 mg) as a diasteromeric mixture. 1H-NMR (400 MHz, CD3OD) d 7.77 (1H), 5.11 (dd, J=4.6 Hz, J=8.6 Hz, 1H), 4.78 (2H), 4.70 (m, 1H), 4.24 (dd, J=5.0 Hz, J=9.3 Hz, 1H), 1.34 (s, 9H); IR (KBr) 3274, 1681, 1652, 1608 cm−1; HRMS m/z 692.2670 (calc. of monoisotopic mass for C35H40N4O11 gives 692.2694).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([Cl:10])[CH:3]=1
Reactant: N#Cc1ccc(Br)cc1Cl
Solvent: C1CCOC1
Product: NCc1ccc(Br)cc1Cl
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-chlorobenzonitrile (2500 mg, 11549 μmol) in THF (20 mL) at 0° C. was added borane-methyl sulfide complex, 2.0 m sol in THF (28873 μl, 57747 μmol). Ice bath removed and reaction stirred overnight warming to 23° C. Reaction cooled to 0° C. and quenched with MeOH (15 mL). Reaction then partitioned between CHCl3 (100 mL) and 1M NaOH (100 mL). Organic dried with brine and MgSO4. Organic then concentrated to an oil under reduced pressure and purified on silica (80 g) eluting with 0>6% 2M NH3 in MeOH/DCM and product isolated as a colorless oil. MS (ESI pos. ion) m/z: 220/222 (MH+). Calc'd exact mass for C7H7BrClN: 219/221
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].C(O)C>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(F)cc1F
Yield: 83.5 %

Procedure:
In a fashion similar to that for preparation 13, 2,4-difluorobenzaldehyde (5.00 g, 35.2 mmol), hydroxylamine hydrochloride (2.94 g, 42.3 mmol), NaOH (7.04 g, 88.0 mmol; as a 50% solution by weight in water), ethanol (15 ml), H2O (15 ml), and ice (30 g) gave 2,4-difluorobenzaldehyde oxime (4.62 g, 84%) which was used without purification.