Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)S(O[C:17]1[CH:30]=[C:29]2[C:20]([O:21][C:22]3[C:23]([F:51])=[CH:24][C:25]([C:44]#[C:45][C:46]4([CH3:50])[CH2:49][O:48][CH2:47]4)=[CH:26][C:27]=3[C@:28]32[N:35]=[C:34]([NH:36]C(OC(C)(C)C)=O)[CH2:33][O:32][CH2:31]3)=[CH:19][CH:18]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:51][C:23]1[C:22]2[O:21][C:20]3[C:29](=[CH:30][C:17]([C:7]4[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[CH:18][CH:19]=3)[C@:28]3([N:35]=[C:34]([NH2:36])[CH2:33][O:32][CH2:31]3)[C:27]=2[CH:26]=[C:25]([C:44]#[C:45][C:46]2([CH3:50])[CH2:49][O:48][CH2:47]2)[CH:24]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC1(C#Cc2cc(F)c3c(c2)[C@]2(COCC(NC(=O)OC(C)(C)C)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)COC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C#Cc2cc(F)c3c(c2)[C@]2(COCC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1
Temperature: 85 °C
Yield: 15.5 %

Procedure:
In a microwave vial, 2-fluoropyridin-3-ylboronic acid (0.065 g, 0.459 mmol), Pd(PPh3)4 (0.042 g, 0.037 mmol) and (S)-5-(tert-butoxycarbonylamino)-4′-fluoro-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthene]-7′-yl trifluoromethanesulfonate (0.230 g, 0.367 mmol) were taken up in DMF (3 mL). Aqueous sodium carbonate (1.0 M, 1.10 mL, 1.10 mmol) was added. Argon was blown through the vessel which was then sealed and heated in an 85° C. oil bath for 4 h. The reaction was cooled and concentrated, and the residue was diluted with water (15 mL) and the aqueous phase was extracted with 3% MeOH-DCM (3×25 mL). The organics were combined, washed with dilute brine (7 mL), dried over sodium sulfate and concentrated. The residue was purified through silica gel (33 mL) which had been deactivated with Et3N (3.3 mL), using 33% EtOAc in hexane. The resulting residue was transferred to a microwave vessel in DCM (3 mL), and TFA (0.283 mL, 3.67 mmol) was added. The vessel was sealed and heated in a 60° C. oil bath for 1.5 h. The reaction was cooled and concentrated, and the residue was neutralized with 0.5 M aqueous Na2CO3 (15 mL). The aqueous phase was extracted with 5% MeOH-DCM (3×25 mL). The organics were combined, washed with dilute brine (7 mL) and dried over sodium sulfate. The residue was purified through silica gel (33 mL) using 7.5% MeOH-DCM to afford 27 mg of (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-((3-methyloxetan-3-yl)ethynyl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine. m/z=474.0[M+H]+.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]([OH:14])=[N:5]1)(=O)C.[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:15][O:14][C:6]1[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][NH:4][N:5]=1
Reactant: CCOC(=O)c1cn(C(C)=O)nc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]nc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-acetyl-3-hydroxy-1H-pyrazole-4-carboxylate (2.1 g, 10.6 mmol) and potassium carbonate (1.5 g, 10.6 mmol) in 45 mL of DMF is stirred at RT for 30 minutes. Dimethyl sulfate (1.0 mL, 10.6 mmol) in 25 mL of DMF is then added dropwise over 10 min, and the resulting reaction mixture is heated to 70° C. for 4 h. The solvent is evaporated in vacuo, and the residue is dissolved in water and extracted with CH2Cl2 (2×30 mL). The combined organic extracts are dried (Na2SO4), filtered, and evaporated in vacuo to give a yellow/brown oil. Purification by silica gel column chromatography (gradient from 50% EtOAc/hexane to 80% EtOAc/hexane) affords the title compound as a clear, viscous oil which slowly solidifies on standing.
Reaction SMILES: Cl[C:2]1[N:23]=[C:5]2[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=3[O:21][CH3:22])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:22][O:21][C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]4)[CH:32]=3)[N:23]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: COc1ccc(C(F)(F)F)cc1Nc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ccc(C(F)(F)F)cc1Nc1cccn2nc(Nc3cccc(N4CCN(C)CC4)c3)nc12

Procedure:
N(8)-(2-Methoxy-5-trifluoromethyl-phenyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridine-8-yl)-(2-methoxy-5-trifluoromethyl-phenyl)-amine, 3-(4-methylpiperazin-1-yl)aniline with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.005 g, 20%). MP=198-200° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.44 (s, 1H), 8.37 (d, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 7.30 (m, 2H), 7.24 (s, 1H), 7.16 (m, 2H), 7.09 (m, 1H), 6.93 (m, 1H), 6.48 (m, 1H), 3.97 (s, 3H), 3.10 (m, 4H), 2.45 (m, 4H), 2.21 (s, 3H). MS=498 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[NH:18][CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.[OH-].[Na+].[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29](Cl)=[O:30])=[CH:23][CH:22]=1>O1CCOCC1.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:29]([O:28][CH2:27][C:24]4[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=4)=[O:30])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To (+)-3-hydroxymorphinan (HM) hydrobromide (50.0 g, 154.2 mmol), sodium hydroxide (12.3 g, 308.4 mmol) in a mixture of 1,4-dioxane (200 mL) and water (200 mL) was added Cbz-Cl (24.2 mL, 169.6 mmol) dropwise at room temperature. The reaction mixture was stirred vigorously at room temperature overnight. After the reaction was completed, water (200 mL) was added. The mixture was extracted with diethyl ether (500 mL×2). The combined organics were dried over MgSO4, filtered, and evaporated under vacuum. Standing under high vacuum provided the title compound (57.7 g, 99%) as a light yellow solid. The compound was used for the next step without further purification.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14]1[CH2:17][C:16](=O)[CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[O:14]1[CH2:17][CH:16]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:15]1
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (10.8 g, 1.2 eq, 58.0 mmol) and oxetan-3-one (3.5 g, 1.0 eq, 14 mmol) in 1,2-dichloroethane (100 mL) was stirred at room temperature. Sodium triacetoxyborohydride (16.4 g, 1.6 eq, 77.3 mmol) was added in portions to the above solution and the heterogeneous mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2 (200 mL) and pardoned with aqueous saturated NaHCO3 solution (100 mL). The layers were separated and the organic layer was washed with brine solution (2×50 mL). The combined organic layers were dried over Na2SO4. Removal of the solvents and purification of the crude mixture by column chromatography on silica gel (ISCO System) using 20% MeOH in CH2Cl2/CH2Cl2 (gradient system from 0:1 to 1:9) as eluent gave tert-butyl 4-(oxetan-3-yl)piperazine-1-carboxylate in 84% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)(Cl)Cl>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[C:17]([CH3:23])[CH:18]=1)=[O:34]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3C)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)cc3C)c2cc1OC
Yield: 79 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-3-methyl-aniline (50 mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate (23 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to give 59 mg (yield 79%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][OH:37])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[CH3:47][S:48]([O:37][CH2:36][C@@H:12]1[CH2:13][C@H:14]([S:16][C:17]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][N:11]1[C:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:39][CH:38]=1)=[O:10])(=[O:50])=[O:49]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COS(C)(=O)=O)cc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
A solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol (22.33 g: 41.37 mmole) is diluted with dichloromethane (300 ml) and the mixture is cooled to -30° C. To this mixture, triethylamine (6.92 ml: 1.2 eq.) and methanesulfonyl chloride (3.52 ml: 1.1 eq.) are added, and the mixture is stirred for 20 minutes. The reaction mixture is successively washed with dilute hydrochloric acid and water, dried over magnesium sulfate, and filtered. The filtrate is concentrated in vacuo to give crude (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (27.81 g: 45.02 mmole). Yield: 100%.
Reaction SMILES: [OH:1][S:2]([OH:5])(=O)=[O:3].O=S(=O)=O.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:11]1[C:10]([OH:16])=[CH:15][CH:14]=[C:13]([S:2]([OH:5])(=[O:3])=[O:1])[CH:12]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Agent: O=S(=O)=O
Product: O=S(=O)(O)c1ccc(O)cc1
Reaction time: 1 h

Procedure:
478 parts of 20% oleum are added with stirring to 500 parts of melted phenol, with cooling to ensure that the temperature does not exceed 70° C. The mixture is then sulfonated at 105° C. for 1 hour. The phenolsulfonic acid formed is heated slowly at from 150° to 155° C. under reduced pressure of 11 to 13 torr, and this temperature is maintained until 1 g of the condensation product neutralizes 3.8 to 4.0 cm3 of 1-normal sodium hydroxide solution against Congo red. 100 parts of the hydroxyphenyl sulfone-(poly)hydroxyphenyl sulfone monosulfonic acid obtained are melted at 90° C. with 42 parts of water, and 14.4 parts of urea are added. After cooling to 55° C., 38.4 parts of 37% formaldehyde are added dropwise in the course of 2 hours and stirring is continued for about 4 hours until the condensation product gives a clear solution in water.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17]2[C:22]([CH2:23][OH:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:26]I>CS(C)=O.O>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:25])[C:17]2[C:22]([CH2:23][O:24][CH3:26])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: CN(c1ncccc1CO)C1CCN(Cc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COCc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a mixture of powdered potassium hydroxide (356 mg) in dry dimethylsulfoxide (2 ml) under nitrogen is added a solution of 1-benzyl-4-(N-methyl-N-(3-hydroxymethyl-2-pyridyl)amino)piperidine (XXX, EXAMPLE 35, 494 mg) in dry dimethylsulfoxide (1.2 ml) followed by methyl iodide (118 μl). The resulting mixture is stirred at 20°-25° for 30 min and is then diluted with water (15 ml) and extracted with methylene chloride (2×20 ml). The combined organic phases are washed with water (2×10 ml) and saline (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give a concentrate which is then chromatographed (silica gel, a gradient of ethyl acetate/hexane (20/80→40/60)) to give the title compound, NMR (CDCl3, 400 MHz) 8.22, 7.67, 7.31, 7.25, 6.89, 4.40, 3.50, 3.41, 3.28, 2.94, 2.77, 2.01, 1.86 and 1.70δ.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[CH:22]([CH3:25])[C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][CH:22]([CH3:25])[C:23]#[N:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(Br)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C#N)Oc1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
A mixture of the phenol from Step 1 (150 g), (+) 2-bromo-propionitrile and milled potassium carbonate in methylethyl ketone (1 L) was refluxed for 8 hrs. The reaction mixture was cooled and filtered. Recrystallization from ethyl acetate/hexane afforded the title compound m.p. 118°-120°.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: CCCCOP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCCCOP(=O)(CCC(N)C(=O)O)Oc1ccccc1
Yield: 74.6 %

Procedure:
Next, 0.64 g (1.19 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[butyl(phenyl)phosphono]butanoate was dissolved in 20 mL of a solvent mixture of methanol and water at 3:1 and mixed with 200 mg of 5% palladium-carbon and hydrogen gas was introduced for 75 minutes. The palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated. The residue was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min, and the fractions containing the compound eluted at 60% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[butyl(phenyl)phosphono]butanoic acid (0.28 g, yield 75%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)(=[O:23])=[O:22].F[C:32]1C=C(S(Cl)(=O)=O)C=C[CH:37]=1>>[CH2:32]([O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)(=[O:22])=[O:23])[CH:4]=2)=[CH:10][CH:11]=1)[CH3:37]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(F)c3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cccc(F)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3-fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=447.1 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 3-fluoro-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(3-fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]1([OH:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>ClCCl.C(O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][CH2:16][C:11]([CH3:10])([OH:17])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC1(O)CCNCC1
Reactant: BrCc1ccc(I)cc1
Solvent: CCO
Solvent: ClCCl
Product: CC1(O)CCN(Cc2ccc(I)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.c. from 4-iodobenzyl bromide and 4-methylpiperidin-4-ol. Yield: 0.22 g (30% of theory); C13H18INO (M=331.19); calc.: molecular ion peak (M+H)+: 332; found: molecular ion peak (M+H)+: 332; Rf value: 0.45 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH:14]=[CH2:15])[CH:4]=1.C(N(CC)CC)C.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(Cl)Cl>[C:23]([C:27]1[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][C:35]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH:14]=[CH2:15])[CH:4]=2)=[O:36])=[CH:31][CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: C=Cc1cc(CN)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(CCC(=O)O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1cc(CNC(=O)CCc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
N-[4-(aminomethyl)-2-vinylphenyl]methanesulfonamide (0.23 mol) and was suspended in methylene chloride and treated with triethylamine followed by 3-(4-tert-butyl-phenyl)-propionic acid and DMTMM (40 mg). The resulting mixture was stirred for 2 days at ambient temperature and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate=3/2) to yield a white solid (73%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:13]([O:15][C:16]([C:18]1[N:19]([CH3:25])[C:20](Br)=[N:21][C:22]=1[CH3:23])=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C:18]1[N:19]([CH3:25])[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:4]=2)=[N:21][C:22]=1[CH3:23])=[O:17])[CH3:14]
Reactant: C#Cc1cccc(NC(C)=O)c1
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Product: CCOC(=O)c1c(C)nc(C#Cc2cccc(NC(C)=O)c2)n1C

Procedure:
The title compound, MS: m/e=326.8 (M+H+), was prepared in accordance with the general method of example 1b from N-(3-ethynyl-phenyl)-acetamide and 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]Cl.C(#N)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[C:19]([I:23])[C:18]([O:21][CH3:22])=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClI
Reactant: COc1ccc2c(c1)OC1CN(C(=O)OC(C)(C)C)CCC21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CO
Product: COc1cc2c(cc1I)C1CCN(C(=O)OC(C)(C)C)CC1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
To a solution of 7-methoxy-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (500 mg, 2 mmol) in methanol (7 mL, 200 mmol) was added dropwise a solution of iodine monochloride (340 mg, 2.1 mmol) in 5 ml of methanol at RT. The mixture was stirred overnight at RT. After 18 h, the solvent was removed and the crude reaction mixture was treated with 50 mL of acetonitrile, di-tert-butyl dicarbonate (0.5 mL) and 10 mg of DMAP (10 mg). The mixture was stirred overnight at RT. After 18 h, solvent was removed and the crude product was purified by ISCO chromatography (Hexane:EtOAc 70:30) which was obtained as a syrup (321 mg, 45%). MS m/z 454 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([CH:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:64]=[CH:63][C:59]([C:60](O)=[O:61])=[CH:58][CH:57]=1)#[N:55]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([CH:48]3[CH2:49][CH2:50][N:51]([C:60](=[O:61])[C:59]4[CH:63]=[CH:64][C:56]([C:54]#[N:55])=[CH:57][CH:58]=4)[CH2:52][CH2:53]3)=[CH:46][CH:47]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(C3CCNCC3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(C3CCN(C(=O)c4ccc(C#N)cc4)CC3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Yield: 89 %

Procedure:
Condensation of 21 with 4-cyanobenzoic acid on a 0.10 mmol scale via General Procedure F furnished 24 (63 mg, 89%): δH (400 MHz, CDCl3) 1.59-1.72 (m, 4H, CH2), 1.83-1.94 (m, 2H, CH2), 2.39 (s, 3H, CH3), 2.79-3.21 (m, 8H, CH3, CH and CH2), 3.65 (s, 2H, CH2), 4.77 (s, 2H, CH2), 4.95 (s, 2H, CH2), 4.97 (s, 2H, CH2), 5.34 (s, 2H, CH2), 6.60 (t, J=8.4 Hz, 1H, CH), 6.69 (dd, J=8.0 and 1.6 Hz, 1H, CH), 7.03-7.12 (m, 4H, 4 CH (Ar)), 7.21-7.82 (m, 12H, 12 CH (Ar)); δC (100 MHz, CDCl3) 21.4, 29.5, 35.9, 42.0, 48.1, 51.3, 52.7, 66.9, 70.6, 113.3, 113.9, 119.9, 120.7, 126.7, 126.9, 127.3, 127.4, 127.9, 128.1 (2), 128.4, 128.5, 129.0, 129.4, 132.3, 132.9, 134.8, 135.0, 135.5, 135.6, 140.0, 143.3, 144.0, 144.8, 158.6, 165.2, 167.0, 168.3; LRMS (ES+) calcd for [C51H48N4O7S+H] 861.33 found 861.38.
Reaction SMILES: [Li].[C:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:16](=O)([O:19]C)[O:17]C>O1CCCC1>[C:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH2:15][C:16]([OH:19])=[O:17])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(=O)OC
Reactant: Cc1cc(C(C)(C)C)ccc1C(=O)O
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)O)c(CC(=O)O)c1
Temperature: -40 °C
Reaction time: 4 h

Procedure:
An amount of 26 mL (198 mmol) of Lithium diiopropylamide (Aldrich) is added to a three neck flask cooled to −40° C. To this is added drops wise, a mixture of 4-tert-butyl-2-methyl-benzoic acid 1.9 g (9.9 mmol) and dimethyl carbonate 3.3 mL (39.6 mmol) in 5 mL of tetrahydrofuran, while keeping the temperature at −60° C. After the addition, the temperature is kept between −40° C. to −60° C. for four hours, then brought to 0° C. and quenched with 25 mL of water. The mixture is allowed to stir at room temperature for two hours and acidify to pH 2 with hydrogen chloride, extracted 3× with ethyl acetate, dried over magnesium sulfate and evaporated.