Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1.[H-].[Na+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O.[Cl-].[Na+].O>[CH2:19]([N:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:11]1=[O:12])[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: COc1ccc2c(c1)C(=O)NCCC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCCc2ccc(OC)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A solution of 8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one (10.0 g, 0.052 mol) in N,N-dimethylformamide (30 mL) and allylbromide (23 mL, 0.260 mL) was treated with NaH (60% by wt. dispersion in oil, 2.50 g, 0.063 mol) and the resulting grey suspension stirred at room temperature under an atmosphere of argon. Gas evolution was noted. After 15 minutes, the solution was diluted with brine and partitioned between ethyl acetate and brine. The combined organic layers were concentrated in vacuo and purified by chromatography over silica gel eluting with a gradient of hexane to 1:1 ethyl acetate/hexane to yield 8 g (83%) of 2-allyl-8-methoxy-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one as a colorless oil: 1H NMR(CDCl3) d7.23(m, 1H), 7.03(d, J=9 Hz, 1H), 6.90(dd, J=3, 9 Hz, 1H), 5.91(m, 1H), 5.23(m, 2H), 4.20(d, J=6 Hz, 2H), 3.82(s, 3H), 3.18(t, J=6 Hz, 2H), 2.72(t, J=6 Hz, 2H), 1.96(pentet, J=6 Hz, 2H); 13C NMR(CDCl3) d170.59(CO), 158.42(NCO), 136.88, 133.81, 129.43, 129.35, 129.33, 117.56, 117.54, 112.98, 55.26, 49.43, 45.37, 29.57, 29.22; MS(FAB)m/z=232.1(MH+).
Reaction SMILES: [NH2:1][CH:2]([C:14]1[S:15][C:16]([Br:19])=[CH:17][N:18]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+].C(O)(C(F)(F)F)=O>CO>[NH2:1][CH:2]([C:14]1[S:15][C:16]([Br:19])=[CH:17][N:18]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(N)c2ncc(Br)s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NC(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 50 °C

Procedure:
The crude mixture from Step 1 was dissolved in methanol (3 mL), and sodium hydroxide (1.0 M in water, 0.950 mL, 0.950 mmol) was added to the resulting solution. The reaction mixture was then heated to a temperature of 50° C. for 30 minutes. The reaction was subsequently cooled, acidified with TFA (0.1 mL) and concentrated to afford racemic trans-4-[amino(5-bromo-1,3-thiazol-2-yl)methyl]cyclohexanecarboxylic acid, which was used in subsequent synthetic transformations without purification. MS ESI calc'd. for C11H15BrN2O2S [M+H]+ 319, 321. found 319, 321.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[CH2:3][O:2]1.[CH:11](O)=[O:12]>>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][CH:11]=[O:12])=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: Nc1ccc2c(c1)COC2
Reactant: O=CO
Product: O=CNc1ccc2c(c1)COC2
Yield: 69 %

Procedure:
1,3-Dihydro-2-benzofuran-5-amine (300 mg, 2.2 mmol) was added to HCOOH (10 mL), and the reaction was stirred at reflux overnight. The reaction was concentrated, basified to pH=8 with sat Na2CO3, and extracted with EtOAc. Organics were washed with brine, dried (Na2SO4), and concentrated to give 250 mg (69%) of N-(1,3-dihydro-2-benzofuran-5-yl)formamide as a yellow oil.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)([OH:3])=O.S(Cl)(Cl)=O.[CH2:18]([NH:21][CH2:22][CH:23]=[CH2:24])[CH:19]=[CH2:20].[OH-].[Na+]>ClCCl.O>[CH2:18]([N:21]([CH2:22][CH:23]=[CH2:24])[C:1]([CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)=[O:3])[CH:19]=[CH2:20]
Reactant: CC1(C)CC(C(=O)O)CC(C)(C)N1
Reactant: C=CCNCC=C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: C=CCN(CC=C)C(=O)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Yield: 42 %

Procedure:
4-Carboxy-2,2,6,6-tetramethylpiperidine (100 grams; 0.5405 mole) is added to thionyl chloride (300 mls) in portions and the reaction mixture is heated at reflux for 3 hours. The thionyl chloride is then removed by distillation, the last traces being removed by azeotropic distillation with toluene. The residual acid chloride is slurried in dichloromethane (300 mls), and a solution of diallylamine (105 grams; 1.081 mole) in dichloromethane (100 mls) is slowly added thereto while stirring and allowing the temperature to rise. Upon completion of the addition, the reaction mixture is heated at reflux for 18 hours, cooled to room temperature, and treated successively with 100 mls of water, and 5 N sodium hydroxide, while stirring, to adjust the pH to about 11. The organic phase is separated, and washed with dilute aqueous sodium hydroxide having a pH of 11. The aqueous phase is separated and the organic phase is washed twice with 100-ml portions of very dilute aqueous hydrogen peroxide (5 mls of 30% hydrogen peroxide diluted to 100 mls with water). After the second washing, the organic phase is washed twice with water, treated with activated carbon, dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum to remove dichloromethane and unreacted diallylamine. The residue is then distilled under vacuum to obtain 60 grams of the desired product, bp 118°-128° C. at 0.05 mm of mercury, mp 64°-67° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5](Cl)[CH2:6][C:7]1[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[C:9]([O:10][CH3:11])[CH:8]=1.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CC[O:27]CC>C(Cl)Cl.O>[CH3:11][O:10][C:9]1[CH:8]=[C:7]([CH:16]=[CH:15][C:12]=1[O:13][CH3:14])[CH2:6][C:5](=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOCC
Reactant: c1ccccc1
Reactant: COc1ccc(CCCl)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(=O)c2ccccc2)cc1OC

Procedure:
42.8 Grams (0.32 moles) of aluminum chloride was added in portions to a solution of 45.9 g. (0.2 mole) of homoveratryl chloride and benzene (25 ml.) in methylene chloride (300 ml.). The mixture was then refluxed 1.5 hours, cooled and poured into a mixture comprised of 300 ml. of ice, 100 ml. of water and 225 ml. of concentrated hydrochloric acid. The organic phase was separated and the aqueous layer extracted with chloroform. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and the solvent removed at reduced pressure to give an oil. Chromatography (2×) over alumina (ethyl acetate) followed by treatment with ether gave 3',4'-dimethoxydesoxybenzoin, m.p. 80°-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1.[H-].[Na+].Br[CH:21]([CH3:23])[CH3:22].Cl>CN(C)C=O.C(#N)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]([CH:21]([CH3:23])[CH3:22])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][S:7][C:6]=2[CH:17]=1
Reactant: CC(C)Br
Reactant: Clc1ccc2c(Nc3ccncc3)csc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)N(c1ccncc1)c1csc2cc(Cl)ccc12
Temperature: 50 °C
Yield: 76.1 %

Procedure:
A solution of 6-chloro-3-(4-pyridinylamino)benzo[b]thiophene (2.43 g, 9.3 mmole) in 20 mL of dimethylformamide was added to a suspension of NaH (0.48 g of 60% in oil, 12.1 mmole) in DMF. To this was added 2-bromopropane (1.26 g, 10.2 mmole) and the reaction mixture was heated to 50° C. During the next 5 hours, an additional 200 mg of NaH and 1 g of the bromo compound were added three separate times. The reaction mixture was then quenched into water and extracted with ethyl acetate (3×). The combined organics were washed with water (3×), dried (MgSO4), filtered and concentrated. Purification of the residue via flash chromatography (C6H5CH3 →5%Et3N/C6H5CH3) gave 1.57 of an oil. This was dissolved in acetonitrile, treated with ethereal HCl and the salt was crystallized out with additional ether to give 1.20 g of a yellowish powder, mp: 244°-246° C.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:9](=[O:11])[CH2:8][N:5]2[CH2:4][CH2:3][O:2][CH2:7][CH2:6]2)[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)CN1CCOCC1
Yield: 25.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-morpholinoacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 116, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-morpholinoacetyl)pyrrolidine-2-carboxamide (9.2 mg, 25.4%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.99 (s, 1H), 7.52-7.60 (m, 2H), 7.29-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.95-7.02 (m, 4H), 4.67-4.71 (m, 1H), 3.74 (m, 1H), 3.42-3.50 (m, 1H), 3.28-3.35 (m, 2H), 3.11-3.28 (m, 4H), 2.56-2.73 (m, 3H), 2.33-2.40 (m, 2H), 2.11-2.28 (m, 2H), 1.88-1.97 (m, 2H). MS (EI) for C30H32FN3O4. found 518.5 (MH+).
Reaction SMILES: [CH3:1][C:2](=[CH:4][C@H:5]([OH:10])[C@H:6]([OH:9])[CH2:7][CH3:8])[CH3:3].[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1.COC(OC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][C:11]1([CH3:16])[O:10][C@@H:5]([CH2:4][CH:2]([CH3:3])[CH3:1])[C@@H:6]([CH:7]=[CH2:8])[O:9]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC[C@@H](O)[C@@H](O)C=C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: C=C[C@H]1OC(C)(C)O[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the crude alcohol resulting from Example 9A dissolved in dichloromethane was added p-toluenesulfonic acid (500 mg) and 2,2-dimethoxypropane. The reaction was stirred at ambient temperature for 24 hours and poured into saturated sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate and concentrated by distillation to give the title compound. 1H NMR (CDCl3, 300 MHz) δ0.92 (d, J=6 Hz, 3H), 0.96 (d, J-6 Hz, 3H), 1.17 (ddd, J=4.5, 9.0, 15 Hz, 1H), 1.38 (s, 3H), 1.48 (s, 3H), 1.75 (m, 1H), 4.24 (ddd, J=3, 6, 9 Hz, 1H), 4.48 (m, 1H), 5.22 (ddd, J=1, 2, 9 Hz, 1H), 5.27 (ddd, J=1, 2, 17 Hz, 1H), 5.81 (ddd, J=7.5, 9, 17 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[C:12]1[NH2:18].Cl.[CH3:20][C:21](=O)[CH2:22][C:23](=O)[CH3:24]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:12]2[C:13](=[C:21]([CH3:20])[CH:22]=[C:23]([CH3:24])[N:18]=2)[C:14]([C:16]#[N:17])=[CH:15]1
Reactant: CC(C)c1ccc(-n2cc(C#N)cc2N)c(Br)c1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Reaction time: 4 h

Procedure:
Part C: A mixture of 18.51 g (0.0609 mole) of 1-(2-bromo-4-isopropylphenyl)-2-amino-4-cyano-pyrrole, 300 mL of ethanol, 0.6 mL of conc. hydrochloric acid, and 10 mL (9.75 g, 0.0974 mole) of 2,4-pentanedione was refluxed with stirring under a nitrogen atmosphere for 4 hrs. The mixture was allowed to cool and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with 10% sodium bicarbonate solution, then with brine. The solution was dried with anhydrous sodium sulfate and evaporated to give 21.76 g of dark, tarry residue. The residue was chromatographed on silica gel by eluting in step gradients of 0, 10, 15, 20, 25, and 30% ethyl acetate in hexane. The initial fraction is 17.6 g (78%) 1-(2-bromo-4-isopropylphenyl)-3-cyano-4,6-dimethyl-7-azaindole; m.p. 105.8°. Mass spec: (m+H° =368.0749; calculated, 368.0762 (79Br). Rf =0.45 on silica gel thin layer chromatography with 70:30 hexane-ethyl acetate.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C
Yield: 83 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.48 g, 2.2 mmol) (Example 1, Step 2), tert-butyl 4-aminopiperidine-1-carboxylate (from Aldrich, 0.67 g, 3.4 mmol) and N,N-diisopropylethylamine (1.2 mL, 6.7 mmol) in isopropyl alcohol (7.6 mL) was heated at 90° C. for 2 h. The precipitate was washed with isopropyl alcohol to give the desired product (0.70 83%). LCMS calculated for C17H23N4O4S (M+H)+: m/z=379.1. Found: 379.2.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][CH2:7][CH2:8][CH:9]1[CH2:13][N:12]([CH2:14][CH3:15])[C:11](=O)[N:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH3:23]>>[ClH:3].[Cl:6][CH2:7][CH2:8][CH:9]1[CH2:13][N:12]([CH2:14][CH3:15])[C:11](=[NH:23])[N:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N
Reactant: CCN1CC(CCCl)N(c2ccccc2)C1=O
Product: CCN1CC(CCCl)N(c2ccccc2)C1=N
Product: Cl
Reaction time: 3.5 h

Procedure:
To 250 ml of phosphorus oxychloride was added 95.6 g (0.378 mole) of 4-(2-chloroethyl-1-ethyl-2-oxo-3-phenyl imidazolidine and the mixture stirred at 70°-100° C. for 3.5 hours and concentrated on the rotary evaporator, yielding an oil. The oil was added to approximately 500 ml of liquid ammonia and stirred while the ammonia was allowed to evaporate. The residue was partitioned between chloroform and dilute NaOH. The chloroform layer was concentrated and the residue dissolved in isopropyl ether. The isopropyl ether was treated with carbon black and filtered. The ether was made acidic with ethereal HCl and the resulting precipitate was collected by decanting the ether. The residue was crystallized from isopropyl alcohol and isopropyl ether. Yield 61 g (56%); m.p. 175°-177° C. Analytical sample recrystallized from isopropyl alcohol and isopropyl ether; m.p. 176°-177.5° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:8]([F:11])([F:10])[F:9])[CH2:4][C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH2:54])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:50]=[CH:51][C:52]([CH2:53][NH:54][C:5](=[O:6])[CH2:4][CH:3]([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:55][CH:56]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(O)CC(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CNC(=O)CC(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.2 %

Procedure:
A solution of 2.1 g of 4,4,4-trifluoro-3-trifluoromethyl-butyric acid (10 mmol) in 80 ml DMF was treated with 3.12 g of TBTU (10 mmol) and 8.55 ml of N,N-diisopropylethyl amine and stirred for 5 min at rt under argon. Then 1.93 ml of 4-tert-butylbenzylamine (11 mmol) were added and the reaction mixture was stirred 17 h at rt. The reaction mixture was then diluted with 400 ml water and extracted twice with EtOAc, the combined organic phases washed with brine, dried over magnesium sulfate filtered and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; heptane/EtOAc 4:1) to give 2.14 g of N-(4-tert-butyl-benzyl)-4,4,4-trifluoro-3-trifluoromethyl-butyramide as a light yellow solid (60%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:37][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH2:21][CH2:20][C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:12]=3)[NH:16][CH:15]=2)=[O:38])=[CH:25][CH:26]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Br)cc12)c1ccc(Cc2cccc(F)c2)cc1
Reactant: OB(O)c1ccccc1
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(-c3ccccc3)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 16.4 %

Procedure:
A mixture of benzeneboronic acid (0.024 g; 0.195 mmol), N-(2-(5-bromo-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide (0.080 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020; 0.017 mmol) and sodium carbonate (0.038 g; 0.355 mmol) in a mixture of DME (3 mL) and water (1 mL) was irradiated in the microwave oven at 130° C. for 20 minutes. The resulting solution was partitioned between water and ethyl acetate and the organic layer was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC (method 2) to afford 0.013 g (16%) of the title compound as a white solid.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][C:12]([NH:17][S:18]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)(=[O:20])=[O:19])([CH2:15][OH:16])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.CCOC(C)=O.CCCCCC>CCOC(C)=O.C(OCC)C>[OH:16][CH2:15][C:12]1([NH:17][S:18]([C:21]2[S:22][C:23]([Cl:26])=[CH:24][CH:25]=2)(=[O:19])=[O:20])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(NS(=O)(=O)c2ccc(Cl)s2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=S(=O)(NC1(CO)CCNCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
4N HCl (5 mL) was added to a stirred solution of N-[1-Boc-4-(hydroxymethyl)piperidin-4-yl]-5-chlorothiophene-2-sulfonamide 5 (0.7 g, 1.7 mmol) in EtOAc (4 mL). The solution was allowed to stir at 25° C. After 30 min, a cloudy solution formed. After 2 h a precipitate formed. TLC (1: 1 EtOAc-hexane) indicated the reaction was complete. The solvent was reduced to ˜2-3 mL, diluted with diethyl ether (6 mL) and filtered through a filter funnel. The precipitate was washed with diethyl ether (3×5 mL) to obtain N-[4-(hydroxymethyl)piperidin-4-yl]-5-chlorothiophene-2-sulfonamide as an amorphous white solid (0.48 g, 90.7%). Mass Spectrum (+ESI): 311 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:21][OH:22])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1.Cl>C1COCC1.CN(C1C=CN=CC=1)C.CO>[F:27][C:28]([F:38])([F:39])[C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36](=[O:37])[O:22][CH2:21][C:8]2([C:6](=[O:7])[NH:5][CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[Cl:1])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(C(=O)NCc2ccccc2Cl)CC1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)OCC1(C(=O)NCc2ccccc2Cl)CCNCC1
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 4-(2-chlorobenzylcarbamoyl)-4-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 1.3 mmol), in THF were added DMAP (32 mg, 0.26 mmol, 0.2 equiv.) and 4-trifloromethylphenylisocyanate (0.28 mL, 1.97 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h. The reaction mixture was concentrated to dryness. To a solution of the above crude mixture in CH3OH (3 mL) was added HCl (4 M in dioxane, 1 mL, 4 mmol, 3 equiv.). The reaction mixture was stirred overnight. The white solid was filtered and dried to give (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (615 mg, 93%). LRMS (M-Boc+H+) m/z 470.1.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[CH2:16]([NH2:19])[CH:17]=[CH2:18].S(=O)(=O)(O)O>O>[CH2:16]([NH:19][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6])[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CCNc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.0 g (17 mmol) of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid were dissolved in 12.9 ml (172 mmol) of allylamine. The mixture was heated at reflux for 5 days and allowed to stand for 2 days. 10 ml (134 mmol) of allylamine and 15 ml of water were added, and the mixture was heated at reflux for 14 days, cooled to RT, added to ice, acidified with 10% strength sulfuric acid and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. The residue was crystallized from diethyl ether. This gave 4.2 g of a yellow solid of a purity of 88%.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].[CH3:35][N:36]([CH2:38][C:39]1[O:48][C:42]([CH2:43][S:44][CH2:45][CH2:46][NH2:47])=[CH:41][CH:40]=1)[CH3:37]>>[CH3:37][N:36]([CH2:38][C:39]1[O:48][C:42]([CH2:43][S:44][CH2:45][CH2:46][NH:47][C:23]([NH:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH3:20])=[O:24])=[CH:41][CH:40]=1)[CH3:35]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: CN(C)Cc1ccc(CSCCNC(=O)NCCN(C)CCN(Cc2ccc(F)cc2)c2ccccn2)o1

Procedure:
Preparation is effected analogously to Example 63, using 0.56 g (1.8 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[5-[(dimethylamino)methyl]-furfuryl]thio]ethylamine as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS(+FAB method): m/z (rel. int. [%])=543 ([M+H]+, 14), 109 (100); IR (KBr): 1641 cm-1 (C=O). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from isopropanol/ether; m.p.: 90° C. (isopropanol/ether).