Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH2:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COc1cc(-c2nc(N)nc(OCc3ccccc3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. EI-MS m/e (%): 392 (M+, 40), 91 ([PhCH2]+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][N:5]([CH3:15])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38])[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:5]([CH3:15])[N:4]=[CH:3][C:2]=2[F:1])[CH:8]=1)=[O:14])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:39])([F:38])[F:40]
Reactant: Cn1ncc(F)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(F)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
To a solution of 4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (84 mg, 0.372 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (130 mg, 0.372 mmol)[from Preparation 6], diisopropylethyl amine (323 uL, 1.86 mmol) in DCM (4 mL) was added PyBrop (208 mg, 0.446 mmol) in one portion. After 1 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 0.5% MeOH-DCM) affording the title compound (135 mg, 65%) as a white solid: LCMS (ES) m/z=557 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9]S(C)=O)=[C:4]([NH:14][CH3:15])[CH:3]=1.C(O)C>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH3:9])=[C:4]([NH:14][CH3:15])[CH:3]=1
Reactant: CNc1cc(F)ccc1C(=O)CS(C)=O
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone (161.0 g), prepared in a similar manner to that described in Example 1, in acetic acid (770 ml) was added to a stirred mixture of zinc dust (228.2 g), acetic acid (210 ml) and ethanol (392 ml) at 80° over 1 hour. The mixture was stirred at 80° for a further 2 hours and then allowed to cool to ambient temperature. The combined filtrates obtained after filtration and washing the residue with dichloromethane (400 ml) were concentrated by distillation until the temperature of the remaining mixture reached 132° and then cooled to ambient temperature. Water (1 1) and dichloromethane (330 ml) were added sequentially, the mixture stirred for 10 minutes and the layers then separated. The aqueous phase was extracted with further dichloromethane (2×200ml), the organic extracts combined, then washed with aqueous sodium hydroxide solution (5M; 200 ml) and evaporated in vacuo. Distillation in vacuo (b.p. 74°, 0.4 mm Hg) of the residue gave 4'-fluoro-2'-(methylamino)acetophenone, m.p. 52°-53°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CN(C)C=O>[CH3:13][O:12][C:10](=[O:11])[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[CH:16][N:17]([CH3:19])[CH3:18]
Reactant: COC(=O)Cc1ccc(OC)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(=CN(C)C)c1ccc(OC)cc1
Temperature: 100 °C

Procedure:
Methyl 4-methoxyphenylacetate (3.3 g) was dissolved in N,N-dimethylformamide (3 cm3) treated with N,N-dimethylformamide dimethyl acetal (6 cm3) and heated at 100° C. for 18 h. The reaction was then cooled and evaporated under high vacuum to afford crude methyl-3-dimethylamino-2-(4-methoxyphenyl)propenoate (3.6 g) which was used without further purification. δH (250 MHz; CDCl3); 2.68 (6H, s), 3.62 (3H, s), 3.8 (3H, s), 6.82 (2H, d, J 8.7 Hz), 7.1 (2H, d, J 8.7 Hz) and 7.54 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].[F-].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[Cl:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccccc1Cl
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)ccc1Nc1ccccc1Cl
Temperature: 180 °C

Procedure:
A mixture of 1-bromo-4-fluoro-3-nitrobenzene (3.00 mL, 13.6 mmol), 2-chloroaniline (2.87 mL, 27.3 mmol) and potassium fluoride (0.792 g, 13.6 mmol) was heated at 180° C. for 48 h. Upon cooling the mixture, DCM (300 mL) was added and the mixture was successively washed with water (100 mL), 10% HCl (2×50 mL) and brine (50 mL). The resulting organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography on SiO2(DCM:hexanes=25:75) to afford the title compound as a red crystalline solid. MS (ESI, pos. ion) m/z: 328.9 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=O>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccccn1
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Cc1ccccn1)C(=O)N2
Yield: 77 %

Procedure:
Starting from 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-2H-indol-2-one and pyridine 2-carboxaldehyde and following the method described in Example 10, the desired compound was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=[CH2:2].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(O)=O.[Na+].CC(C)=O>C(Cl)(Cl)Cl>[CH:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:13]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: C=Cc1ccc(CN2CCN(CC(=O)OCC)CC2)cc1
Yield: 43.5 %

Procedure:
Synthesized according to General Procedure B: 8 (5.33 g, 26.4 mmol, 1 equiv.), ethyl chloroacetate (3.1 mL, 29.0 mmol, 1.1 equiv.), NaHCO3 (2.77 g, 33.0 mmol, 1.25 equiv.), acetone (52.8 mL), chloroform (30.0 mL). Purification with flash column chromatography on silica gel (1:1 hexanes:EtOAc) afforded 9 (3.31 g, 70%) as an orange oil. 1H-NMR (500 MHz, CDCl3): δ 7.35 (d, 2H, J=8.0 Hz), 7.26 (d, 2H, J=8.0 Hz), 6.69 (dd, 1H, J=11.0, 17.5 Hz), 5.72 (dd, 1H, J=0.5, 17.5 Hz), 5.21 (dd, 1H, J=1.0, 11.0 Hz), 4.17 (q, 2H, J=7.0 Hz), 3.49 (s, 2H), 3.19 (s, 2H), 2.59 (br s, 4H), 2.52 (br s, 4H), 1.26 (t, 3H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 170.2, 137.7, 136.5, 136.4, 129.3, 126.0, 113.4, 62.6, 60.5, 59.5, 53.0, 52.7, 14.2.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (69 mg, 80%), MS (ISP) m/z=347.4 [(M+H)+], mp 235.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:16][C:15]=2[CH3:25])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][NH2:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:33][O:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)=[O:24])=[CH:16][C:15]=2[CH3:25])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: Cc1cc(/C=C/C(=O)O)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(/C=C/C(=O)NOC2CCCCO2)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylic acid (338 mg, crude) in DMF (4 mL) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (153 mg), HOBt (203 mg), and EDCI (233 mg) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with water and extracted with AcOEt. The organic phase was washed with sat NH4Cl aq solution, sat NaHCO3 aq solution, and brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform:methanol=90:10) to give (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (306 mg) as pale yellow form.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=2)[N:4]=1.C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[Cl:33][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:21])([F:20])[F:1])=[N:4]2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a solution of {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol (Example 30, 1.23 g, 4.16 mmol) in dichloromethane (20 ml) under an atmosphere of argon was added triethylamine (0.75 ml, 5.4 mmol) and the mixture stirred at room temperature for 10 minutes. Methanesulfonyl chloride (0.42 ml, 5.4 mmol) was added dropwise over 5 minutes and the whole mix stirred at room temperature for 18 hours. The reaction mixture was then washed twice with water followed by saturated sodium bicarbonate. The organic layer dried over sodium sulphate and the solvent removed by rotary evaporation to give the title compound as a brown oil (1.24 g, 94%)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:27])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:33]O>>[CH3:33][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:27])=[CH:8][CH:9]=1)=[O:3]
Reactant: CO
Reactant: Cc1ccc(C=C2C(=O)Nc3ccccc32)c(-c2ccc(C(=O)O)cc2)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2cc(C)ccc2C=C2C(=O)Nc3ccccc32)cc1

Procedure:
The resultant compound 29 (22.0 g) was added to 1000 ml methanol, and the mixture was refluxed with heat for 8 hours through use of 50 ml of conc. sulfuric acid. After completion of reaction, the reaction mixture was cooled, methanol evaporated, followed by extraction with ethyl acetate. The extract was washed with water, saturated sodium bicarbonate water, and saturated brine, and subsequently dried over sodium sulfate, and then evaporated. The resultant crude product was purified by silica gel column chromatography (chloroform), to thereby obtain 5.0 g (yield 21.9%) of the E-isomer of the title compound in the form of orange-colored crystals and 16.7 g (yield 73.2%) of the Z-isomer of the title compound in the form of yellow-colored crystals. The melting point and elementary analysis data are shown in Table 11, and NMR and MS spectrum data are shown in Table 12.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][CH2:29][C:30]1[N:31]2[CH:37]=[N:36][CH:35]=[C:32]2[S:33][CH:34]=1>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:32]4[S:33][CH:34]=[C:30]([CH2:29][CH2:28][OH:27])[N+:31]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: OCCc1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc(CCO)[n+]4c3)[C@H](C)[C@H]12
Yield: 26.8 %

Procedure:
The same procedure as in Example 1 was repeated except that 87 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 100 mg of 3-(2-hydroxyethyl)imidazo[5,1-b]thiazole were used, thereby obtaining 25 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:9]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C.[Ni]>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:10]2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A large excess of Raney® nickel was added in portions to a stirred solution of ethyl 1-benzyl-5-nitro-3-phenyl-1H-indole-2-carboxylate (1.20 g, 3 mmol) and hydrazine (1.5 mL, 47.9 mmol) in 50 mL of ethanol. After stirring at room temperature for 2 h the catalyst was then removed by filtering through a short pad of Celite®521. The filtrate was concentrated to give ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (1.0 g, 90%) as an off-white solid: 1H NMR (DMSO-d6) δ 0.91 (t, J=7.0 Hz, 3 H), 4.03 (q, J=7.0 Hz, 2 H), 4.77 (s, 2 H), 5.71 (s, 2 H), 6.61 (d, J=1.8 Hz, 1 H), 6.75 (d, J=2.2 Hz, 1 H), 7.21-7.45 (m, 11 H); MS (EI) m/z 371.2 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1(Cl)[C:10](=[CH:14][C:15](=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[N+:16]([O-:18])=[O:17])[N+:11]([O-:13])=[O:12]>[Cu]>[N+:21]([C:20]1[CH:19]=[C:15]([N+:16]([O-:18])=[O:17])[CH:14]=[C:10]([N+:11]([O-:13])=[O:12])[C:9]=1[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([O-:23])=[O:22]
Reactant: Cc1ccc(I)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [Cu]
Product: Cc1ccc(-c2c([N+](=O)[O-])cc([N+](=O)[O-])cc2[N+](=O)[O-])cc1

Procedure:
4-iodotoluene is reacted with picryl chloride in the presence of copper bronze at 215° C. to yield 2′,4′,6′-trinitro-4-methylbiphenyl (1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]=[O:13])=[C:4]([CH3:28])[CH:3]=1.[C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[CH2:30][C:31]([CH3:33])=[O:32].[H-].[Na+].C([Li])CCC>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])=[C:9]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH:10]=[CH:11][CH:12]([OH:13])[CH2:33][C:31](=[O:32])[CH2:30][C:29]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[C:4]([CH3:28])[CH:3]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Cc1cc(F)ccc1C(=C(C=CC=O)c1nnnn1C)c1ccc(F)cc1C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(=C(C=CC(O)CC(=O)CC(=O)OC(C)(C)C)c1nnnn1C)c1ccc(F)cc1C
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5,5-bis(4-fluoro-2-methylphenyl)-4-(1-methyl-1H-tetrazol-5-yl)-2,4-pentadienal (1.0 g, 2.5 mmoles) in tetrahydrofuran at -50° C. was added the dianion of t-butyl acetoacetate (2.5 mL of a 1M solution, 2.5 mmoles) prepared by adding t-butyl acetoacetate (4.0 g, 25.0 mmoles) in tetrahydrofuran (4 mL) to a suspension of sodium hydride (1.0 g of 60% dispersion, 25.0 mmoles) in tetrahydrofuran at -5° C. followed by cooling to -30° C. and the addition of butyl lithium (11.4 mL of 2.2M solution, 25 mmoles). After stirring for 1.5 hours, analytical TLC indicated starting aldehyde and another 0.5 mL of dianion solution was added. The solution was stirred an additional 0.5 hour and quenched with 1N hydrochloric acid. The mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with methanol in methylene chloride to produce 0.6 g of the title compound; m.p.=65°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C@@H:4]([OH:8])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C@H:4]([OH:8])[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: O=C(O)[C@H](O)c1ccccc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](O)c1ccccc1Cl
Yield: 94 %

Procedure:
In a four necked round bottomed flask, 500 gm of (R)-2-chloromandelic acid was taken in 2600 ml methanol. Then 18.8 gm of sulfuric acid was added and heated to reflux, till completion of reaction. Then excess of methanol was distilled off under reduced pressure. Residue was taken in dichloromethane and washed with aqueous sodium bicarbonate solution. Dichloromethane was distilled under reduced pressure to obtain 522 gm of Methyl-(R)-2-hydroxy-2-(2-chlorophenyl)acetate as an oil. Yield: 94%. Purity: 98.5%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH:14]([C:18]([NH:20][CH3:21])=[O:19])[CH2:13]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([NH:33][C:34]1[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=1[CH3:42])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:30][C:31]([NH:33][C:34]3[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=3[CH3:42])=[O:32])[CH:14]([C:18]([NH:20][CH3:21])=[O:19])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)C1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Reactant: Cc1cc(C)c(NC(=O)CCl)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CNC(=O)C1CN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1c(C)cc(C)cc1C
Yield: 51.5 %

Procedure:
A mixture of 5.8 g of 4-[4,4-bis(4-fluorophenyl)butyl]-N-methyl-2-piperazine-carboxamide, 3.6 g of 2-chloro-N-(2,4,6-trimethylphenyl)acetamide, 2.12 g of sodium carbonate and 150 ml of MIK is stirred and refluxed for 18 hours. The reaction mixture is cooled and washed with water. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is dried, yielding 4.34 g of 4-[4,4-bis(4-fluorophenyl)butyl]-2-[(methylamino)carbonyl]-N-(2,4,6-trimethylphenyl)-1-piperazineacetamide (compound 2, mp. 90.2° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8]C)[CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]1[NH:12][CH:13]=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:10][C:11]1[N:12]([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH:13]=[CH:14][N:15]=1
Reactant: COc1cccc(Br)c1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1nccn1-c1cccc(O)c1

Procedure:
A stirred mixture of 3-bromoanisole (100 g, 0.53 mole), 2-methylimidazole (41 g, 0.50 mole), potassium carbonate (96 g, 0.60 mole), cuprous chloride (2.5 g) and N-methyl-2-pyrrolidinone (300 ml) was heated at reflux temperature for 15 hr and then concentrated to remove the solvent and excess 3-bromoanisole. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was concentrated to a black syrup that was then dissolved in toluene and extracted twice with water and then extracted with 48% hydrobromic acid solution. The hydrobomic acid extract was heated at reflux temperature for 7 hr and then distilltion of water and methylbromide was begun with addition of additional 48% hydrobromic acid solution as necessary to maintain a reasonable volume. Distillation was continued until the distillation head temperature reached 124° C. The mixture was concentrated under vacuum. The concentrate was diluted with 500 ml of water and basified to pH 8 with addition of potassium carbonate in small portions. The precipitate was collected, washed with water, and dried to give 39.7 g. Recrystallization from 50% aqueous ethanol gave 31.4 g (36%), mp 178°-181° C.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[I-].[Na+].[N-:26]=[N+:27]=[N-:28].[Na+]>CC(C)=O>[N:26]([C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])=[N+:27]=[N-:28]
Reactant: COc1cc(C(C)C)ccc1C1(Cl)C(=O)c2ccccc2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(C(C)C)ccc1C1(N=[N+]=[N-])C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 99396.7 %

Procedure:
To a solution of 2-chloro-2-(4-isopropyl-2-methoxyphenyl)-1H-inden-1,3(2H)-dione (0.10 g, 0.3 mmol) in acetone (5 ml) were added with sodium iodide (54 mg, 0.36 mmol) and sodium azide (50 mg, 0.76 mmol) and distilled water (1 ml), followed by stirring at 80° C. for 6 hrs. The reaction mixture was added water, and extracted diethyl ether, and washed with water and brine in that order. The washed organic layer was concentrated to afford the title compound (100 g, 98%).