Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[CH3:10])=[O:4].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:11])[C:9]=1[CH2:10][Br:12])=[O:4]
Reactant: COC(=O)c1scc(Br)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1scc(Br)c1CBr
Yield: 56.7 %

Procedure:
4-Bromo-3-methyl-thiophene-2-carboxylic acid methyl ester (3.0 g, 12.8 mmol), example 31-a, N-bromosuccinimide (2.33 g, 13.1 mmol), and benzoyl peroxide (310 mg, 1.28 mmol) were suspended in 32 mL of benzene and heated at reflux temperature for 16 hours. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-40% ethyl acetate in hexanes to produce 2.28 g of a yellow solid. NMR (CDCl3, 200 MHz): δ=7.48 (s, 1H), 4.91 (s, 2H), and 3.94 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([CH3:13])[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1.FC(F)(F)C(O)=O.[H][H]>CO.[Pd]>[NH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:3]([CH3:13])[C:2]([F:15])([F:1])[F:14])=[CH:10][N:9]=1
Reactant: [H][H]
Reactant: CC(Oc1ccc(C#N)nc1)C(F)(F)F
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(Oc1ccc(CN)nc1)C(F)(F)F

Procedure:
Add (±)-5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carbonitrile (810 mg, 3.7 mmol), 10% Pd/C (Degussa type E101, 50% water by wt, 300 mg), and trifluoroacetic acid (4 mL) in methanol (50 mL) to a pressure vessel. Pressurize the vessel to 40 psi with hydrogen for 0.25 h. Filter the mixture through Celite® and wash the cake with warm ethanol followed by DCM under a nitrogen atmosphere. Concentrate in vacuo to obtain the crude product as a trifluoroacetic acid salt. Prepare the free base with SCX ion chromatography, then purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (20:1) to obtain the title compound (676 mg, 82%). GC-MS m/z: 220 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14]C2CCCCO2)[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].CCCCCC>CCO>[Br:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1ccc(OC2CCCCO2)cc1OCc1ccccc1Br
Solvent: CCCCCC
Solvent: CCO
Product: O=Cc1ccc(O)cc1OCc1ccccc1Br
Reaction time: 1 h
Yield: 109.4 %

Procedure:
2-(2-Bromobenzyloxy)-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (4.4 g) obtained in step 1) was dissolved in a mixture of 10% HCL (30 mL) and EtOH (20 mL), followed by stirring for 1 hour and extraction with ethyl acetate. The extract was dried over MgSO4 and concentrated. The solid thus formed was cleansed with hexane to afford the object compound (3.78 g, 91%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.N([O-])=O.[Na+].[ClH:15]>O.[Cu]Cl>[Cl:15][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: Cl
Reactant: Nc1ccc2[nH]ncc2c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc2[nH]ncc2c1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
5-Amino-1H-indazole (15.41 g, 116 mmol) was suspended in a mixture of water (250 mL), ice (250 mL), and concentrated HCl (100 mL). The mixture was cooled in an ice-salt bath to an internal temperature of −5° C. To this mixture, was added a solution of sodium nitrite (8.78 g, 127 mmol) in water (75 mL), which had been cooled to 0° C. The resulting diazonium solution was stirred for 15 minutes at −5° C. A solution of copper (I) chloride (14.9 g, 151 mmol) in concentrated HCl (150 mL) was cooled to 0° C. and then added to the diazonium solution dropwise, causing an orange precipitate to form. The cooling bath was removed to allow the reaction to warm to room temperature. Gas evolution began at 10° C. internal temperature. After stirring at room temperature for 1.5 hours, the gas evolution subsided. The flask was then heated to 60° C. for 30 minutes, then cooled to ˜15° C. A brown precipitate formed. The precipitate was collected by suction filtration and dried in a vacuum dessicator over NaOH for 16 hours to give crude 5-chloro-1H-indazole (25.6 g) as a tan powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][C:10](=[O:26])[CH2:11]P(OCC(F)(F)F)(OCC(F)(F)F)=O>>[CH3:8][O:9][C:10](=[O:26])[CH:11]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Product: COC(=O)C=Cc1cccs1
Yield: 74.9 %

Procedure:
Thiophene-2-carbaldehyde (4.00 g, 35.7 mmol) and [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (12.5 g, 39.3 mmol) were treated by the method outlined in Example 34, step a to afford the subtitle compound (4.5 g, yield: 75%). MS calculated for C8H8O2S+H: 169, observed: 169.
Reaction SMILES: Cl.[NH2:2][OH:3].[N:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=4)[NH:19][C:18]=3[N:17]=[C:16]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=O)[C:39]([F:42])([F:41])[F:40])[CH:33]=3)[N:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>CO.N1C=CC=CC=1>[N:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]2[C:26]3[C:25]4[C:20](=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:24]=4)[NH:19][C:18]=3[N:17]=[C:16]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38](=[N:2][OH:3])[C:39]([F:40])([F:41])[F:42])[CH:33]=3)[N:15]=2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=O)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C(=NO)C(F)(F)F)c3)nc(NCCCN3CCCCC3)c12
Temperature: 60 °C
Yield: 100.1 %

Procedure:
Hydroxylamine hydrochloride (0.08 g, 1.2 mmol) was added to methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoroacetyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (compound of Example 33) (0.285 g, 0.515 mmol) in MeOH (4.00 mL) and pyridine (0.666 mL) to give a yellow solution. After heating at 60° C. 5 days, the mixture was concentrated to dryness and the residue was dissolved into DCM (75 mL) and MeOH (15 mL) and this solution was washed with sat. NaHCO3 (20 mL). The aqueous layer was extracted two time with a mixture of CH2Cl2 (50 mL) and MeOH (10 mL) and the combined organic layers were dried over anh. MgSO4, filtered and concentrated to dryness to give methyl 4-((3-(piperidin-1-yl)propyl)amino)-2-(3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (293 mg, 100% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32-1.43 (m, 2H) 1.44-1.56 (m, 4H) 1.76-1.87 (m, 2H) 2.23-2.44 (m, 6H) 3.57-3.67 (m, 2H) 3.88 (s, 3H) 4.04-4.12 (m, 2H) 7.25-7.33 (m, 1H) 7.34-7.46 (m, 2H) 7.50 (m, J=7.6, 4.1 Hz, 1H) 7.55 (d, J=7.4 Hz, 1H) 7.81 (dd, J=8.2, 1.2 Hz, 1H) 7.99 (d, J=1.2 Hz, 1H) 8.36 (d, J=8.2 Hz, 1H) 12.07 (d, J=3.5 Hz, 1H); MS m/z 569.2 (M+H)+; HPLC >95%, RT=1.88 minutes.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[S:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[C:12]#[N:13].[CH3:17][N:18]([CH3:21])[CH:19]=O>>[CH3:17][N:18]([CH:21]=[N:6][C:7]1[S:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[C:12]#[N:13])[CH3:19]
Reactant: CN(C)C=O
Reactant: N#Cc1cc([N+](=O)[O-])sc1N
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1sc([N+](=O)[O-])cc1C#N
Reaction time: 120 h

Procedure:
Phosphorus oxychloride (5 ml) was added dropwise, with stirring, to dry N,N-dimethylformamide (20 ml) maintaining the temperature below 5° C. The solution was allowed to stand for fifteen minutes then treated, at 0°-5° C., with a suspension of 2-amino-3-cyano-5-nitrothiophene (5.1 g) in dry N,N-dimethylformamide (50 ml), allowed to attain room temperature, then kept at 20° C. for five days. It was then poured on to ice, the precipitate removed and the filtrate basified with ammonium hydroxide solution to give 2-dimethylaminomethyleneamino-3-cyano-5-nitrothiophene (m.p. 230°). A mixture of this material (0.5 g), benzylamine (0.26 g) and ethanol (100 ml) was refluxed for twelve hours, treated with acetic acid (0.5 ml) and heating continued for a further thirty minutes. The solvent was removed in vacuo and the residue diluted with water to give 4-benzylamino-6-nitrothieno[2,3-d]pyrimidine (0.4 g) (Compound No. 136).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20])(C1C=CC(C)=CC=1)(=O)=O.[Br-:21].[Na+]>CN(C)C=O>[Br:21][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][C:17]#[C:18][CH2:19][CH3:20]
Reactant: [Br-]
Reactant: CCC#CC=CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC#CC=CCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 42.7 g. of 1-tosyloxynon-4-en-6-yne (0.14 moles) in 150 ml. of anhydrous dimethylformamide is added 18.7 g. of sodium bromide (0.16 moles) and the mixture is heated at 75° for 2 hour and then allowed to stir overnight at room temperature. The reaction mixture is then diluted with 200 ml. of ice water and extracted with pentane. The pentane extract is washed with water and dried over sodium sulfate. Evaporation of solvent in vacuo and distillation of the residual oil gave 24.3 g. of 1-bromonon-4-en-6-yne (84% yield) b.p. 52°-55° at 0.15 mm.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:10][C:3]2[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(I)cc1
Yield: 90 %

Procedure:
2 mM of p-nitrophenol are reacted overnight with 2 mM of p-iodo benzoic acid chloride in the presence of 2 mM of triethylamine in 20 ml of THF. The solvent is evaporated and the residue is taken up in chloroform and washed with 1N HCl, then with water. The solution is dried over MgSO4. It is purified on a chromatography column (silica; eluant CHCl3 -hexane 85/15 v/v). Yield: 90%.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[CH2:10]=[CH:11][C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:10]=[CH:11][C:12]([NH:14][CH2:15][CH2:16][O:17][C:4]([CH:3]([C:2]([F:9])([F:8])[F:1])[F:7])([F:6])[F:5])=[O:13]
Reactant: C=CC(=O)NCCO
Reactant: FC(F)=C(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CC(=O)NCCOC(F)(F)C(F)C(F)(F)F
Yield: 59.4 %

Procedure:
Hexafluoropropene (15 g, 0.10 mol) was added over 30 minutes (nitrogen atmosphere) at 0° C. to a stirred mixture of CH2═CH(CO)NHCH2CH2OH (6.25 g, 0.054 mol), acetonitrile (180 mL) and powdered K2CO3 (3.5 g). After complete addition, the stirred reaction mixture was gradually brought to room temperature (˜1 h). The resultant pale yellow solution was filtered, and the filtrate was concentrated at the rotary evaporator. The crude product was concentrated further at ˜2 mm Hg for 15 min on a vacuum line to afford 8.5 g of CH2═CH(CO)NHCH2CH2OCF2CFHCF3 as a light yellow, viscous liquid. EI/DIP MS: m/e 265 for M+ (C8H9F6NO); 19F NMR (CDCl3) δ−75.7 (m, 3F), −81.0 to −83.0 (ddm, 2 F), and −212.1 (m, 1 F) ppm. 1H NMR (CDCl3) δ 6.3 (dd, 1H), 6.2 (dd, 1H), 6.19 (dd, 1H), 5.7 (dd, 1H), 4.8 (dm, 1H, JHF=42 Hz), 4.1 (t, 2H) and 3.6 (dt, 2H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][C:20]=2[F:33])[C:7]1=[O:34].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][C:20]=3[F:33])[C:7](=[O:34])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of 4′-{[3-(2,4-dimethoxybenzyl)-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (1.3 g) and trifluoroacetic acid (20 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (20 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (10 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.95 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][CH2:22][CH2:23][OH:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][CH2:22][CH2:23][OH:24])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NCCO)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with 2-aminoethanol (CAS 141-43-5) (36 mg, 0.6 mmol), HATU (141 mg, 0.36 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide 16. LC/MS (ESI+): m/z 309 (M+H). 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.64 (t, J=5.5 Hz, 1H), 8.60 (d, J=7.9 Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.17 (t, J=12.9 Hz, 1H), 8.07 (d, J=24.4 Hz, 2H), 7.98 (d, J=7.7 Hz, 1H), 7.68-7.56 (m, 1H), 4.76 (t, J=5.6 Hz, 1H), 3.57 (q, J=6.0 Hz, 2H), 3.41 (q, J=6.0 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7]2[S:8][C:9]([CH2:17][CH3:18])=[CH:10][C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([N+:21]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>O.[Zn]>[NH2:21][C:4]1[CH:3]=[C:2]([Br:1])[CH:20]=[CH:19][C:5]=1[NH:6][C:7]1[S:8][C:9]([CH2:17][CH3:18])=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc(CC)sc1Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: CCOC(=O)c1cc(CC)sc1Nc1ccc(Br)cc1N
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Ethyl 2-(4-bromo-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate (0.4 g, (0.001 mol) was added to powdered zinc (0.4 g) and ammonium chloride (0.4 g) in water (10 ml) and stirred at 50° C. for 24 hours. The reaction mixture was filtered and the recovered solid washed successively with water and ethyl acetate. The organic phase was separated, washed with water, dried (MgSO4) and evaporated in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:42]=[CH:41][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH:32]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:33]([OH:35])=[O:34])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].O[CH2:44][CH:45]([CH2:47][OH:48])[OH:46]>CN(C)C1C=CN=CC=1.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH:32]([CH2:36][CH2:37][C:38]([O:40][CH2:44][CH:45]([OH:46])[CH2:47][OH:48])=[O:39])[C:33]([O:35][CH2:44][CH:45]([OH:46])[CH2:47][OH:48])=[O:34])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:41][CH:42]=1)=[O:11]
Reactant: OCC(O)CO
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)O)C(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NC(CCC(=O)OCC(O)CO)C(=O)OCC(O)CO)c[nH]4)c3)cc2)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 2-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioic acid (60 mg, 0.10 mmol), glycerol (0.5 ml), 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HCl, 37 mg, 0.19 mmol) and 4-dimethylaminopyridine (DMAP, 5 mg, 0.04 mmol) in anhydrous THF (10 ml) was stirred at 60° C. for 3 hours. The mixture was cooled to room temperature, concentrated and purified by silica gel chromatography eluting with a gradient of 10˜15% MeOH/CHCl3 to give bis(2,3-dihydroxypropyl) 2-{[(5-{-4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanedioate as colorless oil. Yield: 40 mg, 53%.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.[Pt](=O)=O>[N:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: c1ccc(CN2CCOCC2)nc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: C1CCC(CN2CCOCC2)NC1
Yield: 52.2 %

Procedure:
First, 2-[(4-morpholinyl)methyl]pyridine (94.0 g, 0.53 mol) is dissolved in glacial acetic acid (600 ml) and hydrogenated in the presence of platinum(IV) oxide (10.0 g) as catalyst for 2 hours at a hydrogen pressure of 3 bar and a temperature of 50° C. After cooling, the catalyst is filtered off, the filtrate is freed from solvent and the residue is distilled in vacuo. The desired compound (51.0 g) is obtained in the form of a colorless liquid, boiling point 4 mm Hg 91°-92° C.
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: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: 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: [C:1]1(/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([CH3:14])[CH3:13].[OH-].[Na+].O>C(O)C>[CH:12]([C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:10]/[C:9](=[O:11])/[CH:8]=[CH:7]/[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CC(=O)/C=C/c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(/C=C/C(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.7 %

Procedure:
A mixture of 81.0 grams (0.555 mol) trans-4-phenyl-3-buten-2-one, 81.7 grams (0,552 mol) 4isopropylbenzaldehyde, 12 mL of 10% sodium hydroxide, 150 mL water and 220 mL ethanol was stirred at ambient temperature for 15 hours. The crystalline product was collected by vacuum filtration to give 90.0 grams (59% of theoretical yield) of E,E-1-(p-isopropylphenyl)-5-phenyl-1,4-pentadien-3-one as a yellow solid. Melting point=76.0°-78.0° C. IR (KBr) 2960, 1655, 1595, 1345, 1195, 980, 820, 760, 695 cm-1 ; FDMS, m+ /z 276 (C20H20 0). 1H NMR (CDCl13) d 7.74 (d, 2H, J=-16 Hz), 7.59 (m, 2H), 7.55 (d, 2H, J=8 Hz), 7.39 (m, 3H), 7.26 (d, 2H, J=8 Hz), 7.09 (d, 1H, J=16 Hz), 7.045 (d, 1H, J=16 Hz), 2.93 (septet, 1,H, J=7 Hz), 1.26 (d, 6H, J=7 Hz). Anal. Calcd. for C20H20 0: C, 86.92; H, 7.29. Found: C, 86.87, 7.32.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClC(Cl)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH2:27][CH2:28][CH3:29])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(OS(=O)(=O)CC)cc3)ccnc2n1

Procedure:
The product from Example 6 (100 mg, 0.228 mmol) was reacted with ethane sulfonyl chloride (28 mg, 0.228 mmol), N,N-diisopropylethylamine (88.5 mg, 0.685 mmol), and catalytic DMAP in dichloroethane for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (30 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3 H) 1.34 (t, J=7.17 Hz, 3 H) 1.79-1.87 (m, 2 H) 2.40 (s, 3 H) 2.98 (t, J=7.54 Hz, 2 H) 3.47 (q, J=7.35 Hz, 2 H) 6.34 (d, J=7.35 Hz, 1 H) 7.14-7.19 (m, 2 H) 7.27 (d, 2 H) 7.39 (s, 2 H) 7.46 (d, 1 H) 7.78 (d, J=8.46 Hz, 1 H) 8.39 (d, J=6.99 Hz, 1 H) 8.92 (d, J=8.82 Hz, 1 H); MS (ESI+) m/z 494 (M+H)+.
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:16][C@:15]([OH:18])([CH3:17])[C@:14]([OH:25])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([O:26][CH2:27][C:28](O)=[O:29])[CH:6]=[CH:5][C:4]2=1)[CH3:2].OC1C2N=NNC=2C=CC=1.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([C@@:3]12[CH2:16][C@:15]([OH:18])([CH3:17])[C@:14]([OH:25])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([O:26][CH2:27][C:28]([N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)=[O:29])[CH:6]=[CH:5][C:4]2=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCC(=O)O)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCC(=O)N3CCN(C)CC3)ccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of the compound of Example 70 (25 mg, 0.07 mmol) in dichloromethane (3 mL) was added hydroxybenztriazole (10 mg, 0.073 mmol), 1-methylpiperazine (0.008 mL, 0.073 mmol), diisopropylethylamine (0.017 mL, 0.1 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (14 mg, 0.073 mmol). The mixture was stirred at room temperature for 4 days and then quenched with saturated aqueous ammonium chloride solution. After the mixture was diluted with water, it was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated. The title compound was isolated by flash chromatography eluting with a gradient of 30% ethyl acetate in hexane to 100% ethyl acetate. Mass spectrum (m/e) 493 (M++1).