Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl.[CH3:6][N:7]([CH3:11])[CH2:8][CH2:9]Cl.[OH-].[Na+]>O>[CH:1]([NH:4][CH2:9][CH2:8][N:7]([CH3:11])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)NCCN(C)C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
Into a 50 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel were placed 6.0 g (0.10 mol) of isopropylamine and 5 ml of water. And then, while maintaining the solution temperature within a range of from 30° C. to 50° C., 10 ml of aqueous solution of 5.0 g (35 mmol) of 2-(dimethylamino)ethyl chloride hydrochloride was slowly dropped into the flask, and the mixture was stirred for 2 hours. Subsequently, 10 ml of aqueous solution of 2.8 g (70 mmol) of sodium hydroxide was slowly dropped into the flask in an ice bath, and the mixture was reacted for 10 minutes. After the completion of the reaction, the reaction solution was subjected to extraction with 25 ml of hexane twice, and the hexane layer was concentrated under reduced pressure. The resultant concentrate was distilled under reduced pressure (65° C., 4.0 kPa), to provide 1.4 g of 1-isopropylamino-2-dimethylaminoethane. (Isolation yield: 31%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([CH3:19])[N:13]=[C:12]([NH:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[N:11]=2)=[C:4]([CH3:29])[CH:3]=1.C(O[CH:35](N(C)C)[N:36]([CH3:38])[CH3:37])(C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[C:14](/[CH:19]=[CH:35]/[N:36]([CH3:38])[CH3:37])[N:13]=[C:12]([NH:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[N:11]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1Sc1nc(Nc2ccc(C#N)cc2)nc(C)c1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1Sc1nc(Nc2ccc(C#N)cc2)nc(/C=C/N(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(4-(4-bromo-2,6-dimethylphenylthio)-6-methyl-5-nitropyrimidin-2-ylamino)benzonitrile (50 mmol) in DMF (300 ml) is added tert-butoxybis(dimethylamino) methane (60 mmol) over 15 minutes. The mixture is stirred at room temperature overnight. DMF is partially removed. The residue is washed with water and extracted with ethyl acetate (×3). The combined organic layers are washed with brine, dried (MgSO4) and concentrated to dryness to give the desired product which is used in next step without further purification.
Reaction SMILES: N1C=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].C(O)CC#C.CCCCC>C(Cl)Cl>[O:12]([CH2:2][CH2:3][C:4]#[CH:5])[S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10]
Reactant: c1ccncc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: C#CCCO
Solvent: ClCCl
Solvent: CCCCC
Product: C#CCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.6 %

Procedure:
The compound was prepared following a procedure of Hummel et al. Liebigs Ann. Chem. 746, 211-213 (1971). Anhydrous pyridine (20.0 mL, 19.6 g, 0.248 mol) was added to a stirred solution of trifluoromethanesulfonic anhydride (70.0 g, 0.248 mol) in anhydrous CH2Cl2 (500 mL) at 0° C. over a dry nitrogen atmosphere in an oven-dried apparatus. A heavy white precipitate formed immediately, and the resulting slurry was stirred for 15 min at 0° C. A solution of 3-butyn-1-ol (16.6 g, 0.236 mol) in anhydrous CH2Cl2 (80 mL) was added dropwise at 0° C. The slurry was warmed to room temperature and stirred for 2 h. Pentane (1000 mL) was added and the precipitated salts were filtered and washed with pentane. Fractional distillation of the combined filtrates gave 39.9 g (84% yield) of 3-butynyl triflate as a colorless liquid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:25]=4)[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)c1

Procedure:
Example 44 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 7.40 (s, 1H), 7.36–7.30 (m, 5H), 7.27–7.20 (m, 1H), 6.93 (d, 1H, J=7.6 Hz), 5.70–5.63 (m, 1H), 3.24 (q, 2H, J=6.6 Hz), 2.84 (d, 2H, J=11.4 Hz), 2.52 (quintet, 1H, J=7.2 Hz), 2.47–2.37 (m, 1H), 2.26 (t, 2H, J=7.2 Hz), 1.92 (t, 2H, J=11.6 Hz), 1.75 (d, 2H, J=12.5 Hz), 1.65–1.53 (m, 6H), 1.25 (d, 6H, J=7.2 Hz), 1.00 (q, 2H, J=2.9 Hz); ESMS m/e: 482.3 (M+H)+; Anal. Calc. for C28H36ClN3O2.0.540 CH2Cl3: C, 64.93; H, 7.08; N, 7.96. Found: C, 65.00; H, 7.22; N, 7.81.
Reaction SMILES: C1(=O)OC(=[O:5])C2=CC=CC=C12.[NH2:12][C:13]1[N:18]=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[C:15](Cl)[N:14]=1.S([O-])(O)=O.[Na+].[OH-].[Na+]>C(O)(C)C.C(OC(C)C)(C)C.O>[NH2:12][C:13]1[N+:18]([O-:5])=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][N:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCNc1cc(Cl)nc(N)n1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CC(C)O
Product: CCCCCCNc1ccnc(N)[n+]1[O-]
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
5.95 g of urea/H2O2 complex and 9.07 g of phthalic anhydride were suspended in 90 ml of isopropanol, in a three-necked flask. The mixture was stirred for 30 min at room temperature (20-25° C.). 10 g of 2-amino-4-hexylamino-6-chloropyrimidine were then added while controlling the exotherm at +30° C. After reaction for 3 hours, 100 ml of sodium hydrogen sulfite were poured thereinin to destroy the residual oxidizing agents. The mixture was permitted to separate out by settling and the upper phase was concentrated under vacuum. The residue obtained was taken up in a water (80 ml)/30% sodium hydroxide (20 ml) mixture. The solid obtained was reimpasted in 150 ml of isopropyl ether. The solid was filtered off and washed. It was dried in a heated desiccator. 4.52 g of the expected compound were thus obtained, for a yield of 42%.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([F:24])[C:22]=1[F:23].C(COC)OC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[F:13][C:12]([F:15])([F:14])[C:4]1[CH:3]=[C:2]([C:19]2[CH:18]=[C:17]([F:16])[C:22]([F:23])=[C:21]([F:24])[CH:20]=2)[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1
Reaction time: 0.17 h

Procedure:
A mixture of 4-bromo-6-trifluoromethyl-1,3-dihydrobenzoimidazol-2-one (1.12 g, 4 mmol, Example 6a), 3,4,5-trifluorophenylboronic acid (1.1 g, 6 mmol, Lancaster), PdCl2(PPh3)2 (35 mg, 0.05 mmol, Aldrich), Na2CO3H2O (1 g, 8 mmol), dimethoxyethane (7mL), H2O (3 mL) and EtOH (2 mL) was subjected to microwave irradiation at 120° C. with stirring for 10 min. Water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography, eluting with 35% EtOAc/hexane to give the title compound as a light-brown solid. MS (ESI, pos. ion) m/z: 333 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2[C:15](=[O:21])[C:16]1[S:20][CH:19]=[CH:18][CH:17]=1)([CH3:3])[CH3:2].[C:22](=[O:28])=[N:23]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[N:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:22]([NH2:23])=[O:28])[C:9](=[O:14])[CH:8]2[C:15](=[O:21])[C:16]1[S:20][CH:19]=[CH:18][CH:17]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2c(n1)C(C(=O)c1cccs1)C(=O)N2
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc2c(n1)C(C(=O)c1cccs1)C(=O)N2C(N)=O

Procedure:
The title compound was prepared from 5-isopropoxy-3-(2-thenoyl)-4-azaoxindole (Example 9C) according to the procedure of Example 2C, using 5-isopropoxy-3-(2-thenoyl)-4-azaoxindole (70 mg, 0.23 mmol), N-chlorosulfonyl isocyanate (25 L, 0.29 mmol) and acetonitrile (1.5 mL). Reaction time: 4 hours. The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in chloroform for 3 days. After removal of the solvent in vacuo, the product was purified by flash chromatography on silica gel using 2:1 ethyl acetate/hexane as eluant and trituration with ether. Yield: 30 mg (37%). M.p. 194°-196° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[Cl:1][CH2:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1Cc2cc(CCCl)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
5-Chloroacetyl-2-oxindole (4.18 g) in 30 mL trifluoroacetic acid in an ice bath was treated with 4.65 g triethylsilane and stirred at room temperature for 3 hours. The mixture was poured into 150 mL of water and the precipitate collected by vacuum filtration, washed with 50 mL of water and dried to give 2.53 g (65% yield) of 5-(2-chloroethyl)-2-oxindole as a reddish-brown solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:17])[C:15]=1[Li].CN([CH:21]=[O:22])C>>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:17])[C:15]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: [Li]c1c(Br)cncc1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=Cc1c(Br)cncc1Br

Procedure:
Following the procedure of Gribble and Saulnier, (Tetrahedron Lett., 21:4137-4140 (1980)) reacting 3,5-bromopyridine (Aldrich) with LDA, and reacting the 3,5-dibromo-4-lithiopyridine with DMF provided 3,5-dibromo-4-pyridinecarboxaldehyde, which was then converted to the title compound by DIBAL reduction. 1H NMR (CDCl3) δ: 8.65 (s, 2H), 4.97 (s, 2H), 2.32 (s, br, 1H).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([C:16]2[O:22][C@H:21]3[C@H:18]([C:19](=[O:23])[NH:20]3)[N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH:24][CH2:25][C:26]#[C:27][C:28]([O:30][CH3:31])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:16]([NH:17][C@@H:18]1[C@@H:21]([O:24][CH2:25][C:26]#[C:27][C:28]([O:30][CH3:31])=[O:29])[NH:20][C:19]1=[O:23])(=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Reactant: COC(=O)C#CCO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C#CCO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
0.41 ml of boron trifluoride etherate was added to a suspension of 4.70 g (25 mmols) of (1R, 5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one and 14.3 g (125 mmols--5 equivalents) of methyl 4-hydroxy-2-butinoate (R. A. Earl, Organic Synthese 60, 81) in 40 ml of anhydrous methylene chloride at room temperature. The mixture was stirred at room temperature for 1 hour, whereupon a clear solution formed. The solution was then poured into dilute NaHCO3 solution, the mixture was extracted with methylene chloride and the extracts were washed with water and dried over MgSO4. After the solvent had been evaporated off in vacuo and the residue had been filtered on 120 g of silica gel (toluene:ethyl acetate 2:3), 4.74 g (63%) of methyl 4-[3(R)-benzoylamino-2-azetidinon-4(R)-yloxy]-2-butinoate were obtained as colorless crystals, melting point: 142°-143° C, RF : 0.29 (toluene:ethyl acetate 2:3), [α]D20 =18.37° (1.0345 percent in acetone).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:1][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: CCOC(=O)CCBr
Product: CCOC(=O)CCNc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 66.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (100 mg, 0.47 mmol) and ethyl 3-bromopropanoate (0.01 mL, 0.57 mmol) to provide 459 (97 mg, 66% yield) as a white powder. LC-MS (M+H=312, obsd.=312). 1H NMR (400 MHz, DMSO-D6) δ 8.54 (dd, J=6.3, 14.0, 1H), 8.03 (d, J=8.7, 1H), 7.29 (m, 2H), 6.88 (d, J=6.8, 1H), 6.17 (s, 1H), 4.68 (t, J=7.5, 2H), 4.01 (q, J=7.1, 2H), 2.63 (dd, J=21.6, 29.0, 4H), 1.10 (t, J=7.1, 3H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH2:10]O)=[N:5]2.Cl.S1C2C=C[N:18]=CC=2C=C1CN>>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH2:10][NH2:18])=[N:5]2
Reactant: NCc1cc2cnccc2s1
Reactant: OCc1ccc2nccn2n1
Agent: Cl
Product: NCc1ccc2nccn2n1

Procedure:
Intermediate 1 was prepared from imidazo[1,2-b]pyridazin-6-ylmethanol (1-4) following the procedures similar to procedure of intermediate D from D-3. MS (m/z): 149 (M+1)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:26])[N:11]([CH3:25])[C:12]([CH:16]([OH:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:10](=[O:26])[N:11]([CH3:25])[C:12]([CH:16]([OH:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:13]([C:38]2[CH:37]=[C:36]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:41]=[CH:40][CH:39]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Cn1c(C(O)Cc2ccccc2)c(Br)cc(OCc2ccccc2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cn1c(C(O)Cc2ccccc2)c(-c2cccc(-c3ccccc3)c2)cc(OCc2ccccc2)c1=O
Yield: 25 %

Procedure:
To a solution of 3-(benzyloxy)-5-bromo-6-(1-hydroxy-2-phenylethyl)-1-methylpyridin-2(1H)-one (0.34 g, 0.821 mmol) in 2 mL THY was added PdCl2(dppf)-CH2Cl2 adduct (67 mg, 0.082 mmol), biphenyl-3-ylboronic acid (179 mg, 0.903 mmol), and 1 N aqueous cesium carbonate solution (2 mL, 2 mmol). The resulting mixture was microwaved in a sealed vial at 155° C. for 10 min. The aqueous layer was removed and discarded, and the organic layer was collected, dried over anhydrous magnesium sulfate, concentrated and purified by silica gel chromatography to afford 3-(benzyloxy)-5-(biphenyl-3-yl)-6-(1-hydroxy-2-phenylethyl)-1-methylpyridin-2(1H)-one (100 mg, 0.205 mmol, 25% yield).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[O:32]1[CH2:33][CH2:34][N:29]([C:35]([O:1][C:2]2[C:3]([C:12]([NH:14][C:15]3[CH:16]=[C:17]([C:25]([F:26])([F:27])[F:28])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=3)=[O:13])=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:36])[CH2:30][CH2:31]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc2ccccc2cc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc2ccccc2cc1OC(=O)N1CCOCC1
Yield: 81.2 %

Procedure:
Using 3-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-2-naphthamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2)=[O:5]
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)CCC2)c1ccccc1Cl

Procedure:
2-Chlorobenzoyl chloride (11.8 g) was added dropwise to a stirred mixture of 5-aminoindan (9.0 g), potassium carbonate (9.3 g), ethyl acetate (90 ml) and water (90 ml) under ice-cooling. The mixture was further stirred under ice-cooling for one hour, at the end of which time the organic layer was separated, washed with water, dried (MgSO4) and distilled to remove the solvent. The procedure gave crystals of 5-(2-chlorobenzoylamino)indan. The crystals were collected by filtration and recrystallized from isopropyl ether to give colorless needles, m.p. 144°-145° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1>C(O)C.C1COCC1.[Pd]>[CH3:1][S:2][C:3]1[N:4]=[CH:5][N:6]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:8]=1
Reactant: CSc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1cc(Oc2ccc(N)cc2)ncn1
Reaction time: 4 h

Procedure:
A solution of 4-methylsulfanyl-6-(4-nitro-phenoxy)-pyrimidine (0.5 g, 1.9 mmol) in ethanol/THF (25 ml, 1:1) is added catalyst (10% Pd/C, 0.3 g, 0.28 mmol). The starting material is hydrogenated at 4 bar for 4 h at r.t. The catalyst is filtered off and the solvent is removed. Due to instability, the product is used without any further purification for the subsequent reaction.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[N+:21]([O-])=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[CH2:6]([O:5][P:4]([CH2:9][NH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[NH2:21])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CNc1ccc2ccccc2c1[N+](=O)[O-])OCC
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOP(=O)(CNc1ccc2ccccc2c1N)OCC
Reaction time: 2 h
Yield: 60 %

Procedure:
170 mg of (1-nitro-2-naphthylamino)-methanephosphonic acid diethyl ester is reduced in 2 ml of glacial acetic acid with 10 equivalents of iron powder. After two hours, the mixture becomes viscous and then solid. It is diluted with ethyl acetate, the iron is removed, and it is chromatographed with ethyl acetate. The product is obtained in 60% yield.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4])[CH3:15]
Reactant: CCOC(=O)CN
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CNC(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.808 mmol) of 2-bromo-1-(4-chlorophenyl)propan-1-one from Example 112A are dissolved in 1 ml acetonitrile and treated with 226 mg (1.616 mmol) of glycine ethyl ester hydrochloride and 209 mg (1.616 mmol) of N,N-diisopropylethylamine. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is partitioned between water and dichloromethane. The organic phase is separated, dried over sodium sulphate and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1). 91 mg (42% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH2:27]O)[N:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1.C(N(CC)CC)C.CS([Cl:40])(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:40][CH2:27][C:15]1[N:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:17]=[C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[N:14]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CO)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of [4-(5-methyl-3-phenyl-isoxazol-4-yl)-1-(4-nitro-phenyl)-1H-imidazol-2-yl]-methanol (50 mg, 0.13 mmol) in DCM (5 mL) at 0° C. was added triethylamine (92.6 μL, 0.66 mmol) and methanesulfonyl chloride (30.97 μL, 0.40 mmol) and the resulting mixture allowed to warm up to room temperature over 3 h and then stirred for a subsequent 2 h. The mixture was then poured onto a saturated solution of sodium hydrogen carbonate and extracted with DCM. The combined organic layers were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (37 mg, 70%) which was obtained as a yellow foam. MS: m/e=395.0 [M+H]+.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CI.[NH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([OH:22])[C:11]=1[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1.O>CN(C)C=O>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([C:11]3[C:12]([O:22][CH3:1])=[N:13][N:14]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:10]=3[NH2:9])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: O=C([O-])[O-]
Reactant: Nc1c(-c2ccc3c(c2)OCO3)c(O)nn1Cc1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1nn(Cc2ccccc2)c(N)c1-c1ccc2c(c1)OCO2
Reaction time: 10 h
Yield: 25 %

Procedure:
Cesium carbonate (1.05 g) and methyl iodide (0.46 g) were sequentially added at room temperature under an atmosphere of nitrogen to a solution of 5-amino-4-(1,3-benzodioxol-5-yl)-1-benzyl-1H-pyrazol-3-ol (1.0 g) (Preparation 59) in anhydrous dimethylformamide (10 ml). After 10 h, the reaction mixture was diluted water (100 ml) and the mixture was extracted with ether (3×100 ml). The organic fractions were washed with brine (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (silica, 50 g) eluted with hexane:ethyl acetate (1:1) yielding the title compound as a white solid (260 mg).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>C1COCC1>[C:15](=[O:16])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OC1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCCCC1
Reaction time: 0.08 h
Yield: 90.5 %

Procedure:
To a solution of cyclohexanol (1.0 g, 10 mmol) in THF (20 mL) at 0° C. was added pyridine (0.97 mL, 12 mmol). After 5 min stirring under N2, a solution of 4-nitrophenyl chloroformate (2.2 g, 11 mmol) in THF (15 mL) was added slowly. After addition, the reaction mixture was stirred at 0° C. for 30 min, and then at RT for 3 h. The precipitate was filtered, the filtrate was concentrated. The resulting residue was chromatographed (40 g silica gel) eluting with EtOAc (0-20%) in hexanes to give the title compound (2.4 g, 91%) as a white solid.