Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:23]#[N:24])[CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:23]#[N:24])[CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)sc1-c1ccnc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A mixture of {5-[2-(1-cyano-cyclopropyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 18.2) (295 mg), DCM (4 mL) and TFA (1 mL) is stirred for 2 h at rt and then concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 182 mg of the title compound: ESI-MS: 257.1 [M+H]+; tR=2.54 min (System 1); TLC: Rf=0.30 ((DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[CH2:9]1)=[O:7].Cl>CO.O1CCOCC1>[NH:16]1[CH2:15][CH:14]([NH:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:7])[CH2:9]2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(N[C@H]2CCN(C(=O)c3nccs3)C2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1nccs1)N1CC[C@H](NC2CNC2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 1f (3 g, 8.52 mmol) in MeOH (10 mL) was added an HCl solution in dioxane (4M, 20 mL) at room temperature. The mixture was stirred at room temperature for 4 h. The solvent was removed by evaporation. Ether (50 mL) was added to the residue. The white solid was collected by filtration, washed with hexanes, and dried under vacuum. The crude compound 1g was used in the next reaction without further purification. MS m/z (M+H+) 253.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16]C)=O)=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[C:20]([O:22][CH3:23])=[O:21].[H-].[Na+].[N:26]1C=NC=N[CH:27]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]2[C:14](=[O:16])[NH:26][CH:27]=[CH:18][C:12]=2[NH:11][C:10]([CH3:19])=[C:9]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1F
Reactant: c1ncncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccccc1F
Temperature: 25 °C

Procedure:
A solution of 31.5 g (120 mMol) dimethyl 4-(2-fluorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate in 260 ml dimethylformamide is added dropwise, under an atmosphere of nitrogen, to a suspension of 3.8 g (130 mMol) sodium hydride (80% in paraffin oil) in 60 ml dry dimethylformamide. Upon slowing down of the evolution of gas, the reaction mixture is further stirred for ten minutes at ambient temperature and subsequently 10.0 g (120 mMol) s-triazine in 260 ml dimethylformamide are added dropwise thereto. The reaction mixture is heated to 110° C. for 16 hours and, after cooling, evaporated in a vacuum. The dark residue is stirred with 600 ml acetone, filtered and the filtrate evaporated in a vacuum. The crude product is boiled with 300 ml methanol, the crystals formed after cooling are filtered off and, for further purification, are recrystallized from methanol. There is obtained methyl (±)-4-(2-fluorophenyl)-1,4,5,6-tetrahydro-2-methyl-5-oxo-1,6-naphthyridine-3-carboxylate in the form of pale beige crystals; mp 315°-316° C. (decomp.).
Reaction SMILES: C([O:5][C:6](=[O:32])[CH:7]([C:25]([O:27]C(C)(C)C)=[O:26])[CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][C:15]([C:11]2[O:12][C:13]([CH3:14])=[C:9]([CH2:8][CH:7]([C:6]([OH:32])=[O:5])[C:25]([OH:27])=[O:26])[N:10]=2)=[CH:16][CH:17]=1)=[O:20]
Reactant: COC(=O)c1ccc(-c2nc(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)o2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2nc(CC(C(=O)O)C(=O)O)c(C)o2)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of methyl 4-(4-(3-tert-butoxy-2-(tert-butoxycarbonyl)-3-oxopropyl)-5-methyloxazol-2-yl)benzoate (4.0 g, 8.99 mmol, 1.00 equiv) in dichloromethane (20 mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred overnight at 35° C. and then concentrated under vacuum to remove dichloromethane. Saturated sodium bicarbonate solution was added to the residue until the pH value of the solution was adjusted to 2-3. The resulting solution was extracted with 200 mL of ethyl acetate. The organic layer was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to yield 3.0 g (100%) of 2-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methyl)malonic acid as a light yellow solid. LC-MS: (ES, m/z): 334 [M+H]+, 272, 115.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[Cl:19]N1C(=O)CCC1=O>C1C=CC=CC=1>[Cl:19][C:7]1[CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=[CH:5][C:6]=1[NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Solvent: c1ccccc1
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O

Procedure:
To the m-phenoxybenzyl ester of N-(p-trifluoromethylphenyl)valine (1.57 g) in about 15 ml benzene, with stirring and under nitrogen, is added N-chlorosuccinimide (0.53 g). The reaction mixture is heated to reflux for about 2 hours. The reaction is cooled and partitioned between ether and water. Aqueous phase is back-extracted with ether. The combined ether phases are washed with water and brine, dried over sodium sulfate, filtered and evaporated. The reaction product is put on preparative TLC plates and eluted using 10% ether/hexane to yield the m-phenoxybenzyl ester of N-(2-chloro-4-trifluoromethylphenyl)valine, MS m/e 477.1 (M+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH:7]1[CH2:11][O:10][CH:9]([O:12][CH3:13])[O:8]1)=[O:4].[CH2:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1CCCCC1>[F:15][C:2]([F:14])([F:1])[C:3]([NH:5][CH2:6][CH:7]1[CH2:11][O:10][CH:9]([O:12][CH2:13][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[O:8]1)=[O:4]
Reactant: COC1OCC(CNC(=O)C(F)(F)F)O1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCCCC1
Product: CCCCCCCCCCCCCCCCCCOC1OCC(CNC(=O)C(F)(F)F)O1
Reaction time: 2 h

Procedure:
3 g of 2,2,2-trifluoro-N-(2-methoxy-[1,3]dioxolan-4-ylmethyl)acetamide (Ortho 1, 13.09 mmol) were mixed with 3.54 g of octadecanol (13.09 mmol). The mixture was melted at 80° C. and left for 2 hours after the addition of 32 mg of pyridinium para-toluenesulfonate (0.13 mmol). The crude reaction product was then dissolved in cyclohexane, washed with a saturated sodium hydrogen carbonate solution and then with a saturated sodium chloride solution, dried over magnesium. sulfate and then concentrated to dryness. This crude product was used as it was for the next step.
Reaction SMILES: CS(O)(=O)=O.O[CH2:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([CH:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:28]2[CH2:29][CH2:30][N:31]([CH2:7][CH2:8][CH2:9][N:10]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:11]3=[O:19])[CH2:32][CH2:33]2)=[CH:39][CH:38]=1
Reactant: O=c1[nH]c2ccccc2n1CCCO
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of 2.7 parts of 1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate, 2.88 parts of 1-[bis(p-fluorophenyl)methyl]piperazine, 2.66 parts of sodium carbonate and 100 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 1-[3-{4-[bis(4-fluorophenyl)methyl]-1-piperazinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 197.3° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][OH:26])[S:22][C:23]=1[CH3:24]>CO>[Br:18][C:19]1[CH:20]=[C:21]([CH2:25][O:26][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[S:22][C:23]=1[CH3:24]
Reactant: C1=CCOC=C1
Reactant: Cc1sc(CO)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cc1sc(COC2CCCCO2)cc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.6 ml of 1,2-dihydropyrane and 0.2 g of p-toluene sulfonic acid were added to 5.4 g of 4-bromo-2 hydroxymethyl-5-methylthiophene 9 in 40 ml of methanol. The reaction mixture was stirred at room temperature for 24 hours. Methanol was distilled under vacuum and the remainder was distilled by an oil pump. The yield was 6.82 g of the product 10 (90%), Tmelt=125-130° C. (5 mm Hg), nd165=1.5610. Mass-spectrum, m/z: 291, [M]+. 1H NMR spectrum (CDCl3, δ, ppm, J/Hz): 1.45-1.95 (m, 6H, 3×CH2), 2.37 (s, 3H, CH3), 3.50-3.65 (m, 1H, CH), 3.80-4.0 (m, 1 H), 4.55-4.85 (m, 3H), 6.82 (s, 1 H, CH). The results found (%): C, 45.43; H, 5.20; S, 10.92. C11H15BrO2S. The results calculated (%): C, 45.37; H, 5.19; S, 11.01.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=3)[CH:7]=2)=[CH:15][CH:14]=1
Reactant: Cc1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccc(Cl)cc1
Product: Cc1cc2ncc(C#Cc3ccc(Cl)cc3)cn2n1

Procedure:
The title compound, brown solid, MS: m/e=268.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-chloro-4-ethynylbenzene.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[C@H:39]([OH:40])[CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@H:35]4[C@H:39]([OH:40])[CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]4)=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Product: Cc1c(C(=O)N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl (3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.CO.N>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: NC1CC1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Agent: N
Solvent: CCO
Solvent: CO
Product: OCC1CC(n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Reaction time: 18 h

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 0.958 mmol) was dissolved in absolute ethanol (5 mL) and cyclopropylamine (0.66 mL, 9.6 mmol) was added. The solution was refluxed under nitrogen for two hours. Additional cyclopropylamine (0.66 mL) was added and reflux continued for an additional 18 hours. The solution was cooled and methanol saturated with ammonia at 0° C. (5 mL) was added. After two days at ambient temperature, volatiles were removed in vacuo and the residue chromatographed on silica gel. (±)-(1R*, 2S*, 3S*, 5S*)-5-[5,6-Dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol was eluted with 7% methanol-chloroform and solidified from ethyl acetate-hexanes to white powder (210 mg, 59%), m.p. 223°-224° C.; 1H-NMR(DMSO-d6)δ: 7.64 and 7.46 (both s, 2, aromatic CH), 7.11 (m, 1, NH), 5.11 (t, J=4.3 Hz, 1, OH), 4.77 (d, J=7.0 Hz, 1, OH), 4.67 (d, J=3.7 Hz, 1, OH), 4.65-4.30 (m, 2, OCH and NCH), 3.85-3.75 (m, 1, OCH), 3.7-3.4 (m, 2, OCH2), 2.85-2.70 (m, 1, NCH of cyclopropyl), 2.15-1.80 (m, 3, CH2 and CH of cyclopentane), 0.80-0.50 (m, 4, 2 CH2 of cyclopropyl); mass spectrum (CI): 372(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]1[O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[O:11]1>>[NH2:15][C:14]1[C:16]([C:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[O:5])=[CH:17][C:18]2[O:19][CH2:10][O:11][C:12]=2[CH:13]=1
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1ccc2c(c1)OCO2
Product: Nc1cc2c(cc1C(=O)c1ccccc1Cl)OCO2

Procedure:
(6-amino-1,3-benzodioxol-5-yl)-(2-chlorophenyl)-methanone (Xbb) was prepared by reacting 2-chlorobenzaldehyde with 0.020 moles of 3,4-methylendioxy aniline in a manner analogous to Example 1. MH+/Z=276.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([CH2:11][CH3:12])[CH2:9][CH:8]([CH2:13][S:14]([OH:17])(=[O:16])=O)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C(Cl)Cl.CN(C=O)C>[CH2:24]([N:26]([CH2:27][CH3:28])[S:14]([CH2:13][CH:8]1[CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:10]([CH2:11][CH3:12])[CH2:9]1)(=[O:16])=[O:17])[CH3:25]
Reactant: CCOC(=O)C1CC(CS(=O)(=O)O)CC1CC
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CC(CS(=O)(=O)N(CC)CC)CC1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
A solution of (3-(ethoxycarbonyl)-4-ethylcyclopentyl)methanesulfonic acid (3.18 g, 12.03 mmol) in DCM (10 mL) and DMF (10 mL) was cooled to about 0° C. Oxalyl chloride (24.1 mL, 48.1 mmol) was added dropwise while the temperature was kept at about 0° C. After the addition was complete, the reaction mixture was warmed to ambient temperature and stirred for about 1 h. The solvent was removed under reduced pressure. The residue was dissolved in DMF (10 mL) and then added dropwise to a solution of TEA (2.51 mL, 18.03 mmol) and diethylamine (0.937 mL, 9.02 mmol) in DMF (10 mL) at about 0° C. The reaction mixture was stirred at ambient temperature for about 16 h. The solvent was removed under reduced pressure. The material was purified by silica gel (120 g) chromatography eluting with a gradient of 10-60% EtOAc in heptane to provide ethyl 4-((N,N-diethylsulfamoyl)methyl)-2-ethylcyclopentanecarboxylate (0.570 g, 30%) as a yellow oil: LC/MS (Table 1, Method b) Rt=2.60 min; MS m/z: 320 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C>ClCCl>[CH2:15]([NH:14][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=2)=[CH:28][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(N)cc2)cc1)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 49.7 %

Procedure:
Add trifluoroacetic acid (0.24 mL) dropwise to a solution of {2-[4-(4-Amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (100 mg, 0.24 mmol) in dichloromethane (5 mL) at room temperature and stir overnight. Concentrate on a rotary evaporator, dilute with saturated aqueous sodium bicarbonate then extract with dichloromethane (3×50 mL). Dry the dichloromethane extracts over sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 4-[4-(2-benzylamino-ethyl)-phenoxy]-phenylamine, (38 mg): 1H NMR (CDCl3, 300.00 MHz): 7.42-6.67 (m, 14H), 3.86 (s, 2H), 3.61 (s, 2H), 2.88 (m, 4H); m/z=319.2 (M+1); HPLC=97% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: Cl.[NH:2]=[C:3]1[N:9]=[CH:8][CH:7]=[CH:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(N(CC)CC)C.Br[CH2:25][C:26]([C:28]([F:31])([F:30])[F:29])=O>O1CCOCC1>[F:29][C:28]([F:31])([F:30])[C:26]1[N:2]=[C:3]2[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][N:9]2[CH:25]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C=CC=NC(=N)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cn2c(n1)CNCCC2
Temperature: 120 °C

Procedure:
To a stirred mixture of compound from Step B (0.42 g, 1.68 mmol) and triethylamine (0.64 mL, 4.6 mmol) in dioxane was added 1-bromo-3,3,3-trifluoroacetone. The resultant mixture was heated at 50° C. overnight. After solvent was removed, the residue was dissolved in isopropanol and refluxed overnight. After an aqueous work-up, the residue purified by flash chromatography (silica gel, 4% of 10% methanolic ammonium hydroxide solution in dichloromethane). The intermediate was dissolved in acidic (three drops of concentration hydrochloric acid) methoxyethanol (8 mL) and heated at 120° C. overnight. After solvent was removed, the residue was treated with 4 N hydrogen chloride in dioxane for 3 h. Purification by flash chromatography (silica gel, eluting with 6% of 10% methanolic ammonium hydroxide in dichloromethane) gave the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[S:23]([NH:22][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][C:13]([NH:12][CH:7]1[C:8]2[C:4](=[C:3]([CH2:1][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:36])(=[O:24])=[O:25]
Reactant: O=Cc1cccc2c1CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Reactant: C1CCNCC1
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCc2c(CN3CCCCC3)cccc21

Procedure:
3-(Naphthalen-2-yl-sulfonylamino)-3-phenyl-N-(4-piperidin-1-ylmethyl-indan-1-yl)-propionamide was prepared from N-(4-formyl-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide Example 4, Step G and piperidine, using essentially the same procedure described in Example 1, Step H, yielding a white solid. MS (ESI) m/z 568 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13](I)[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:21]1([CH3:33])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(COC)OC>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.O>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([C:22]4[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[CH3:33])[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Reactant: CCC(CC)N1CCc2c(C)nc3c(I)cccc3c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)cccc3c21
Temperature: 80 °C
Reaction time: 48 h
Yield: 15.2 %

Procedure:
1-(1-Ethylpropyl)-6-iodo-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline (200 mg, 0.526 mmol), mesitylboric acid (95 mg, 0.579 mmol), barium hydroxide octahydrate (249 mg, 0.782 mmol) and tetrakistriphenylphosphinepalladium (12 mg, 0.01 mmol) were suspended into a mixture of dimethoxyethane (6 mL) and water (1 mL), followed by stirring at 80° C. for two days in nitrogen atmosphere. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was purified by silica gel column chromatogrpahy (ethyl acetate), to give the title compound (28 mg, 0.08 mmol) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]1([C:36]2[O:37][C:38]([CH3:44])=[C:39]([CH2:41][CH2:42]O)[N:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:42][CH2:41][C:39]2[N:40]=[C:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:37][C:38]=2[CH3:44])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: O=Cc1ccc(O)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
A solution of 2,4-dihydroxy-benzaldehyde (2 g, 14.5 mmol) in 20 ml THF was cooled to 0° C. To this solution were added triphenylphosphine (9.7 g, 37 mmol), 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethanol (2.84 g, 14 mmol) and finally during 0.75 hours a solution of di-tert-butyl azodicarboxylate (8.52 g, 37 mmol) in 20 ml THF. The reaction mixture was stirred overnight at room temperature, evaporated to dryness, purified by chromatography (SiO2; AcOEt/heptane) and the product was crystallized from AcOEt/ether/heptane to yield 2.2 g (46%) of the title compound as a colorless solid.
Reaction SMILES: C(O)(=O)C.[N+:5]([O-:8])(O)=[O:6].[CH3:9][C:10]1([CH3:28])[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([CH3:27])=[CH:22][C:23]([CH3:26])=[C:24]([CH3:25])[C:12]=2[O:11]1>C(OC(=O)C)(=O)C>[CH3:9][C:10]1([CH3:28])[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([CH3:27])=[C:22]([N+:5]([O-:8])=[O:6])[C:23]([CH3:26])=[C:24]([CH3:25])[C:12]=2[O:11]1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c2c(c1C)OC(C)(C)C2c1ccccc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C)C2c1ccccc1
Yield: 48.1 %

Procedure:
The mixed solution of acetic anhydride (3 ml) and acetic acid (3 ml) was cooled and nitric acid (3 ml) was added cautiously with stirring. Then a solution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydrobenzofuran (3.7 g, 13.9 mmol) in acetic anhydride (3 ml) was added dropwise and the mixture was stirred for 30 minutes. The reaction mixture was poured into ice-cold water and the product was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane-isopropyl ether, 9:1) and crystallized from methanol to obtain the desired compound (2.08 g, yield: 48.1%), m.p. 155°-156° C.