Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[Cl:42])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1ccc(Cl)c(Sc2ccc(Br)cc2)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(Cl)ccc3Cl)cc2)c1C
Yield: 33.3 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,5-dichlorobenzene (0.2 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,5-dichloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.089 g, 33%) as a solid.
Reaction SMILES: [CH:1]([C@@H:3]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5])=O.[CH2:22]([O:24][C:25](=[O:45])[C:26]([CH3:44])=[C:27](CC)[CH:28]([N:32]([C:34](=[O:41])[CH:35]([NH2:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH3:23].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:16]([O:15][C:14]([N:13]([CH3:21])[C@@H:3]([C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5])[CH2:1][NH:40][C@H:35]([C:34]([N:32]([CH3:33])[C@@H:28]([CH:29]([CH3:31])[CH3:30])/[CH:27]=[C:26](\[CH3:44])/[C:25]([O:24][CH2:22][CH3:23])=[O:45])=[O:41])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](C=O)C(C)(C)c1ccccc1
Reactant: CCOC(=O)C(C)=C(CC)C(C(C)C)N(C)C(=O)C(N)C(C)(C)C
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC[C@@H](N(C)C(=O)OC(C)(C)C)C(C)(C)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
To a stirred slurry of tert-butyl (1S)-1-formyl-2-methyl-2-phenylpropyl(methyl) carbamate (104 mg, 0.40 mmole, Reference Example 19) with ethyl 4-[(2-Amino-3,3-dimethyl-butyryl)-methyl-amino]-2,5-dimethyl-hex-2-enoic acid ethyl ester (122 mg, 0.40 mmole) in MeOH (2.5 ml), a solution of zinc chloride (32.7 mg, 0.6 eq) and sodium cyanoborohydride (34.4 mg, 0.48 mmol) in MeOH (2.5 ml) is added over 5 minutes at room temperature. The resulting mixture is stirred for 15-24 hours at room temperature under an inert atmosphere. After concentration, the residue is taken up in ethylacetate, washed with sodium bicarbonate. The aqueous phase is extracted with ethylacetate. The combined organic layers is washed with brine, dried and is chromatographed (silica gel, flash column) to give a white solid. (0.164 mg, 81%) M.W. 587.8 [M+H] 588.3
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10](SC)[N:9]=2)=[CH:4][CH:3]=1>[Ni].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CSc1ncc(CO)c(-c2ccc(F)cc2)n1
Agent: [Ni]
Solvent: CCO
Product: OCc1cncnc1-c1ccc(F)cc1
Yield: 57.1 %

Procedure:
A mixture of [4-(4-fluorophenyl)-2-(methylsulfanyl)pyrimidin-5-yl]methanol (10.3 g), Raney-nickel (77 g) and ethanol (500 mL) was heated under reflux for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (4.8 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:38]([O:40][C:41]([C:43]1[C:44]2[S:52][CH:51]=[C:50]([CH2:53]Br)[C:45]=2[C:46]([Cl:49])=[N:47][CH:48]=1)=[O:42])[CH3:39].[I-].[K+]>CN(C)C=O>[CH2:38]([O:40][C:41]([C:43]1[C:44]2[S:52][CH:51]=[C:50]([CH2:53][O:13][C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[N:3][N:4]=4)[CH:8]=3)[C:45]=2[C:46]([Cl:49])=[N:47][CH:48]=1)=[O:42])[CH3:39]
Reactant: Cc1nnc(-c2cccc(O)c2)o1
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnc(C)o4)c3)csc12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A suspension of 3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenol (0.15 g, 0.85 mmol) (from Example 7 supra), potassium carbonate (0.25 g, 1.8 mmol) and 18-Crown-6 (10 mg, 0.04 mmol) (Aldrich) in N,N-dimethylformamide (5 mL) was heated at 65° C. in a sealed tube with magnetic stirring for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.27 g, 0.8 mmol) (from Example 1 supra) and potassium iodide (0.13 g, 0.8 mmol) were then added and mixture heated at 65° C. in the sealed tube for another 20 hours. After cooling, mixture was partitioned between ethyl acetate (2×100 mL) and water (2×100 mL). Organic layers were washed with brine, then combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, 20% ethyl acetate in dichloromethane as solvent) to give 4-chloro-3-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.22 g, 63.1%).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C([Li])CCC.O>O1CCCC1.CCCCCC>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)#[CH:2]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(C=C(Br)Br)cc2)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 7.88 g of β,β-dibromo-p-(trans-4-pentylcyclohexyl)styrene in 150 ml of absolute tetrahydrofuran was placed at -78° C. in a sulphonation flask under argon gasification and treated within 10 minutes with 63 ml of a 1.2N solution of butyl lithium in hexane. After completion of the addition, the mixture was stirred at -78° C. for a further 1 hour and at -10° C. for 1 hour, then poured into 100 ml of water and extracted three times with 100 ml of petroleum ether each time. The organic phases were washed with 100 ml of water and with 100 ml of saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residual crystallizing oil on silica gel with hexane gave 4.13 g (85%) of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene as colourless crystals (purity 99.3%); m.p. (C-N) 39.4° C., cl.p. 42.1° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1.Cl[CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[S:18][CH:19]=1>C1OCCOCCOCCOCCOC1.C1COCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([C:17]2[S:18][CH:19]=[C:15]([CH2:14][O:3][CH2:4][CH2:5][C:6]3[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=3)[N:16]=2)=[CH:25][CH:24]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: Nc1cccc(CCO)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(COCCc3cccc(N)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.1 %

Procedure:
To a solution of 0.027 g (1 mmol) of 95% sodium hydride and 0.5 drop of 15-crown-5 in 20 mL of THF was added dropwise a solution of 0.139 g (1 mmol) of 3-(2-hydroxy ethyl)phenyl amine at 0° C. After stirring for 0.5 hr 0.28 g (1.1 mmol) of 4-chloromethyl-2-(4-tert-butyl phenyl)thiazole was added in one portion. The mixture was stirred at room temperature for 5 hr. At the end of this time, the solution was concentrated and the residue washed with 10 ml of saturated ammonium chloride and extracted 2 times with 30 mL of ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated to recover an oil, which was purified by column chromatography on SiO2 with 30% ethyl acetate:hexane elution to provide 0.125 g of product as an oil, used in the next step without further purification. NMR (400 MHz, DMSO-d6) δ 7.83 (d, J=8 Hz, 2H, ArH), 7.50 (d, J=8 Hz, 2H, ArH), 7.45 (s, 1H, N═CH) 7.08 (t, J=8 Hz, 1H, H5), 6.63 (d, J=8 Hz, 1H, H4), 6.54 (s, 1H, H2), 6.51 (d, J=8 Hz, 1H, H6) 4.59 (s, 2H, OCH2), 3.71 (t, J=7 Hz, 2H, OCH2), 2.87 (t, J=7 Hz, 2H, ArCH2), 1.30 (s, 9H, t-bu).
Reaction SMILES: C(C(O)=O)CCCCCCCCCCCCCC(O)=O.C(O)C1C=CC=CC=1.S(=O)(=O)(O)O.[CH2:34]([O:41][C:42]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([O:60]CC1C=CC=CC=1)=[O:59])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)(C)C.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH2:34]([O:41][C:42]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][C:58]([OH:60])=[O:59])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(CCCCCCCCCCCCCCC(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C(O)CCCCCCCCCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCCCCCCCCCC(=O)OCc1ccccc1
Yield: 78.9 %

Procedure:
A method of synthesis for a compound obtained by converting one terminal of 1,14-tetradecane dicarboxylic acid into a benzyl ester is described. The compound can be synthesized by using Japanese Patent Application Public Disclosure (Kokai) Hei 04-18245 or “Organic Synthesis II” pages 276-277 as references. That is, 5 g (17.5 millimoles) of 1,14-tetradecane dicarboxylic acid, 8.37 g of benzyl alcohol, 50 ml of toluene and para-toluene sulfonic acid were placed in a flask and were allowed to reflux while using a Dean Stark dehydration device to remove water. After eight hours of refluxing, about one milliliter of water had been removed. The reaction solution was dissolved in hexane and washed using a saturated sodium bicarbonate solution first and water second. The organic phase was dried using sodium sulfate, and the solvent was removed using reduced pressure distillation. The product was recrystallized using hexane, and 8.1 g of 1,14-tetradecane dicarboxylic acid dibenzyl ester was obtained. Next, 4.8 g (16.7 millimoles) of 1,14-tetradecane dicarboxylic acid, 1.8 g of benzyl alcohol, 50 ml of toluene and sulfuric acid were freshly added to 5.97 g (12.8 millimoles) of this 1,14-tetradecane dicarboxylic acid dibenzyl ester, and the mixture was heated and allowed to reflux for five hours. The reaction mixture was subsequently dissolved in 300 ml of isopropanol/chloroform (1/5 volumetric ratio), and the solution was washed with water and dried using sodium sulfate. The solution was concentrated under reduced pressure and recrystallized using a mixed solvent of ether/hexane (1/4 volumetric ratio) to obtain 3.77 g (10.1 millimoles) of 1,14-tetradecane dicarboxylic acid monobenzyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:27][C:26]4([CH3:29])[CH2:28][CH:22]3[CH2:23][C:24]([CH3:31])([CH3:30])[CH2:25]4)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[CH2:27][C:26]4([CH3:29])[CH2:28][CH:22]3[CH2:23][C:24]([CH3:31])([CH3:30])[CH2:25]4)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2csc(C3CCN(C(=O)OC(C)(C)C)CC3)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC2CC(C)(CN2C(=O)c2csc(C3CCNCC3)c2)C1
Yield: 81.6 %

Procedure:
4-[4-(1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-thiophen-2-yl]-piperidine-1 carboxylic acid tert-butyl ester [Enantiomer E] (0.06 g) was dissolved in DCM (2 mL) and TFA (1 mL) and the reaction stirred at room temperature for 2 hours. The solvent was evaporated and the residue product was purified by flash chromatography on a SCX-2 cartridge, washing with acetonitrile and then eluting with 2 M ammonia in methanol. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.038 g). LCMS m/z 347.17 [M+H]+ RT=6.63 min (Analytical Method 2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]1[CH2:19][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1>>[OH:18][C@@H:17]([CH2:19][NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:24][CH2:23]1)[CH2:16][O:15][C:14]1[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Reactant: Oc1ccc2[nH]c3ccccc3c2c1OC[C@@H]1CO1
Product: Oc1ccc2[nH]c3ccccc3c2c1OC[C@@H](O)CNCC1CCN(CCC(F)(F)F)CC1
Yield: 16.6 %

Procedure:
Prepared from 3-hydroxy-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.260 g, 1.09 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.229 g, 1.09 mmol) according to the procedure used for Example 2 without heating to give 0.084 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[Cl:21][C:22]1[CH:23]=[C:24]([C:17]2[CH:18]=[C:13]3[N:12]=[C:11]([CH2:10][CH2:9][C:4]4[N:3]=[C:2]([NH2:1])[CH:7]=[C:6]([CH3:8])[CH:5]=4)[NH:20][C:14]3=[N:15][CH:16]=2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: Cc1cc(N)nc(CCc2nc3cc(Br)cnc3[nH]2)c1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4cc(Cl)cc(Cl)c4)cnc3[nH]2)c1
Yield: 30.9 %

Procedure:
The title compound is synthesized according to General Procedure A. 100 mg of 2-[2-(2-amino-4-methylpyridin-6-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine in 5.0 ml dioxane, 903 μl Na2CO3 solution, 65 mg of 3,5-dichlorophenylboronic acid, 13 mg of PdCl2(PCy3)2, 120° C. for 64 h. During extraction with 20 ml of CH2Cl2/H2O the title compound starts precipitating in the organic layer. Subsequently, 37 mg of the pure title compound can be obtained as a colorless powder after filtration and lyophilization from 2.0 ml dioxane and 1.0 ml water. M.p. 224° C. ESI-MS: 398.3, 400.2, 402.3 (MH+; 100%, 65%, 13%). TLC: Rf=0.24 (dichloromethane/methanol 10:1).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]4[O:23][CH2:22][O:21][C:18]=4[CH:19]=3)[CH:14]([CH3:24])[N:13]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:12]=2)=[CH:7][CH:6]=1)(=O)C>[OH-].[Na+].CO.CCOC(C)=O.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]4[O:23][CH2:22][O:21][C:18]=4[CH:19]=3)[CH:14]([CH3:24])[N:13]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:12]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C2=NN(C(=O)N(C)C)C(C)c3cc4c(cc32)OCO4)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC1c2cc3c(cc2C(c2ccc(N)cc2)=NN1C(=O)N(C)C)OCO3
Temperature: 25 °C
Yield: 71.5 %

Procedure:
A solution of 4-(4-acetylaminophenyl)-1,2-dihydro-2-(N,N-dimethylcarbamoyl)-1-methyl-6,7-methylendioxyphthalazine (97 mg, 0.25 mmole) in 1N sodium hydroxide (3 mL) and methanol (7 mL) was heated to reflux for 72 hours, cooled to ambient temperature, diluted with EtOAc (25 mL) and water (25 mL). The aqueous layer was washed with EtOAc and the combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 25% hexanes/EtOAc to leave a light yellow foamy solid (63 mg, 72%). 200 MHz 1H NMR (CDCl3); δ7.45 (d, 2H, J=8.6 Hz, ArH2 '), 6.84 (s, 1H, ArH), 6.76 (d, 2H, J=8.6 Hz, ArH), 6.71 (s, 1H, ArH), 6.01 (d, 2H, J=2.9 Hz, OCH2O), 5.25 (q, 1H, J=7.1 Hz, CHCH3), 3.95 (brs, 2H, NH2), 3.07 (s, 6H, N(CH3)2), 1.33 (d, 3H, J=7.1 Hz, CHCH3): FTIR (PTFE film); 3456 cm-1, 3343, 3220, 1631, 1605, 1482, 1379, 1251, 1036.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F:24][C:25]1[CH:26]=[C:27]([C:38]([F:41])([F:40])[F:39])[CH:28]=[C:29]([CH:37]=1)[C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:34](=[O:35])[CH2:33][NH:32][C:30](=[O:31])[C:29]2[CH:37]=[C:25]([F:24])[CH:26]=[C:27]([C:38]([F:39])([F:41])[F:40])[CH:28]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(O)CNC(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2)C1

Procedure:
The title compounds were prepared as white solids from the EDCI coupling of 3-amino-azetidine-1-carboxylic acid tert-butyl ester (BetaPharma) and (5-fluoro-3-trifluoromethyl-benzoylamino)-acetic acid (analog synthesis by the procedure described in Organic Synthesis XII, 40-2, 1932) using the procedure described in Step F of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:10]([CH3:12])[CH3:11])[CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)=[O:4].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:10]([CH3:11])[CH3:12])[CH2:7][NH:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1C[C@@H](N(C)C)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](N(C)C)CN1
Reaction time: 16 h

Procedure:
A mixture of (2S,4R)-4-dimethylamino-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (Stage B.2, 420 mg), 10% palladium on carbon (80 mg) and MeOH (10 mL) was stirred for 16 h under an atm. of hydrogen. Filtration and evaporation gave the title compound which was used without purification in the following steps.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:11]([C:6]1([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(Cc2ccccc2)CCCC1
Temperature: 40 °C
Reaction time: 72 h
Yield: 97.9 %

Procedure:
A solution of 1-benzylcyclopentane carboxylic acid ethyl ester (0.40 g, 1.7 mmol) in 10 mL of THF and 5 mL of methanol was treated with a solution of 200 mg of lithium hydroxide hydrate in 5 mL of water and the mixture was stirred for 3 days at room temperature and at 40° C. for 3 days. The mixture was diluted with water, washed with ether and acidified with excess 6 N HCl. The aqueous layer was extracted with ether and the combined extracts were washed with water and brine and were dried (MgSO4). Evaporation gave 0.34 g (96%) of 1-benzylcyclopentane carboxylic acid as a thick yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[CH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:9][O:21]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cccc([N+](=O)[O-])c1C
Solvent: ClCCl
Product: Cc1c(C2CO2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2-Methyl-1-nitro-3-vinylbenzene (2 g, 12.26 mmol) was dissolved in DCM (50 ml) then cooled to 0° C. and added mCPBA (3.17 g, 14.14 mmol) then stirred at room temperature for 16 hrs. When TLC showed starting materials, more mCPBA (1.58 g, 7.07 mmol) was added. The reaction was stirred for another 16 hrs. The reaction was washed with saturated aqueous Na2S2O3, NaHCO3, brine; then dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography through a 120 g ISCO Redi-Sep column eluting with 0-20% ETOAc/hexane to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[F:20][C:21]1[CH:32]=[CH:31][C:24]([C:25](N(OC)C)=[O:26])=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=1.O>C(OCC)C>[F:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)=[O:26])=[C:23]([C:33]([F:34])([F:35])[F:36])[CH:22]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1C(F)(F)F
Reactant: Cc1ccnc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1ccnc(C(=O)c2ccc(F)cc2C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
2-bromo-4-methylpyridine (4.7 g) was dissolved in diethylether (150 ml), and the mixture was cooled to −78° C. under argon atmosphere. 1.6M n-butyllithium hexane solution (16.8 ml) was added dropwise to the solution, and the mixture was stirred for 30 minutes. The reaction solution was added dropwise to a solution of 4-fluoro-N-methoxy-N-methyl-2-trifluoromethylbenzamide (6.2 g) in diethylether (50 ml) under argon atmosphere at −78° C. The mixture was allowed to be at room temperature and stirred overnight, and water was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 2-(4-fluoro-2-trifluoromethylbenzoyl)-4-methylpyridine (4.5 g) as pale yellow amorphous.
Reaction SMILES: [BH4-].[Na+].[N:3]([CH2:6][C:7]1[CH:14]=[C:13]([F:15])[C:10]([C:11]#[N:12])=[C:9]([F:16])[CH:8]=1)=[N+]=[N-].Cl>O.C1COCC1.[Pd]>[NH2:3][CH2:6][C:7]1[CH:8]=[C:9]([F:16])[C:10]([C:11]#[N:12])=[C:13]([F:15])[CH:14]=1
Reactant: N#Cc1c(F)cc(CN=[N+]=[N-])cc1F
Agent: [Pd]
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(CN)cc1F

Procedure:
This reaction was carried out according to the procedure described in J. Chem. Res. (M) (1992) 3128. To a suspension of 520 mg of 10% Pd/C (50% moisture) in 20 mL of water was added a solution of sodium borohydride (0.834 g, 0.0221 mol) in 20 mL of water. Some gas evolution resulted. 4-Azidomethyl-2,6-difluorobenzonitrile (1.26 g, 6.49 mmol; see step (v) above) was dissolved in 50 mL of THF and added to the aqueous mixture on an ice bath over 15 min. The mixture was stirred for 4 h, whereafter 20 mL of 2M HCl was added and the mixture was filtered through Celite. The Celite was rinsed with more water and the combined aqueous phase was washed with EtOAc and subsequently made alkaline with 2M NaOH. Extraction three times with methylene chloride followed and the combined organic phase was washed with water, dried (Na2SO4) and evaporated. Yield: 0.87 g (80%).