Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:32]=1.C([Sn](CCCC)(CCCC)C=C)CCC.CC(=O)OCC>CN(C=O)C.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]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16]([CH:31]=[CH2:32])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1nc(C)n2c1C(CCc1ccc(C(F)(F)F)cc1)N(C(=O)OC(C)(C)C)CC2
Temperature: 90 °C

Procedure:
A slightly yellow homogeneous solution of 1-iodo-3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.500 g; 2.802 mmol) in anhydrous DMF (15 ml) was treated successively at rt with tris(dibenzylideneacetone)dipalladium(0) (82 mg; 0.090 mmol), triphenylphosphine (91 mg; 0.350 mmol), and finally with tributyl(vinyl)tin (1.63 ml; 5.604 mmol). The resulting mixture was heated to 90° C., under nitrogen, for 20 h. The reaction mixture was cooled to rt, EA (200 ml) was added, and the resulting solution was washed with water (2×125 ml). The resulting yellow organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give an orange oil. Purification by FC (DCM/MeOH=40/1) gave the pure product 3-methyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-1-vinyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.936 g; 77%). LC-MS: tR=0.88 min.; [M+H]+=436.48 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[NH:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11]
Reactant: CN(C)CCN
Reactant: N#Cc1ccc(Cl)cc1F
Product: CN(C)CCNc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 2-dimethylamino-ethylamine analogously to the preparation of Intermediate 113.1 as a colorless oil; 1HNMR (CDCl3) δ 9.20 (bs, 1H), 7.18-7.10 (m, 2H), 6.95 (d, 1H), 4.60 (s, 2H), 3.80 (s, 2H), 3.25-3.05 (m, 4H), 2.25 (s, 6H); HPLC: AtRet=1.26 min.
Reaction SMILES: [H-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:18])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:6][C:5]=1[OH:19].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:19][C:5]1[CH:6]=[C:7]([C:10]([CH3:18])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])[CH:8]=[CH:9][C:4]=1[Br:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(O)c1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a -18° C. slurry of 23.0 g. (0.575 mole) of potassium hydride in 400 ml. of N,N-dimethylformamide was added over a 45 minute period a solution of 150 g. (0.5 mole) of 2-(4-bromo-3-hydroxyphenyl)-2-methyloctane in 400 ml. of N,N-dimethylformamide (reaction temperature ≤-15° C.). The reaction mixture was stirred 15 minutes longer after which a solution of 98.3 g. (0.575 mole) of benzyl bromide in 200 ml. of N,N-dimethylformamide was added. The mixture was then warmed to room temperature and stirred 30 minutes longer. It was quenched by addition to 6 liters of ice water. The quenched mixture was extracted six times with 500 ml. of ether. The combined extract was washed twice with one liter portions of water and once with one liter of saturated sodium chloride, dried over magnesium sulfate and evaporated to a quantitative yield of the title product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[N:6]1[C:13](Cl)=[N:12][C:10](Cl)=[N:9][C:7]=1Cl>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:7]1[N:9]=[CH:10][N:12]=[C:13]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:6]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCCOc1ncnc(OCCOC)n1
Temperature: 110 °C
Yield: 1608.9 %

Procedure:
In 100 ml of dry toluene containing 10 g of anhydrous sodium carbonate was dissolved 20 g of monomethoxypolyethylene glycol having an average molecular weight of 4000 (Nippon Oil and Fats) and the solution was heated at 110° C. for 30 minutes. Then, 500 mg of cyanuric chloride was added and the mixture was heated at 110° C. for 24 hours. The reaction residue was filtered off, followed by addition of 300 ml of petroleum ether to cause precipitation. The precipitate was washed with several portions of petroleum ether to recover 10 g of 2,4-bis(O-methoxypolyethylene glycol)-6-chloro-s-triazine (yield 50%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[CH3:17][C:18]([O-])([CH3:20])[CH3:19].[Na+].BrCC1CC1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Agent: BrCC1CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1C2COCCN2c2nc(Cl)ncc2N1CC1CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a round-bottomed flask equipped with a magnetic stirrer was added 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (800 mg, 3.32 mmol), DMSO (5 ml), sodium 2-methylpropan-2-olate (351 mg, 3.66 mmol). The reaction mixture was cooled to 0° C. and (bromomethyl)cyclopropane (0.372 ml, 3.66 mmol) was added in DMSO (1 mL). The reaction was removed from the ice-bath and stirred at 20° C. for 16 hours. The heterogeneous suspension was added to water (10 mL) to give a precipitate, which was collected by filtration, was successively washed with water, a small amount of ethanol and diethyl ether. The collected solid was dried in-vacuo to afford 2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (746 mg, 2.53 mmol, 76% yield) as a off white solid. MS [M+H] found 295.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[C:7]1([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: BrCc1ccccc1
Solvent: CCOCC
Product: c1ccc(CN2CCCC2)cc1

Procedure:
A 25.0 ml portion of pyrrolidine was reacted with 10.9 ml of benzyl bromide in ether as described in Example 3, giving 12.3 g of 1-(phenylmethyl)pyrrolidine, which was then reacted with butyl lithium and diphenylphosphine chloride as described in Example 3, giving diphenyl]2-(1-pyrrolidinylmethyl)phenyl]phosphine.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][CH:15]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH:27]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:10]1[O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11]1
Reactant: O=CCCCC1CC(c2ccccc2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCNCC1CCCCC1CC(c2ccccc2)=NO1
Yield: 74.5 %

Procedure:
4-(3-Phenyl-4,5-dihydroisoxazol-5-yl)butanal (20.9 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 25.5 mg (69.2%) of the target compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:36]Br>C(Br)CBr>[Br:36][CH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6]
Reactant: BrBr
Reactant: COc1ccc(C(=O)c2cccc(C)c2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: BrCCBr
Product: COc1ccc(C(=O)c2cccc(CBr)c2)cc1
Reaction time: 17 h
Yield: 60.8 %

Procedure:
A solution of the benzophenone (17.5 g, 77.4 mmole) of Step A in ethylene bromide (26.5 mL) (containing a small amount of benzoyl peroxide) is heated at reflux. A solution of bromine (12.7 g, 79.6 mmole) in ethylene bromide (15 mL) is added dropwise over 30 minutes while the mixture is irradiated with a Photolamp (300 W). Reflux is continued for 17 hours (TLC, 9:1 petrolether-ethylacetate, traces of starting material still present). The solvent is removed in vacuo and the residue (brown oil, 39.22 g) is purified by flash chromatography (on silica Merck-60, preabsorbed in dichloromethane, eluted with 9:1 petrolether-ethyl acetate) to give unreacted starting material (2.59 g, ca. 15%) along with the desired product (14.36 g, 61% or 71.5% based on recovered unreacted starting material) and some mixed fractions (ca. 5.20 g). The light yellow solid melts at 58°-61° C. and it is used as such in the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9](F)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.[NH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][NH:27][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][N:8]=2)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]3[NH:22][C:21]2[CH:23]=[CH:24][C:18]([O:17][C:16]([F:25])([F:26])[F:15])=[CH:19][CH:20]=2)[CH:30]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: NCc1cccnc1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: N#Cc1cnc2cnc(NCc3cccnc3)cc2c1Nc1ccc(OC(F)(F)F)cc1
Yield: 3.8 %

Procedure:
Following the procedure described above in Example 29, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.200 g, 0.963 mmol) was reacted with 4-(trifluoromethoxy)aniline (0.14 mL, 0.19 g, 1.1 mmol), then with 3-(aminomethyl)pyridine. The crude product was purified twice by preparative HPLC, and lyophilized to give a fluffy, bright yellow solid (16 mg, 3.8% yield): 1H NMR (400 MHz, DMSO-D6) δ 4.57 (d, J=6.6 Hz, 2 H) 7.12 (s, 1 H) 7.33 (dd, J=7.6, 4.8 Hz, 1 H) 7.38 (s, 4 H) 7.52 (t, J=6.1 Hz, 1 H) 7.75 (d, J=7.6 Hz, 1 H) 8.29 (s, 1 H) 8.43 (d, J=3.8 Hz, 1 H) 8.59 (s, 1 H) 8.86 (s, 1 H) 9.67 (s, 1 H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[CH2:16][CH:15]([CH2:17][NH2:18])[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23.C(N(CC)CC)C.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[CH2:16][CH:15]([CH2:17][NH:18][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23
Reactant: NCC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.7 %

Procedure:
A mixture of 8-bromo-5-aminomethyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione hydrochloride (134 mg, 0.405 mmol), triethyl amine (124 μL, 0.892 mmol), benzoic acid (54 mg, 0.446 mmol), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (69 mg, 0.446 mmol) and N-hydroxybenzotriazole (68 mg, 0.446 mmol) in DMF (6 mL) was stirred for 20 h at room temperature and 0.1N hydrochloric acid (20 mL) was added. The precipitates formed were collected by filtration, washed with distilled water, and dried in vacuo to give 87 mg of the title compound (52%): mp 180.5°~182° C.; 1H NMR (270 MHz, DMSO-d6) δ11.86 (s, 1H), 8.56 (t, 1H, J=6 Hz), 7.34~7.54 (m, 5H), 7.12 (s, 1H), 7.17 (s, 2H), 4.96~5.06 (m, 1H), 3.90~4.00 (m, 1H), 3.72~3.82 (m, 1H), 3.43 (dd, 1H, J=17, 10 Hz), 3.19 (dd, 1H, J=17, 3 Hz).
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][SiH:9]([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[CH2:22])=[CH2:14]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:1]1([CH:7]([CH3:12])[CH2:8][Si:9]([C:19]2[CH:18]=[CH:17][C:16]([CH2:21][CH3:22])=[C:15]([CH2:13][CH3:14])[C:20]=2[Si:9]([Cl:10])([Cl:11])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:12])([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C[SiH](Cl)Cl)c1ccccc1
Reactant: C=Cc1ccccc1C=C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCc1ccc([Si](Cl)(Cl)CC(C)c2ccccc2)c([Si](Cl)(Cl)CC(C)c2ccccc2)c1CC
Yield: 70.4 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 18.5 g (0.084 mole) of 3-(phenyl)-1,1-dichloro-1-silabutane and 90 μl of 1% chloroplatinic acid solution in isopropanol were placed and then 5.0 g (0.038 mole) of divinylbenzene was added dropwise for 10 min. The solution was reacted for 6 hours at room temperature under the dry nitrogen atmosphere. Vacuum distillation gave 15.2 g (186°-188° C./0.03 mmHg) of bis{(2-phenylpropyl)dichlorosilyl}diethylbenzene in 70.4% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:8]([C:10]2[C:15]([F:16])=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)=O)[CH:7]=1.Cl.[NH2:27][OH:28]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6](/[C:8](/[C:10]2[C:15]([F:16])=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)=[N:27]/[OH:28])[CH:7]=1
Reactant: COc1ccc(F)cc1C(=O)c1nccc(-c2cnccc2C)c1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(F)cc1/C(=N/O)c1nccc(-c2cnccc2C)c1F
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of (5-fluoro-2-methoxyphenyl)(3′-fluoro-4-methyl-3,4′-bipyridin-2′-yl)methanone (0.024 g, 0.071 mmol) and hydroxylamine hydrochloride (0.033 g, 0.480 mmol) in pyridine (Volume: 0.353 ml) was refluxed for 3 hr, allowed to cool to room temperature, and then concentrated in vacuo. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 0-95% EtOAc in hexanes over 15 min, tr=0.5, 1.5 2.5 min) gave the title compound (22 mg, 0.061 mmol, 87% yield) as a yellow residue. ESI MS (M+H)+=356.1.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1)[CH3:6])C.CO.[Li+].[OH-].Cl>O.C1COCC1>[CH2:18]([O:17][C:9]1[CH:8]=[C:7]([CH:5]([CH3:6])[C:4]([OH:25])=[O:3])[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C(C)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1

Procedure:
2-(3-Benzyloxy-5-trifluoromethyl-phenyl)-propionic acid ethyl ester (1.4 g, 4.0 mmol) in 2:2:1 MeOH:THF:H2O was treated with 1N aqueous LiOH (3 mL) at room temperature overnight. The mixture was acidified with 10% aqueous HCl and extracted three times with EtOAc. The combined organic layers were concentrated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:24]=[C:25]1[NH:30][CH2:29][CH2:28][CH2:27][N:26]1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@@H:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:34]2[CH2:35][CH2:36][CH:31]([N:26]3[CH2:27][CH2:28][CH2:29][NH:30][C:25]3=[O:24])[CH2:32][CH2:33]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CN1C(=O)c2ccccc2[C@H]1[C@@H](CC=O)c1ccc(Cl)c(Cl)c1
Product: CN1C(=O)c2ccccc2[C@H]1[C@@H](CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 199.8 %

Procedure:
(3S)-3-(3,4-Dichlorophenyl)-3-((1R)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (2.09 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (1.111 g) by a method similar to that described in Example 1 to give the title compound (3.31 g); mp 170°-210° C. (d); [α]D =36° (c=1.0); MS: m/z=515(M+1); NMR (CD3SOCD3): 1.66 (m,2), 1.78 (m,2), 2.18 (m,2), 3.05 (s,3), 4.39 (m,1), 4.86 (d,1, J=4), 6.75 (m,1), 6.95 (d,1, J=1.6), 7.3 (d,1, J=8), 7.5 (m,2), 7.64 (m,1), 7.94 (d,1, J=7.6). Analysis for C27H32Cl2N4O.1.5 H2O.1.5 HCl: Calculated: C, 54.30; H, 6.16, N, 9.38; Found: C, 54.33; H, 5.92; N, 9.19.
Reaction SMILES: [Si:1]([O:8][CH:9]=[C:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:22][CH:23]([Cl:27])[C:24](Cl)=[O:25]>C1CCCCC1.C(Cl)Cl>[Si:1]([O:8][CH:9]=[C:10]1[CH:11]2[CH:12]([C:23]([Cl:27])([Cl:22])[C:24]2=[O:25])[CH:13]=[CH:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC=C1C=CC=C1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCCCC1
Product: CC(C)(C)[Si](C)(C)OC=C1C=CC2C1C(=O)C2(Cl)Cl

Procedure:
A 3-neck, 5 L flask equipped with a heating mantle, a mechanical stirrer, an argon inlet, and a pressure-equalized dropping funnel was charged with the 6-(tert-butyldimethylsilyloxy)fulvene from the previous Preparation dissolved in 2 L of cyclohexane. After this solution was brought to reflux, 150 mL of triethylamine was added in one portion. Then, 100 mL of dichloroacetyl chloride was added dropwise to the refluxing mixture over a 1.5 hr period. The cooled reaction mixture was diluted with 1.5 L of methylene chloride and filtered to remove the triethylamine hydrochloride by-product. The dark solution of the crude reaction product could be stored as such for a few days. The solvent was removed by evaporation immediately before its use in the next reaction.
Reaction SMILES: C[O:2][C:3]1[C:4]([Cl:22])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH3:13])[C@@H:9]3[CH2:14][C:15]4[C:20]([C@H:8]3[C:7]=2[CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=4.B(Br)(Br)[Br:24]>C(Cl)Cl>[BrH:24].[OH:2][C:3]1[C:4]([Cl:22])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH3:13])[C@@H:9]3[CH2:14][C:15]4[C:20]([C@H:8]3[C:7]=2[CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=4
Reactant: COc1cc2c(cc1Cl)CCN(C)[C@@H]1Cc3ccccc3[C@@H]21
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Br
Product: CN1CCc2cc(Cl)c(O)cc2[C@@H]2c3ccccc3C[C@H]21
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 147 mg (0.47 mmol) of Compound Q from Step F above in 10 mL methylene chloride at -78° C. was treated with 90 mL boron tribromide, and the mixture was stirred for 4 hours while coming to room temperature. The reaction was quenched with 10 mL dry methanol and stirred for 10 minutes. The solvent was evaporated under reduced pressure, and the residue was treated with a second 10 mL portion of methanol. After 10 minutes, the solvent was evaporated at 10 mm Hg and 50° C. for 45 minutes to give 180 mg (100%) of the crude hydrobromide, 200 MHz NMR(d6-DMSO) d 2.97(s,3H), 2.90-3.90(m,7H),5.02(d,1H,J=8 Hz),6.99(s,1H),7.36(m,5H).
Reaction SMILES: [CH3:1][C:2]([C@H:18]1[C:21](=[O:22])[NH:20][C@@H:19]1[CH2:23][C:24](=[O:39])[CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27])([O:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6])[CH3:3].C1(C)C=CC(S([N:49]=[N+:50]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C>C(#N)C>[N+:49](=[C:25]([C:24](=[O:39])[CH2:23][C@@H:19]1[C@@H:18]([C:2]([CH3:1])([O:4][C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[O:6])[CH3:3])[C:21](=[O:22])[NH:20]1)[C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=1)=[O:27])=[N-:50]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
To a solution of 4-nitrobenzyl 4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate (58.3 mg) in acetonitrile (1.17 ml) was added a solution of p-toluenesulfonyl azide (25.3 mg) in acetonitrile (0.228 ml) at 0° C. After stirring for 5 minutes at 0° C., a solution of triethylamine (53.7 μl) in acetonitrile (0.483 ml) was added dropwise. The stirring mixture was allowed to warm to ambient temperature during 15 minutes and kept at the same temperature for 20 minutes. The solvent was distilled off and the residue (85.9 mg) was flash chromatographed on silica gel (1 g) eluting with a mixture of methylene chloride and ethyl acetate (50:1 to 3:1) to give 4-nitrobenzyl 2-diazo-4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate (58.4 mg) as an amorphous solid
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[C:5]([N+:20]([O-])=O)[CH:4]=1)#[N:2].O.NN.[CH:26](O)=O>C(O)C.[Pd].C(OC)(OC)OC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=3)[CH:26]=[N:20][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(Nc2ccc(C#N)cc2[N+](=O)[O-])cc1
Reactant: O=CO
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: COC(OC)OC
Solvent: O
Product: COC(=O)c1ccc(-n2cnc3cc(C#N)ccc32)cc1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzonitrile (2.00 g, 12.04 mmol) and methyl 4-aminobenzoate (1.94 g, 12.83 mmol) in DMSO (40 mL) was cooled in an ice-bath and potassium tert-butoxide (2.96 g, 26.38 mmol) was added over 15 min. The reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was quenched with ice; the solid product was recovered by filtration, washed with water and dried under vacuum to afford 2.4 g (68%) of methyl 4-[(4-cyano-2-nitrophenyl)amino]benzoate. To a solution of methyl 4-[(4-cyano-2-nitrophenyl)amino]benzoate (0.2 g, 0.67 mmol) in ethanol (4 mL) was added palladium on carbon (10 wt. %, 0.06 g) and hydrazine hydrate (0.13 g, 2.60 mmol) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, filtered through celite, and the solvent evaporated. The residue was dissolved in ethyl acetate, washed with water, dried (Na2SO4) and evaporated under reduced pressure to afford a crude oil. To a solution of the oil in trimethyl orthoformate (10 mL) was added formic acid (0.31 g, 7.7 mmol, 3 eq) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate and the organic layer was dried (Na2SO4) and evaporated to afford a crude solid. Purification by flash column chromatography (silica, CHCl3/MeOH 98:2) afforded 0.12 g (63%) of methyl 4-(5-cyano-1H-benzimidazol-1-yl)benzoate. MS [M+H] 277.