Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:12])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:12][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccncc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cnccc1CCl
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 95.1 %

Procedure:
To a mixture of 1.12 g of (3-fluoropyridin-4-yl)methanol and 5 ml of chloroform was added dropwise 1.26 g of thionyl chloride at room temperature, and the mixture was stirred at room temperature for 1.3 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layers were combined and washed with saturated brine and dried over magnesium sulfate. The resulting mixture was concentrated under reduced pressure to obtain 1.22 g of 4-chloromethyl-3-fluoropyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]3[C:30]4[O:29][C:28]([C:31]([NH2:33])=O)=[CH:27][C:26](=[O:34])[C:25]=4[CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]3[C:30]4[O:29][C:28]([C:31]#[N:33])=[CH:27][C:26](=[O:34])[C:25]=4[CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccc(F)cc4)cc3)c2o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(=O)c2cccc(/C=C/c3ccc(OCCCCc4ccc(F)cc4)cc3)c2o1
Yield: 95 %

Procedure:
Following the process described in example 2 (point D), reacting 8-[(E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethen-1-yl]-4-oxo-4H-1-benzopyran-2-carboxamide with phosphorous oxychloride in DMF for 0.5 h at 0° C., the title compound was prepared (95% yield).
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O-2].[Mg+2:22]>O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Mg+2:22].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
Stearic acid and magnesium oxide were reacted to yield a reaction product of magnesium stearate, water and an excess of magnesium oxide. To this end 50 grams of 60-70 micron, technical grade (95% purity) magnesium oxide, known to exhibit medium reactivity with stearic acid, was introduced into the open-topped reactor.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][C:18]([C:22]2[O:23][C:24]([CH:27]([CH3:29])[CH3:28])=[N:25][N:26]=2)([CH3:21])[CH2:17][CH2:16]1)=O)(C)(C)C>O1CCOCC1>[CH:27]([C:24]1[O:23][C:22]([C:18]2([CH3:21])[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[N:26][N:25]=1)([CH3:29])[CH3:28]
Reactant: CC(C)c1nnc(C2(C)CCN(C(=O)OC(C)(C)C)CC2)o1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1nnc(C2(C)CCNCC2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.5 %

Procedure:
150 mL saturated dioxane-HCl was added to 19 g 4-(5-isopropyl-(1,3,4)oxadiazol-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester in 100 mL dioxane at 0° C. The mixture was stirred at RT for 2 h. The precipitate was filtered and washed with ethyl acetate to give 15.1 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]\[N+:17]([O-:19])=[O:18])=[C:11]([O:20][CH2:21][O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:4][CH:3]=[CH:2][CH2:1][CH:16]2[N+:17]([O-:19])=[O:18])=[C:11]([O:20][CH2:21][O:22][CH3:23])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cc(OCc2ccccc2)ccc1/C=C\[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COCOc1cc(OCc2ccccc2)ccc1C1CC=CCC1[N+](=O)[O-]
Temperature: -78 °C
Yield: 190.3 %

Procedure:
Nitrostyrene 14 (0.65 g, 2.06 mmol) was dissolved in toluene (0.6 mL) in a 2 mL sealed tube and cooled to −78° C. Butadiene was bubbled into the solution to double the volume and then the tube was sealed and heated to reflux for 48 h. To prevent bumping of the butadiene gas, the tube was cooled again to −78° C. and used directly in purification by column chromatography (SiO2; 3:1, Hex:EtOAc) to afford cyclohexene 15 (0.72 g, 1.96 mmol, 95%). 1H NMR (500 MHz, CDCl3) δ 7.40 (m, 4H), 7.36-7.28 (m, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 6.56 (dd, J=8.4, 2.5 Hz, 1H), 5.86-5.77 (m, 1H), 5.71 (ddd, J=9.8, 5.1, 2.3 Hz, 1H), 5.27-5.20 (m, 1H), 5.20 (s, 2H), 5.00 (s, 2H), 3.70 (dt, J=17.0, 8.7 Hz, 1H), 3.49 (s, J=12.7 Hz, 3H), 2.84-2.74 (m, 1H), 2.71 (ddd, J=13.2, 8.4, 1.5 Hz, 1H), 2.45 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 159.2, 156.1, 136.9, 129.3, 128.6, 127.0, 122.5, 120.9, 107.8, 120.6, 94.6, 85.6, 70.1, 31.5, 31.3, 29.7.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N(C)C)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)c1ccc(O)cc1
Temperature: 0 °C
Yield: 75.2 %

Procedure:
A mixture of 4-methoxy-N,N-dimethylbenzenesulfonamide (37 g) and aluminum chloride (69 g) in benzene (170 ml) was stirred under reflux for 30 minutes. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by recrystallization from toluene to give 4-hydroxy-N,N-dimethylbenzenesulfonamide (26 g).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[C:34]([O-])(=[O:38])[C@H:35]([CH3:37])[OH:36].[Na+].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([C:34](=[O:38])[C@@H:35]([OH:36])[CH3:37])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: C[C@H](O)C(=O)[O-]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(=O)[C@H](C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.3 %

Procedure:
To a mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) and sodium L-lactate (38 mg, 0.34 mmol) in DCM (2 mL) was added HOBt (33 mg, 0.25 mmol) and EDCI (64 mg, 0.34 mmol). The resulting mixture was allowed to stir at r.t. for 18 h then partitioned between DCM and sat. aq. NH4Cl. The organic phase was dried (phase separator), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-25%). The resulting residue was triturated with Et2O and further purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient MeOH 45-60%) affording 840 (29 mg, 23%). LCMS (method I): RT 3.10 min, [M+H]+ 521.3. 1H NMR (DMSO, 400 MHz): δ 8.44 (1 H, brd s), 8.07-8.03 (1 H, m), 7.64-7.63 (1 H, m), 7.25-7.24 (2 H, m), 5.24 (1 H, brd s), 4.94 (1 H, dd, J=21.10, 10.14 Hz), 4.59-4.58 (2 H, m), 4.46-4.12 (4 H, brd s), 4.18-4.17 (2 H, m), 3.79 (4 H, t, J=4.51 Hz), 3.72 (3 H, s), 3.34-3.32 (2 H, m), 3.09 (3 H, s), 1.34 (3 H, t, J=7.43 Hz), 1.20 (3 H, d, J=6.71 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:22]Cl.[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:22][N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: C1CNCCNC1
Reactant: COc1ccc(S(=O)(=O)n2cc(CCl)c3cc(Br)ccc32)cc1
Product: COc1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3cc(Br)ccc32)cc1

Procedure:
Using essentially the same procedure as described in example 127, 5-Bromo-1-(4-methoxybenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCC)C2)oc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCO[C@@H]1CN(c2nc(C(=O)O)c(C)o2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 82.8 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (113i) (0.21 g, 0.42 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and THF (5 mL), to obtain 153 mg of the title compound as a colorless solid (82%).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH:3]=[CH:4][C:5]([OH:7])=[O:6].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][Si:2]([CH3:9])([CH3:8])[CH:3]=[CH:4][C:5]([O:7][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: OCc1ccccc1
Reactant: C[Si](C)(C)C=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[Si](C)(C)C=CC(=O)OCc1ccccc1
Reaction time: 0.08 h
Yield: 94.3 %

Procedure:
A solution of 3-trimethylsilylacrylic acid (510 mg, 3.54 mmol) [J. Org. Chem., 56, pp. 4766-4772, 1991] in dichloromethane (8 ml) was added successively with benzyl alcohol (0.59 ml, 5.71 mmol), dicyclohexylcarbodiimide (DCC, 914 mg, 4.44 mmol) and 4-dimethylaminopyridine (4-DMAP, 43 mg, 0.352 mmol) under ice cooling, the mixture was stirred for 5 minutes, and then stirring was further continued at room temperature for 16 hours. The reaction mixture was cooled on ice, and then added with aqueous hydrochloric acid (1 N, 5 ml), the mixture was filtered under reduced pressure, and the resulting urea was washed with ethyl acetate. After the layers were separated, the organic layer was washed with saturated aqueous sodium hydrogencarbonate and water, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography [hexane/ethyl acetate (24:1)] to obtain benzyl 3-trimethylsilylacrylate (782 mg, 94%) mentioned in the title as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[NH3:33].O>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH:15]([F:17])[F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:33])=[N:13]2)[CH:7]=1
Reactant: N
Reactant: O=C1COC[C@](c2cc(Br)ccc2F)(C(F)F)N1
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)COC1

Procedure:
To a solution of (R)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholin-3-one (10 g, 30.86 mmol) in CH2Cl2 (100 mL) was added P2S5 (6.86 g, 30.86 mmol) at room temperature. The resulted yellow suspension was heated to reflux for 6.5 h. The reaction mixture was filtered through a pad of silica gel (200˜300 mesh), washed with CH2Cl2 for 3 times to get a brown solution. The solvent was removed to provide the crude product as a yellow solid, which was dispersed in THF (10 mL), then 25% NH3 water solution (60 mL) was added at room temperature. 20 hours later, the reaction mixture was extracted with IPAC. The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to provide the title compound as a yellow solid.
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([O:25]C(=O)C1C=CC=CC=1)[CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([OH:25])[CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(Oc1ccc2c(c1)c1c(n2C(=O)c2ccccc2)CCC(C(=O)O)C1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1CCc2c(c3cc(O)ccc3n2C(=O)c2ccccc2)C1

Procedure:
A solution of 8.1 g. of 9-benzoyl-6-benzoyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid in 250 ml. of ethyl acetate over 1.5 g. of 10 percent palladium-on-charcoal was subjected to a hydrogen atmosphere at about 40 psig while being heated with a heat lamp. The reaction was stopped when a theoretical amount of hydrogen had been adsorbed (1 hour) and the resulting cooled mixture was filtered and evaporated to dryness under reduced pressure. The residue was crystallized from acetone-n-hexane to yield 4.1 g. of the title compound; m.p. 224°-227°C.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[N:18]#[C:19][NH2:20]>CO>[C:19]([NH:20][C:14](=[NH:17])[CH2:13][CH2:12][CH2:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)#[N:18]
Reactant: COC(=N)CCCCc1csc(NC(=N)N)n1
Reactant: N#CN
Solvent: CO
Product: N#CNC(=N)CCCCc1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
In 10 ml of methanol solution of 2.5 g of methyl 5-(2-guanidinothiazol-4-yl)pentanoimidate was added 0.6 g cyanamide, and the solution was stirred at room temperature for 1.5 hour. The solvent was distilled off, and to the residue was added 10 ml of acetone. The precipitated crystals were filtered off and the product was purified by using dimethylformamide-water. The purified product was dissolved in a mixture of 0.7 ml of acetic acid, 8 ml of ethanol and 16 ml of water, to the solution 11.6 ml of N-NaOH solution was added. The precipitated crystals were collected by filtration to provide 1.9 g of N-cyano-5-(2-guanidinothiazol-4-yl)pentanoamidine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].Cl.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=1)([O-:17])=[O:16].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:29]2[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=3)[CH2:27][CH2:28]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Bromo-1-(4-nitrophenyl)ethanone (269 mg, 1.10 mmol) was added to a stirred solution of 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (200 mg, 0.736 mmol) followed by Hünig's base, then was stirred at RT for 1 h. The reaction mixture was poured into saturated NH4Cl solution and extracted twice with ethyl acetate. The combined organic layers were washed with water, then brine. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC using 5% MeOH/DCM solvent system to yield 1-(4-nitrophenyl)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13][NH:12][CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.C(N(CC)C(C)C)(C)C.COC(C)(C)C>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13][N:12]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:29])([F:31])[F:30])[CH:21]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: Fc1c(Cl)cc(C2(C(F)(F)F)CCNC2)cc1Cl
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Yield: 78.4 %

Procedure:
3-(3,5-Dichloro-4-fluorophenyl)-3-(trifluoromethyl)pyrrolidine (0.9 g) and 4-fluoro-2-(tri-fluoromethyl)benzonitrile (0.62 g) were weighed, dissolved in N,N-dimethylacetamide (10 ml), added with N,N-diisopropylethylamine (1.0 ml) at room temperature and reacted for 1 hour using a microwave reactor (trade name: INITIATOR™, manufactured by Biotage). The reaction solution was diluted by adding t-butyl methyl ether, and the organic layer was washed three times with water and then saturated brine in that order. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure and the residue obtained was purified by column chromatography to obtain 4-[3-(3,5-dichloro-4-fluorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (1.1 g).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:7][C:6]=1[O:21][CH3:22])(C)C>[Ti](Cl)(Cl)(Cl)Cl>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:7][C:6]=1[O:21][CH3:22]
Reactant: COc1cc(CCCC2SC(=O)NC2=O)ccc1OC(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COc1cc(CCCC2SC(=O)NC2=O)ccc1O
Yield: 87 %

Procedure:
According to the same manner as that described in Reference Example 37, 5-[3-(4-isopropoxy-3-methoxyphenyl)-propyl]-2,4-thiazolidinedione was treated with titanium tetrachloride to give 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4-thiazolidinedione as an oil (yield: 87%).
Reaction SMILES: FC(F)(F)C(O)=O.CC(OC([N:15]1[CH2:22][C:21]2[O:20][C:19]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:18][C:17]=2[CH2:16]1)=O)(C)C>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[O:24]([CH2:23][C:19]1[O:20][C:21]2[CH2:22][NH:15][CH2:16][C:17]=2[N:18]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(COc3ccccc3)oc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(OCc2nc3c(o2)CNC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
Trifluoroacetic acid (0.5 mL, 0.65 mmol) was added to a solution of 4,6-dihydro-2-(phenoxymethyl)-5H-pyrrolo[3,4-d]oxazole-5-carboxylic acid 1,1-dimethylethyl ester (0.075 g, 0.19 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 15 minutes and diluted with a saturated solution of Na2CO3. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield 5,6-dihydro-2-(phenoxymethyl)-4H-pyrrolo[3,4-d]oxazole (22 mg, 53% yield, 30% pure) as a clear oil that was used in the next step without further purification. C12H12N2O2LCMS: Rt 1.04, m/z 217 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:10])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@](C)(C(=O)O)c1ccccc1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@](C)(C(=O)N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
630 mg (2.374 mmol) of N-(tert-butoxycarbonyl)-2-phenyl-D-alanine were dissolved in 20 mL of dry DMF and O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoborate (TBTU, 1.37 g, 4.27 mmol), morpholine (0.412 mL, 4.73 mmol) and diisopropylethylamine (1.63 mL, 9.5 mol) were added. The mixture was stirred at room temperature for 1 hour, then the solvent was removed and the residue dissolved with dichloromethane. The solution was washed with saturated NaHCO3, brine, water and dried over Na2SO4. 700 mg of the title compound were recovered (88% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:17]3[N:16]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochlorde salt, of Preparation 44, and 4-pyrimidin-2-yl-benzaldehyde, of Preparation 21, using the method described in Example 1, Step A except that the imine was formed in MeOH at reflux with a reaction time of 2 h. 1H NMR (400 MHz, CDCl3) δ 8.79 (d, 2H), 8.40 (d, 2H), 7.49 (d, 2H), 3.88 (s, 2H), 3.80 (s, 2H), 3.65 (s, 3H), 2.94 (t, 2H), 2.63 (t, 2H).
Reaction SMILES: [CH3:1][Li].[Si:3]([O:10][CH2:11][C@H:12]1[C@@H:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:13]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl-].N.[OH-].N>CCOCC>[Si:3]([O:10][CH2:11][C@@H:12]([NH:13][C:25](=[O:26])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:14]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH3:1])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@H](c2ccc(C(F)(F)F)cc2)[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: [Li]C
Agent: N
Agent: [Cl-]
Agent: [OH-]
Solvent: CCOCC
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a stirred slurry of cuprous iodide (7.9 g, 42 mmol) in 150 mL ether at 0° C. was added methyllithium (1.6 M solution in diethyl ether (52 mL, 83 mmol)). The mixture was stirred at this temperature for 20 minutes. A solution of (2R,3R)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-(4-(trifluoromethyl)phenyl)aziridine-1-carboxylate (6.00 g, 14 mmol) in 150 mL ether was then added via cannula to the lithium dimethylcuprate solution. The mixture was stirred at 0° C. and monitored by TLC. When no starting material could be detected (about 7 hours), 250 mL of an 8:1 mixture of saturated aqueous ammonia chloride and ammonia hydroxide (28-30% in water) was added to the reaction. The resulting reaction mixture was extracted with diethyl ether (2×300 mL). The combined organic layers were washed twice with brine and dried over sodium sulfate. The crude product was then chromatographed eluting with 3% EtOAc in hexane. After removing the solvent, the desired product was obtained as a colorless oil (2.0 g, yield=32%). 1H NMR (400 MHz, CD3OD) δ ppm 0.09 (s, 6 H) 0.90-0.96 (m, 9 H) 1.25-1.33 (m, 12 H) 3.00-3.11 (m, 1H) 3.68-3.80 (m, 3H) 7.43 (d, J=8.02 Hz, 2H) 7.56 (d, J=8.02 Hz, 2H).