Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:22]1[C:30]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][C:28]([CH3:39])=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2[S:40]([C:43]1[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41])[C:3]1[N:7](COCC[Si](C)(C)C)[C:6]2[CH:16]=[CH:17][C:18]([C:20]#[N:21])=[CH:19][C:5]=2[N:4]=1.OC(C1C(COC2C=CC=CC=2)=CC(C)=C2C=1C=CN2S(C1C=CC(C)=CC=1)(=O)=O)C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1.B(F)(F)F.O(CC)CC>C(Cl)Cl>[OH:1][CH:2]([C:22]1[C:30]([CH2:31][O:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:29][C:28]([CH3:39])=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2[S:40]([C:43]1[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=1)(=[O:41])=[O:42])[C:3]1[NH:7][C:6]2[CH:16]=[CH:17][C:18]([C:20]#[N:21])=[CH:19][C:5]=2[N:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(COc4ccccc4)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(COc4ccccc4)cc(C)c32)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(O)c4nc5cc(C#N)ccc5[nH]4)c(COc4ccccc4)cc(C)c32)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (±)-2-(hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (160 mg, 0.231 mmol) in CH2Cl2 (2 mL) was added BF3—OEt2 (0.059 mL, 0.462 mmol) at 0° C., and then the mixture was stirred at room temperature for 2.5 h. The reaction was quenched by 7N NH3 in MeOH. The mixture was filtered off through SiO2. The SiO2 cake was washed with CH2Cl2/MeOH (c.a. 6/1). The combined organics were concentrated to give the title compound, without need of further purification. MS (ESI+) m/z 563.3 (M+H).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.Cl[C:13]1[CH:22]=[C:21]([CH3:23])[C:20]2[C:15](=[CH:16][CH:17]=[C:18](C)[CH:19]=2)[N:14]=1.[C:25](=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:9][C:5]1[CH:4]=[C:3]([C:13]2[CH:22]=[C:21]([CH3:23])[C:20]3[C:15](=[CH:16][C:17]([CH3:25])=[CH:18][CH:19]=3)[N:14]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccc2nc(Cl)cc(C)c2c1
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(OB([O-])[O-])c1
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2cc(C)c3ccc(C)cc3n2)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
3-Methylphenyl borate (1.3 mmol), 2-chloro-4,6-dimethylquinoline (1 mmol), tetrakis(triphenylphosphine)palladium(O) (0.05 mmol) and potassium carbonate (3 mmol) were dissolved in THF (30 mL) and H2O (10 mL). The resulting solution was stirred in a bath at 100° C. for 24 hours. After completion of the reaction, the solvents were removed. The reaction mixture was extracted with dichloromethane and water and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography. The eluate was distilled under reduced pressure. The residue was recrystallized from dichloromethane and petroleum ether, and filtered to yield 2-(3-methylphenyl)-4,7-dimethylquinoline as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[F:11][C:6]1[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=[CH:2][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F

Procedure:
6-Chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.5 g, 1.69 mmol) was dissolved in methanol (15 mL), and Pearlman's catalyst (one weight equivalent, 0.5 g, 20% Pd(OH)2 on carbon, 50% by weight water) was added. This mixture was subjected to a balloon of hydrogen for 3 hours and then filtered through GF/F filter paper. The filtrate was concentrated to 2-fluoro-3-(propylsulfonamido)benzoic acid (396 mg, 90%) as a solid. MS (M−H+) 262. NMR (DMSO-d6, 400 MHz) δ 13.36 (s, 1H), 9.76 (s, 1H), 7.58-7.70 (m, 2H), 7.26 (t, 1H, J=8), 3.10 (t, 2H, J=8), 1.69-1.80 (m, 2H), 0.98 (t, 3H, J=8).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:46])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:23][OH:24])[CH:17]=[C:16]([C:31]([O:33]CC)=[O:32])[C:15]3=[O:36])=[C:8]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:41]=2)[CH:7]=1)[CH3:2].[OH-].[Li+]>O1CCCC1.CO.O>[CH2:1]([NH:3][C:4](=[O:46])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH:22]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:23][OH:24])[CH:17]=[C:16]([C:31]([OH:33])=[O:32])[C:15]3=[O:36])=[C:8]([C:37]2[S:38][CH:39]=[C:40]([C:42]([F:45])([F:43])[F:44])[N:41]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C(CO)C2CCOCC2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C(CO)C2CCOCC2)cn1
Temperature: 100 °C
Yield: 26.2 %

Procedure:
To a solution of ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 103, 107 mg, 0.16 mmol, 1 equiv.) in tetrahydrofuran (1 mL) and methanol (1 mL) was added 2 M lithium hydroxide (0.162 mL, 0.32 mmol). The reaction mixture was heated to 100° C. for 15 min in a microwave. The reaction mixture was cooled to room temperature and diluted with water. The reaction mixture was filtered, and the filtrate was dried. Purification via reverse phase HPLC (C18, acetonitrile/water 0-95% gradient) and concentrated under reduced pressure to provide 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol--yl)pyridin-3-yl)-1-(2-hydroxy-1-(tetrahydro-2H-pyran-4-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a light yellow solid (26.5 mg, 26%).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[C:13]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[C:13]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:14]=[CH:15][C:16]([CH2:19][N:20]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:17][CH:18]=1
Reactant: NCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1Cc1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), C-biphenyl-4-yl-methylamine (0.110 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-biphenyl-4-ylmethyl-2,3-dihydro-isoindol-1-one (0.079 g, 53%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.26 (s, 2H), 4.84 (s, 2H), 7.32-7.56 (m, 12H), 7.89 (d, 1H). GC-MS: m/z 299 (M)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].Cl[C:21]1[CH:26]=[CH:25][NH+:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)CCC.C(OCC)(=O)C>[N:24]1[CH:25]=[CH:26][C:21]([N:16]2[CH2:17][CH2:18][C:11]3([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[CH2:14][CH2:15]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: Clc1cc[nH+]cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccncc1)CC2

Procedure:
tert-Butyl-3,9-diazaspiro[5.5]undecane-3-carboxylate (1 g, 3.931 mmol), 4-chloro-pyridinium chloride (1.765 g, 11.794 mmol) and triethylamine (2.2 ml, 15.725 mmol) were refluxed for 15 h in 1-butanol (50 ml). Saturated sodium hydrogen carbonate solution (30 ml) and ethyl acetate (80 ml) were added, the phases were separated, and the aqueous phase was extracted with ethyl acetate (2×80 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/-hexane/methanol/ammonia (25% aq.), 400:40:40:1). Yield: 0.52 g (39%)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)C=CC=N1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:35]1[CH2:34][CH2:33][CH:32]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:9]=2)[CH2:37][CH2:36]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Reactant: c1cnn(C2CCNCC2)c1
Agent: Cl
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4cncnc4)CC3)cnc12
Yield: 174.5 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.16 g, 0.47 mmol) obtained in Example 21, step 4 and 4-(pyrimidin-5-yl)piperidine (WO2004/094371, 0.09 g, 0.57 mmol), the title compound (0.20 g, 0.41 mmol) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]=O.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C=O
Reactant: C1CCNCC1
Solvent: CCO
Product: Oc1ccc(Cl)cc1CN1CCCCC1

Procedure:
A mixture of 4-chlorophenol (12.86 g), absolute ethanol (30 ml), formaldehyde (7.49 ml of a 37% aqueous solution) and piperidine (10.88 ml) was boiled under reflux for 4 hours. The mixture was evaporated to dryness and toluene (50 ml) was added. The mixture was evaporated to dryness and the residue was dissolved in 2M hydrochloric acid, washed with ethyl acetate, basified with concentrated sodium hydroxide solution and then extracted with dichloromethane to give 4-chloro-2-(piperidinomethyl)phenol as an oil which solidified on standing, m.p. 53°-56° C.
Reaction SMILES: [C:1]([C:9]1[N:10](C(OCC)=O)[C:11]2[C:16]([C:17]=1[NH:18][C:19](=[O:22])[CH2:20]Cl)=[CH:15][CH:14]=[C:13]([Cl:23])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:30][NH:31][CH3:32].O>CN(C=O)C>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[NH:18][C:19](=[O:22])[CH2:20][N:31]([CH3:32])[CH3:30])=[CH:15][CH:14]=[C:13]([Cl:23])[CH:12]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(=O)CCl)c2ccc(Cl)cc21
Reactant: CNC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A mixture of 2-benzoyl-6-chloro-3-(chloroacetylamino)-1-(ethoxycarbonyl)indole (step 1, 890 mg, 2.12 mmol) and dimethylamine hydrochloride (520 mg, 6.36 mmol) in DMF (30 ml) was stirred for 2 h. Water (80 ml) was added and the mixture extracted with an ethyl acetate-toluene mixture (2:1 v/v, 30 ml×2). The combined organic extracts were washed consecutively with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated. The residue was treated with a solution of 1N aqueous KOH (20 ml) and EtOH (40 ml) for 1 h, volatiles removed by evaporation and the residue extracted with ethyl acetate (30 ml×2). The combined organic extracts were dried (MgSO4) and evaporated. The crude product was recrystallized from ethyl acetate/hexane to give 350 mg (47%) of the title compound as a yellow solid. m.p.: 175-176° C. 1H-NMR (CDCl3) δ: 10.60 (1H, br s), 8.83 (1H, br s), 8.08 (1H, d, J=8.8 Hz), 7.88-7.70 (2H, m), 7.68-7.42 (3H, m), 7.29 (1H, d, J=1.8 Hz), 7.07 (1H, dd, J=1.8, 8.8 Hz), 3.04 (2H, s), 2.33 (6H, s)
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.C(Cl)Cl>[C:11]1([NH:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([N:27]([CH3:28])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCl
Reactant: CNc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCN(C)c1ccc(S(=O)(=O)Nc2ccccc2)cc1

Procedure:
The procedure of Example 17 was carried out using nonyl chloride and the product from Step 2 above. mp: 113-116° C.; TLC Rf =0.38 in MeOH/CH2Cl2 ; 1H NMR (CDC13, ppm) δ 7.9 (d, 2H), 7.6 (d, 5H), 7.3 (d, 2H), 7.0 (bs, 1H), 3.0 (s, 3H), 2.0 (t, 2H), 1.4 (m, 12H), 0.9 (t, 3 H)
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)C.[N:15]([O-])=O.[Na+]>O>[C:1]1([N:7]=[N+:8]=[N-:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Phenylhydrazine (6.7 g, 62 mmol) was added dropwise to a cold (0° C.) solution of concentrated hydrochloric acid (60 ml) over a period of 10 minutes. Diethyl ether (20 ml) was then added, followed by the dropwise addition of a solution of sodium nitrite (5 g, 72 mmol) in water (6 ml), keeping the temperature below 5° C. The reaction was then stirred at 0° C. for 1 hour and then extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (2×50 ml), saturated brine (50 ml), dried (MgSO4) and carefully evaporated in vacuo to give the crude title compound as a red oil (3.3 g, 45%).
Reaction SMILES: ClCCl.[CH2:4]([O:6][C:7](=[O:37])[CH:8]([NH:30][C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH:11]=1)[CH3:5].[Cl:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:40]=1[C:41](Cl)=[O:42].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:4]([O:6][C:7](=[O:37])[CH:8]([NH:30][C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32])[CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20](=[O:29])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:41](=[O:42])[C:40]3[C:39]([Cl:38])=[CH:47][CH:46]=[CH:45][C:44]=3[Cl:48])=[CH:26][CH:27]=2)[CH:11]=1)[CH3:5]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc(N)cc2)no1)C(=O)OCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)no1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
A dichloromethane (1 mL) solution 2-allyloxycarbonylamino-3-(3-{1-[(4-amino-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic acid ethyl ester (80 mg, 0.170 mmol) was cooled to 0° C. and 2,6-dichlorobenzoylchloride (39 mg, 0.187 mmol) was added. The mixture was stirred for 15 minutes then pyridine (28 μL, 0.34 mmol)was added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water, 1 M sodium hydroxide and brine. The organic portion was dried over magnesium sulfate and concentrated to give the title compound (84 mg, 78%). MS (CI) m/z 635.3 (M+1), 632.5 (M−1)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:26][NH:27][OH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C[Si]([N:33]=[C:34]=[O:35])(C)C>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH2:26][N:27]([OH:28])[C:34]([NH2:33])=[O:35])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: ONCC1(c2ccc(OCc3ccc4ccccc4n3)cc2)CCCCCC1
Reactant: C[Si](C)(C)N=C=O
Product: NC(=O)N(O)CC1(c2ccc(OCc3ccc4ccccc4n3)cc2)CCCCCC1

Procedure:
In analogy to the procedure of Example 2, the title compound is prepared from 2.3 g (6.11 mmol) of the compound from Example XV and 0.77 g (6.68 mmol) of trimethylsilyl isocyanate.
Reaction SMILES: CN(C)P(=O)(N(C)C)N(C)C.[Al](Cl)([CH2:15][CH3:16])CC.[CH3:18]O.[CH3:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:20]=[CH:21][CH2:22][CH2:23][CH2:15][CH3:16].[CH2:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:18][CH:15]=[CH2:16]
Reactant: CC[Al](Cl)CC
Reactant: CO
Reactant: CCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCCCC
Product: C=CCCCCC=C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 54 grams (0.64 mole) 1-hexene and 7.9 grams (0.072 mole) 1,7-octadiene (molar charge ratio 90:10) in 80 ml pentane was polymerized with the required amount of Et2AlCl/hexamethylphosphoric triamide/δ-TiCl3 catalyst (2.4 millimoles δ-TiCl3). The molar ratio of hexamethylphosphoric triamide to Et2AlCl was 0.7:1 and of Et2AlCl to TiCl3 was 1.5:1. After agitating for 24 hours at 25° C., the resulting copolymer was isolated by methanol coagulation and dried. The conversion to copolymer was 83 percent, inherent viscosity 3.5 and percent gel=0. A copolymer prepared similarly but without hexamethylphosphoric triamide was obtained in 95 percent conversion. It had inherent viscosity of 1.1 and 78 percent gel. These data show the remarkable ability of the modified catalyst to suppress gel formation during polymerization while producing a higher molecular weight copolymer.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:9]([OH:11])=O)=[O:5])[CH3:2].C(Cl)CCl.C(N(C(C)C)CC)(C)C.[CH2:30]([NH:33][CH2:34][CH2:35][CH3:36])[CH2:31][CH3:32]>CN(C=O)C>[CH2:30]([N:33]([CH2:34][CH2:35][CH3:36])[C:9]([C:8]1[CH:7]=[C:6]([CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH2:31][CH3:32]
Reactant: CCCNCCC
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(CO)cc(C(=O)OCC)c1

Procedure:
A mixture of diethyl 1,3,5-benzenetricarboxylate (5.2 g) and borane methylsulfide complex (6.1 g) is stirred in THF (150 mL) at 20-25 degrees C. overnight. The mixture is then treated with methanol, concentrated to dryness, and chouromatographed (silica gel) to give diethyl 5-(hydroxymethyl)isophthalate. Diethyl 5-(hydroxymethyl)isophthalate (3.4 g) is hydroyzed in ethanol and water with lithium hydroxide monohydrate (0.57 g) at 20-25 degrees C. for 3.5 hours at which time the solvents are removed under reduced pressure. Water (100 mL) is added and the mixture is acidified to pH=4 with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and dried over magnesium sulfate, filtered, and concentrated to give 3-(ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid, high resolution MS MH+=225.0769. 3-(Ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid (2.3 g), EDC (3.0 g), 1-HOBT (2.1 g), diisopropylethylamine (2.7 mL), dipropyl amine (2.8 mL), and DMF (50 mL) are stirred at 20-25 degrees C. overnight. The mixture is then partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate, filtered, and concentrated. Chromatography (silica gel) gives ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate, NMR (CDCl3) δ 0.77, 1.0, 1.4, 1.6, 1.7, 3.2, 3.5, 4.4, 4.8, 7.6, 8.0 and 8.1.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9]Br.[C:11]1([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH:12]=1.CCN(C(C)C)C(C)C>CC#N>[Br-:1].[CH:12]12[C:11](=[N+:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:15]([CH2:14][CH2:13]1)[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2]2
Reactant: BrCc1ccccc1CBr
Reactant: C1=C(N2CCCC2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: [Br-]
Product: c1ccc2c(c1)CC1CCC(C2)C1=[N+]1CCCC1
Yield: 60.1 %

Procedure:
1,2-Bis-bromomethyl-benzene (66.4 g, 0.25 mol) was added to a mixture of 1-cyclopent-1-enyl-pyrrolidine (29.4 g, 0.25 mol) and Hünig's base (87 mL, 0.50 mol) in MeCN (200 mL) with vigorous stirring. An exothermic reaction ensued, bringing the mixture to reflux. The mixture was refluxed for 16 h, cooled, the product was filtered off and washed with MeCN to give the pure title compound as a white crystalline solid (48.14 g, 60%). 1H NMR (d6-DMSO, 360 MHz) δ 7.29-7.22 (4 H, m, aromatic), 4.16-4.11 (2 H, m, CH—N+), 4.04-3.99 (2 H, m, CH—N+), 3.60 (2 H, bs, bridgehead CH), 3.05 (4 H, d, benzylic), 2.17-2.05 (4 H, m, N+—C—CH2), 1.92-1.88 (2 H, m), 1.25-1.20 (2 H, m). m/z 240 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C:10]([CH3:13])([O-])[CH3:11].[K+].F[C:16]1C=C(C)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1C.O>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:9]2[C:17]([CH3:16])=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:11][C:10]=2[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cccc1Br
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(Br)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.81 g (16.1 mmol) of 3-bromopyridin-2(1H)-one (O, S. Tee, M. Pavent, J. Am. Chem. Soc. 1982, 104, 4142-4146.) are dissolved in 100 ml of DMF. The mixture is cooled to 0° C., and 2.71 g (24.2 mmol) of potassium tert-butoxide are added. The ice bath is removed, and the mixture is stirred at room temperature for 30 min. 3.00 g (17.7 mmol) of 1-fluoro-2,5-dimethyl-4-nitrobenzene are added, and the mixture is stirred at 80° C. for 18 h, at 100° C. for 36 h and at 120° C. for 18 h. The mixture is then added to water and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1). This gives 2.04 g (38% of theory) of the desired compound.
Reaction SMILES: F[C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]1[O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=2[O:15]1.C(O)(C(F)(F)[F:28])=O>>[CH2:14]1[O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]3[C:7]4[NH:6][C:5]5[C:12](=[CH:13][CH:2]=[CH:3][CH:4]=5)[C:8]=4[CH:9]([F:28])[CH2:10][NH:11]3)=[CH:17][C:16]=2[O:15]1
Reactant: O=C(O)C(F)(F)F
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: NCCc1c[nH]c2ccc(F)cc12
Product: FC1CNC(c2ccc3c(c2)OCO3)c2[nH]c3ccccc3c21
Yield: 85 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with 5-fluorotryptamine (1.59 g, 8.9 mmol), 3,4-methylenedioxybenzaldehyde (1.47 g, 1.1 equiv.) and TFA (1.4 mL, 2 equiv.) to give the title compound (2,34 g, 85%) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[NH2:10][CH:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[K+]>CN(C=O)C.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:10][CH:11]([CH3:21])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[N:3][CH:4]=1)#[N:9]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(N)CNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CNC(=O)OC(C)(C)C)Nc1ccc(C#N)cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
2-Chloro-5-cyanopyridine (477 mg, 3.4 mmol), tert-butyl (2-aminopropyl)carbamate (300 mg, 1.7 mmol) and potassium bicarbonate (345 mg, 3.4 mmol) are dissolved in DMF (10 ml) and stirred at 90° C. under argon for 12 h. The reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (3×75 ml). The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. After removal of the solvent, the residue is purified by flash chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10:1). 265 mg (55% of theory) of the product are obtained as a solid.