Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].P(Br)(Br)[Br:17].COC(C)(C)C>C(OCC)C>[Br:17][CH:2]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC(O)c1cccc(-c2ccccc2)c1
Reactant: BrP(Br)Br
Solvent: COC(C)(C)C
Solvent: CCOCC
Product: CC(Br)c1cccc(-c2ccccc2)c1
Temperature: 0 °C
Yield: 0 %

Procedure:
To a solution of 3.97 g (20 mmol) of 3-(1-hydroxyethyl)biphenyl in 60 ml of dry diethyl ether was added dropwise 2.70 g (9.0 mmol) of phosphorous tribromide with ice-cooling, and the mixture was further stirred with ice-cooling for 3 hours. To the reaction solution were added ice water and tert-butyl methyl ether. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium bicarbonate and water, dried and concentrated to obtain 3.73 g (14.28 nmol) of 3-(1-bromoethyl)biphenyl as an oil.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].COC1C=C(O)C=CC=1O.[CH2:17]([NH:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19]>CO>[CH2:17]([N:20]([CH2:21][CH2:22][CH3:23])[CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH2:18][CH3:19]
Reactant: CCCNCCC
Reactant: C=CC(=O)OC
Agent: COc1cc(O)ccc1O
Solvent: CO
Product: CCCN(CCC)CCC(=O)OC
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
Methanol (128 g) was added to 344 g (4 moles) of methyl acrylate containing 500 ppm of methoxyhydroquinone and, while stirring and placed in a water bath, 404 g (4 moles) of dipropylamine was added dropwise thereinto over a period of 30 minutes. After completion of the dropping, the reaction was continued at 70° C. for three hours. After completion of the reaction, methanol was evaporated therefrom to give 746 g of methyl beta-dipropylaminopropionate. The purity as checked by gas chromatography was 99%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.N12CCCN=C1CCCCC2.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Oc1cnc2c(n1)CCCC2
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: ClCCCCOc1cnc2c(n1)CCCC2
Temperature: 60 °C
Yield: 54.6 %

Procedure:
300 mg (2 mmol) of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline was dissolved in 5 ml of DMF, and 360 μl (2.4 mmol) of 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) and 277 μl (2.4 mmol) of 1-bromo-4-chlorobutane were added thereto. The resultant mixture was stirred with heating at 60° C. for 22 hours to effect a reaction. The DMF in the resultant reaction mixture was distilled off in vacuo to thereby obtain a residue. An aqueous solution of potassium carbonate was added to the obtained residue, followed by extraction with chloroform to obtain an extract. The extract was dried over sodium sulfate anhydride, and subjected to filtration to thereby obtain a filtrate. The solvent of the filtrate was distilled off to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was charged in a column of 20 g of silica gel (Art7734, manufactured and sold by E. Merck, Darmstadt) and eluted with chloroform, to thereby obtain 263 mg of 2-(4-chlorobutoxy)-5,6,7,8-tetrahydroquinoxaline (yield: 54.7%).
Reaction SMILES: C(O)CO.C(=O)=O.[C:8]([O:11][CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:22]=[O:23])[CH2:16][CH2:15]1)(=[O:10])[CH3:9].[BH4-].[Na+]>C(O)C>[C:8]([O:11][CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:22][OH:23])[CH2:16][CH2:15]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OCC[C@H]1CC[C@H](C(CC=O)NC(=O)OC(C)(C)C)CC1
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: OCCO
Product: CC(=O)OCC[C@H]1CC[C@H](C(CCO)NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled (ethylene glycol+dry ice) solution of 2-(trans-4-(1-(tert-butoxycarbonylamino)-3-oxopropyl)cyclohexyl)ethyl acetate (1.88 g, 5.5 mmol) in ethanol (90 mL) was added NaBH4 (0.212 g, 5.5 mmol). The mixture was stirred at −10˜15° C. for 10 min and 0° C. for 10 min, and then quenched by addition of saturated aqueous NH4Cl solution (30 mL) and brine (30 mL). After removal of the volatile by evaporation, the aqueous residue was extracted with EtOAc, dried over Na2SO4. Purification by flash column chromatography (eluent: 30% EtOAc in hexanes to 40%) gave the alcohol product (1.0 g, 53%). LC/MC: 366.1 (MNa)+.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[O:18]1[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22].[CH2:25]([OH:27])[CH3:26]>C(Cl)Cl>[CH2:25]([O:27][CH2:20][C@H:19]([OH:18])[C:21]([O:23][CH3:24])=[O:22])[CH3:26]
Reactant: CCO
Reactant: COC(=O)[C@@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC[C@H](O)C(=O)OC
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
Magnesium trifluoromethanesulphonate (11.85 g, 36.73 mmol) was added in one portion to (S)-methyl oxirane-2-carboxylate (15.0 g, 146.93 mmol) and ethanol (10.29 ml, 176.32 mmol) cooled to 10° C. The resulting suspension was stirred at 10° C. for 20 minutes, allowed to warm to ambient temperature and then warmed to 50° C. for 30 hours. The mixture was allowed to cool and diluted with 9:1 DCM:ether (75 mL), filtered through Celite and washed through with 9:1 DCM:ether (3×50 mL) and evaporated. The residue was purified by flash silica chromatography, elution gradient 10 to 50% Et2O in DCM to give methyl (2S)-3-ethoxy-2-hydroxypropanoate (11.6 g, 53%). 1H NMR (400 MHz, CDCl3) δ 1.19 (3H, t), 3.00 (1H, d), 3.47-3.58 (2H, m), 3.72 (2H, d), 3.81 (3H, s), 4.23-4.34 (1H, m).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=C(C=O)[N:12]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[C:10]=1[O:21][CH3:22])=O)(C)(C)C.COCCN(S(F)(F)F)CCOC.[C:43](O)([C:45]([F:48])(F)[F:46])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:43]([CH:45]([F:48])[F:46])[N:12]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[C:10]=1[O:21][CH3:22]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1nc(C=O)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1OC
Agent: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(C(F)F)cc(N)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a 0° C. solution of methyl 4-[bis(tert-butoxycarbonyl)amino]-6-formyl-3-methoxypyridine-2-carboxylate (0.279 g, 0.680 mmol) in CH2Cl2 (2.72 ml) was added DEOXO-FLUOR® (0.251 ml, 1.360 mmol). The mixture was stirred at 0° C. for 1 h (reaction completed based on TLC and LC). TFA (1 mL) was then added and the reaction mixture was allowed to slowly warm to room temperature and was stirred overnight. The mixture was poured into saturated NaHCO3 and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (ISCO, SiO2 12 g, hexanes/EtOAc 100:0 to 0:100 gradient) to afford methyl 4-amino-6-(difluoromethyl)-3-methoxypicolinate (89 mg, 0.383 mmol, 56.4% yield) as a white solid. ESIMS m/z 233 ([M+H]+); 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 6.54 (t, J=55.4 Hz, 1H), 4.69 (s, 2H), 3.98 (s, 3H), 3.90 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −114.65.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([O:16][CH2:17][CH3:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[CH2:17]([O:16][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19])[CH3:18]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CCON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)OC
Agent: C=O
Agent: CN
Product: CCON(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 50 %

Procedure:
3-[Ethoxy-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 53-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (50% yield); mp 113–114° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.30 (3H, t, J=7.1 Hz, CH3), 3.12 (3H, s, NCH3), 3.96 (2H, q, J=7.1 Hz, OCH2), 4.16 (2H, s, NCH2), 4.86 (2H, s, NCH2), 7.06 (2H, m, aromatics), 7.33 (2H, m, aromatics), 11.65 (1H, broad s, OH). Anal. calcd for C15H17FN2O4: C, 58.43; H, 5.55; N, 9.08. Found: C, 58.30; H, 5.55; N, 9.03.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][NH:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](C)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of (2R,5S)-2,5-dimethylpiperazine (commercially available) (3.495 g, 30 mmol) in dichloromethane (25 mL) at 0° C. was added triethylamine (3.76 mL, 27 mmol) followed by dropwise benzyl chloroformate (4.0 mL, 27 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was then evaporated to dryness. The residue was taken up in aqueous 1N HCl solution and washed with EtOAc. The organic layer was extracted with 1N HCl solution twice and the combined aqueous layers were basicified with 6N NaOH to ˜pH 11. The resulting basic aqueous solution was extracted with EtOAc three times. The combined organic layers were washed with brine, dried (MgSO4) and evaporated to yield phenylmethyl trans-2,5-dimethyl-1-piperazinecarboxylate (enantiomeric mixture) (1.35 g, 18%). LCMS: (M+H)+: 249.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:16][C:15]([F:17])([F:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: C1CNCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
1.08 g (12.5 mmol) of piperazine are placed in the presence of 1 g (4.2 mmol) of 1-bromomethyl-2-trifluoromethyl-benzene and 0.64 mL (4.6 mmol) of triethylamine in 10 mL of toluene. The reaction medium is stirred for 30 min at room temperature and then heated to 110° C. for 6 h. After dry concentration, the obtained residue is taken up with AcOEt and washed with water. After drying on MgSO4, the organic phases are dry concentrated, the obtained residue is purified by flash chromatography on silica (CH2Cl2-MeOH—NH4OH: 90-9-1). 0.7 g of intermediate 7a are thereby isolated as a clear oil (yield 68%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:17]=[C:16](F)[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>>[Br:7][C:8]1[CH:17]=[C:16]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: C1CNCCN1
Product: COC(=O)c1ccc(N2CCNCC2)cc1Br

Procedure:
This example was prepared by substituting piperazine for EXAMPLE 1B and methyl 2-bromo-4-fluorobenzoate for EXAMPLE 1C in EXAMPLE 1D.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: O=C1CSC(=O)N1CCCCCc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.56 g (5.14 mmol) of 3-[5-(imidazo[1,2-a]pyridin-5-yl)pentyl]thiazolidine-2,4-dione and 0.46 ml (5.14 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.37 g (74.6%, light yellow oily substance) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:10][CH2:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1CCC(CCC(O)Cc2ccc(F)cc2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccc(F)cc1

Procedure:
Analogous to the procedure described for Compound 1A, Step C, 5-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (1.95 g, 7.79 mmol) was reacted with tert-butyldimethylsilyl chloride (1.47 g, 9.76 mmol). Purification by medium pressure chromatography (1% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ 7.12 (m, 2H), 6.97 (m, 2H), 5.75 (m, 1H), 3.83 (m, 1H), 3.60 (m, 1H), 2.71 (m, 2H), 2.36-2.24 (m, 3H), 1.70-1.38 (m, 5H), 0.84 (s, 9H), −0.05 (d, 3H), −0.2 (d, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]1([CH:12]2[C:15]3([CH2:17][O:16]3)[O:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[OH:16][CH2:17][C:15]1([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][O:14]1
Reactant: c1ccc(C2COC23CO3)cc1
Reactant: c1c[nH]nn1
Solvent: ClCCl
Product: OCC1(n2nccn2)OCC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1H-1,2,3-triazole (0.043 g, 0.62 mmol) in dry CH2Cl2 (2 mL) was introduced to a stirred solution under N2 of 3-phenyl-1,5-dioxaspiro[3.2]hexane (0.10 g, 0.62 mmol) in dry CH2Cl2 (2 mL) at −78° C. After 3 hours at −78° C., the reaction was allowed to warm to room temperature; then, the solvent was evaporated in vacuo. The resultant oil was purified by flash chromatography on silica gel (CH2Cl2/EtOAc 95:5). 2-Hydroxymethyl-3-phenyl-2-(1,2,3-triazol-2-yl)oxetane was isolated as a pale yellow solid (0.076 g, 59%): mp 77.0-78.3° C.; IR (CDCl3) 3145, 3031, 2969, 1496, 1452, 1323, 1049 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 2H), 7.41 (m, 2H), 7.35 (m, 3H), 5.41 (dd, J=8.2, 7.7 Hz, 1H), 5.08 (dd, J=8.5, 6.0 Hz, 1H), 4.98 (dd, J=7.0, 6.0 Hz, 1H), 4.15 (dd, J=13.0, 7.6 Hz, 1H), 4.10 (dd, J=13.0, 7.6 Hz, 1H), 2.51 (t, J=7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 135.3, 134.1, 128.8, 128.1, 128.0, 99.7, 68.5, 62.9, 47.9; MS (EI) m/z 200 (M+-CH2O), 185, 104 (100), 78; Anal. calculated for C12H13N3O2: C, 62.33; H, 5.67; N, 18.17. Found: C, 62.58; H, 5.30; N, 17.94.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:80][C:81]1[CH:87]=[C:86]([CH3:88])[CH:85]=[C:84]([CH3:89])[C:82]=1[NH2:83].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:80][C:81]1[CH:87]=[C:86]([CH3:88])[CH:85]=[C:84]([CH3:89])[C:82]=1[NH:83][C:23]([C:18]1[NH:19][C:20]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:12]([N:9]1[CH2:8][CH2:7][N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:11][CH2:10]1)=[O:13])=[CH:22][CH:21]=2)=[O:24]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(NC(=O)c2cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc3[nH]2)c(C)c1
Yield: 7 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2,4,6-trimethylaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow solid (7%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([O:8][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[NH:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F

Procedure:
A mixture of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (2.2 g), 2-chloronitrobenzene (1.3 g) and potassium carbonate (1.4 g) in N,N-dimethylformamide (100 ml) was heated at reflux for 3 hours under an atmosphere of nitrogen. The resulting mixture was poured into water (200 ml) and acidified by the addition of a small portion of conc. hydrochloric acid. The solution was extracted with a mixed solvent (ethyl acetate:hexane, 1:1,400 ml) and the organic phase dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue chromatographed on silica gel eluting with ethyl acetate:hexane, 1:1, to give 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-18) as an amorphous solid (1.0-g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:34]=1.[CH3:35][N:36]([CH3:44])[C@@H:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C@H:38]1[OH:43]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:43][C@@H:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C@H:37]4[N:36]([CH3:44])[CH3:35])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:34]=1
Reactant: COc1ccc2c(C(=O)c3ccc(F)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: CN(C)[C@@H]1CCCC[C@H]1O
Product: COc1ccc2c(C(=O)c3ccc(O[C@@H]4CCCC[C@H]4N(C)C)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 77 %

Procedure:
The title compound was prepared in 77% yield by essentially following the procedures outlined in Example 72, Part E, from 4-fluorophenyl 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (Example 59, Part A) and (±)-trans-2-(dimethylamino)cyclohexanol (Part A).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:15][C:16]#[N:17]>>[N:1]1([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:15][C:16]#[N:17])[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#CCBr
Reactant: C1CCN(CCN2CCNCC2)C1
Product: N#CCN1CCN(CCN2CCCC2)CC1

Procedure:
The title compound is synthesized by coupling of 1-(2-Pyrrolidin-1-yl-ethyl)-piperazine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless solid; ES-MS: M+H=223.3.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C(O)(=O)[C:8]1[C:9](=C[CH:12]=[CH:13][CH:14]=1)[OH:10]>C1C=CC=CC=1>[OH:10][C:9]1[CH:8]=[CH:14][CH:13]=[CH:12][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccccc1O

Procedure:
Add 11.8 g of oxalyl chloride dissolved in 25 ml of benzene to a suspension of 6.91 g of salicylic acid and 125 ml of benzene over a period of 20 minutes. Heat the mixture for about 14 hours, cool and evaporate the solvent to give 2-hydroxybenzenecarbonyl chloride as an oil. The crude product can be used directly in the subsequent step.
Reaction SMILES: C([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:25])[CH2:23][OH:24])=[CH:18][CH:17]=1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:33]([NH:25][CH:22]([C:19]1[CH:18]=[CH:17][C:16]([C:15]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:27])[OH:5])=[O:26])=[CH:21][CH:20]=1)[CH2:23][OH:24])=[O:34]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(N)CO)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)NC(CO)c2ccc(C(=O)Nc3ccccc3NC(=O)O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL) at −20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol) followed by Et3N (37 μL, 0.26 mmol). The reaction mixture was allowed to warm up to room temperature then was stirred for 48 h. A solution of sat. NH4Cl was added, followed by DCM and the phases were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel (MeOH/DCM: 4/96) to afford title compound 300 (91 mg, 0.17 mmol, 71% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80 (d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H) 3.84 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([O:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[Br:1])[CH2:13][CH2:14]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(N2CCN(CCO)CC2)c(Br)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCN(CCOCc3ccccc3)CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 34.1 %

Procedure:
Methyl 3-bromo-4-[4-(2-hydroxyethyl)piperazin-1-yl]benzoate (100 mg, 0.291 mmol) was dried with a vacuum pump, and dissolved in N,N-dimethylformamide (2.9 mL). Under ice-cold conditions, sodium hydride (15.2 mg, 0.350 mmol) and benzyl bromide (38 μL, 0.320 mmol) were added sequentially, and the mixture was stirred at room temperature for 15 hours. The reaction solution was added water under ice-cold conditions, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (43 mg (yield 34.3%)) was obtained as a yellow oil.