Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44]>C1COCC1>[N:23]1([CH2:22][CH2:21][CH2:20][NH:19][C:17]([NH:16][C:11]2[S:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:43](=[O:44])[C:42]4[CH:46]=[CH:47][CH:48]=[C:40]([C:39]([F:38])([F:49])[F:50])[CH:41]=4)=[CH:7][CH:6]=3)[C:12]=2[C:13]([NH2:15])=[O:14])=[O:18])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a mixture of 3-(4-aminophenyl)-5-(3-(3-morpholinopropyl)ureido)isothiazole-4-carboxamide (6 mg, 0.015 mmol) and N,N-diisopropylethylamine (0.0078 mL, 0.045 mmol) in 0.8 mL THF at rt was added 3-(trifluoromethyl)benzoyl chloride (0.0024 mL, 0.017 mmol). The reaction was stirred at rt for 2 hours, then quenched with aqueous Na2CO3 solution, stirred 5 min at rt, and then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The solid was chromatographed eluting with CHCl3, then gradient 2.5% to 10% MeOH in CHCl3. The resulting solid was subjected to an EtOAc/NaHCO3 work-up to remove the presence of any silica gel impurity. Upon evaporation of the EtOAc layer the title compound was obtained as a white solid (7 mg, 76%).
Reaction SMILES: NCC1C(F)=C(OC2C=C(C=C(Cl)C=2)C#N)C(C(F)F)=CC=1.N(C1NC(C(O)=O)=C(Cl)N=1)=[N+]=[N-].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+].[N:54]([C:57]1[NH:58][C:59]([Cl:86])=[C:60]([C:62]([NH:64][CH2:65][C:66]2[CH:71]=[CH:70][C:69]([CH:72]([F:74])[F:73])=[C:68]([O:75][C:76]3[CH:81]=[C:80]([C:82]#[N:83])[CH:79]=[C:78]([Cl:84])[CH:77]=3)[C:67]=2[F:85])=[O:63])[N:61]=1)=[N+]=[N-]>CN(C)C=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C>[NH2:54][C:57]1[NH:61][C:60]([C:62]([NH:64][CH2:65][C:66]2[CH:71]=[CH:70][C:69]([CH:72]([F:73])[F:74])=[C:68]([O:75][C:76]3[CH:81]=[C:80]([C:82]#[N:83])[CH:79]=[C:78]([Cl:84])[CH:77]=3)[C:67]=2[F:85])=[O:63])=[C:59]([Cl:86])[N:58]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)F)ccc(CNC(=O)c3nc(N=[N+]=[N-])[nH]c3Cl)c2F)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: N#Cc1cc(Cl)cc(Oc2c(C(F)F)ccc(CN)c2F)c1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(C(F)F)ccc(CNC(=O)c3[nH]c(N)nc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-{[3-(aminomethyl)-6-(difluoromethyl)-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.08 g, 0.245 mmol), 2-azido-4-chloro-1H-imidazole-5-carboxylic acid (0.046 g, 0.245 mmol), EDC (0.047 g, 0.245 mmol) and HOBT (0.037 g, 0.245 mmol) in N,N-Dimethylformamide (DMF) (4 ml) were stirred at RT under an atmosphere of nitrogen for 16 h then ethyl acetate (30 mL) and saturated aqueous NaHCO3 solution (30 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (30 mL), water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. A mixture of 2-azido-5-chloro-N-{[3-[(3-chloro-5-cyanophenyl)oxy]-4-(difluoromethyl)-2-fluorophenyl]methyl}-1H-imidazole-4-carboxamide (0.12 g, 0.242 mmol) and Lindlar Catalyst (5.15 mg, 0.048 mmol) in ethyl acetate (10 ml) was stirred at RT under hydrogen (55 psig) for 16 h. Next day TLC & LCMS show desired product and remaining starting material. More Lindlar Catalyst (5.15 mg, 0.048 mmol) was added and the mixture was stirred at RT under hydrogen (55 psig) for 6 h. The mixture was carefully vented, filtered thru Celite and concentrated under vacuum. The yellow solid was purified by Reverse Phase HPLC (MeCN/water+0.1 TFA) to give a white solid. The salt was stirred with ethyl acetate (15 mL) and saturated aqueous NaHCO3 solution (15 mL) for 15 min. The organic layer was separated, washed with water (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated to give 0.033 g (29%) of the title compound as a white powder. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.39-7.62 (m, 3H), 7.27 (d, 2 H), 6.92 (t, 1H), 4.66 (s, 2H). LCMS m/z 468.3 (M−H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][C@@H:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][C@H:16]1[CH2:27][O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)=O)(C)(C)C>C(Cl)Cl>[O:20]([C@@H:18]1[CH2:19][NH:15][C@H:16]([CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)[CH2:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccccc3)CN2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.2 %

Procedure:
Trifluoroacetic acid (20 ml) was added to a solution of methyl 4-((2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethoxy)benzoate (2.02 g, 3.25 mmol) in methylene chloride (100 ml). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with methylene chloride (50 ml), followed by washing with 1N NaOH. The organic layer was fractionated, followed by washing with saturated brine, drying over anhydrous sodium sulfate and distillation under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 70 g), whereby from chloroform/acetone (10/1) chloroform/methanol (10/1) eluate fractions, the title compound (970 mg, 91%) was obtained as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][C:15]1[NH:16][CH:17]=[C:18]([CH3:20])[N:19]=1>>[CH3:14][C:15]1[N:16]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH:17]=[C:18]([CH3:20])[N:19]=1
Reactant: N#Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1c[nH]c(C)n1
Product: Cc1cn(-c2ccc(C#N)cc2C(F)(F)F)c(C)n1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 4-chloro-3-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and 2,4-dimethyl-imidazole (Trans World Chemicals), with a reaction temperature of 145° C. for 20 hours.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1.[N+:14]([O-])([OH:16])=[O:15]>>[F:6][C:7]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1
Reactant: Fc1cccc(F)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(F)nc1F
Temperature: 7.5 °C
Reaction time: 8 h

Procedure:
To a mixture of concentrated sulphuric acid (600 mL) and fuming nitric acid (90%, 400 mL) in a ice-bath (internal temperature maintained at 5-10° C.) was added drop-wise 2,6-difluoropyridine (200 g, 1.74 mol). The resulting mixture was stirred overnight at room temperature. The mixture was poured slowly into 3 kg of ice and extracted with Et2O (2×2 L). The combined organic layers were washed with aqueous 1.5 N NaOH (2×1 L), then with aqueous saturated NaHCO3 (400 mL) or until pH is around 8-9. The organic layers were dried over MgSO4, filtrated and concentrated under reduced pressure until constant weight (to remove unreacted 2,6-difluoropyridine: 10-12%). The title compound was obtained as a yellow liquid (207.3 g, 74% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[CH3:16][N:17]([CH3:27])[CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:27])[CH:21]=1
Reactant: CN(C)CCc1cccc(N)c1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cccc(CCN(C)C)c1
Yield: 72.8 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (340 mg, 1.20 mmol) was reacted with 3-(2-(dimethylamino)ethyl)aniline (215 mg, 1.31 mmol) to afford the desired product (360 mg, 50%) as a yellow solid: ESI MS m/z 412 [C21H22BrN3O+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:15]1[CH2:16][CH2:17][N:1]([C@H:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])[CH2:13][CH2:14]1
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)[C@@H](c1ccccc1)N1CCOCC1

Procedure:
To (R)-2-amino-2-phenylacetic acid (1.0 g, 6.62 mmol), 1-bromo-2-(2-bromoethoxy)ethane (1.686 g, 0.727 mmol) and sodium carbonate (2.103 g, 19.85 mmol) was added ethanol (40 mL) and the resultant mixture heated at 100° C. for 45 hours. After cooling, the resultant solid was removed by filtration and washed with ethanol. The filtrate was concentrated, and then dissolved in ethanol then a solution of 4N aqueous hydrochloric acid added until the pH of the solution was 3. The resultant solid was removed and discarded. The filtrate was concentrated and purified by reversed phase chromatography (C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to give the title compound. MS (ESI) m/z 222 (MA)+.
Reaction SMILES: [PH2]([O-])=O.[Na+].O.[PH2]([O-])=O.[Na+].C1(=O)[O:15][C:13](=[O:14])[CH:12]=[CH:11]1.[Na].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[C:30]([OH:34])(=[O:33])[CH:31]=[CH2:32]>O>[C:13]([OH:15])(=[O:14])[CH:12]=[CH2:11].[C:13]([OH:15])(=[O:14])/[CH:32]=[CH:31]\[C:30]([OH:34])=[O:33]
Reactant: O=C1C=CC(=O)O1
Agent: C=CC(=O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[PH2][O-]
Solvent: O
Product: O=C(O)/C=C\C(=O)O

Procedure:
Copolymers of acrylic acid and maleic acid were prepared using sodium hypophosphite to promote telomerization. In a typical reaction, sodium hypophosphite monohydrate of a desired amount was added to deionized water and the solution heated to about 90°-100° C. Maleic anhydride was added to the solution and pH adjusted to about 4. Sodium or potassium persulfate (1-10% of total monomer feed) was used to initiate the polymerization. Acrylic acid at the appropriate ratio was added periodically over a 2-4 hour time period. Polymerization was continued until substantially 100% conversion was obtained. Telomers prepared in this manner are listed in Table I.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:8]1[C:12]2([CH2:17][C:16](=[O:18])[NH:15][C:14](=[O:19])[CH2:13]2)[CH2:11][CH2:10][CH2:9]1.CS(Cl)(=O)=O>C(N(CC)CC)C>[CH2:6]([N:15]1[C:14](=[O:19])[CH2:13][C:12]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:17][C:16]1=[O:18])[CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1]
Reactant: O=C1CC2(CCCC2)CC(=O)N1
Reactant: C=CCCCCO
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: C=CCCCCN1C(=O)CC2(CCCC2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
A mixture of 5-hexen-1-ol (5 g) and 8-azaspiro[4.5]decane-7,9-dione (14 ml) in triethylamine (150 ml) was cooled on an ice bath. Methane-sulfonyl chloride (8.6 g) in triethylamine (50 ml) was added dropwise and the mixture was stirred at room temperature for 1 hour. The mixture was filtered off and the filtrate evaporated. Dichloromethane (7.7 g), potassium carbonate (7.6 g) and N,N-dimethylformamide (100 ml) were added to the residue and the mixture was stirred at 160° C. overnight. The mixture was filtered off and the filtrate evaporated. The residue was purified by short open column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 100/0 to 98/2). The pure fractions were collected and evaporated, yielding 1.5 g (13%) of 8-(5-hexenyl)-8-azaspiro[4.5]decane-7,9-dione (interm. 8).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[O:39])=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[O:39])=[CH:34][C:33]=1[C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=1
Reactant: O=Cc1ccc(Cl)c(B(O)O)c1
Reactant: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(Br)o2)c(C)cn1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(-c3cc(C=O)ccc3Cl)o2)c(C)cn1
Yield: 83.6 %

Procedure:
To a solution of N-{4-[5-bromo-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (0.45 g, 0.91 mmol) in 1,4-dioxane (5 mL) was added water (1.2 mL), tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.091 mmol), (2-chloro-5-formylphenyl)boronic acid (0.22 g, 1.19 mmol) and cesium carbonate (0.89 g, 2.74 mmol). The mixture was allowed to stir and subjected to microwave irradiation at 150° C. for 20 min. The mixture was diluted with water and extracted with EtOAc. The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-{4-[5-(2-chloro-5-formylphenyl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (0.42 g, 83%). LCMS (FA): m/z=552.6 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:18]I>O1CCCC1>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([C:12]([F:15])([F:13])[F:14])[N:8]([CH3:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1cccc2nc(C(F)(F)F)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)(F)F)n2C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
To a solution of 4-methoxy-2-trifluoromethylbenzimidazole (1.4 g) in tetrahydrofuran (40 ml) under nitrogen was added sodium hydride (0.32 g; 60% dispersion in oil). The mixture was stirred for 20 minutes at room temperature before methyl iodide (1.35 g) was added. Stirring was continued overnight. The reaction was quenched by the addition of water (10 ml) and the solvent removed in vacuo. Ethyl acetate (50 ml) was added and the organic layer washed with saturated sodium bicarbonate solution (20 ml), water (20 ml) and brine (20 ml). Drying over anhydrous magnesium sulfate followed by the removal of the solvent in vacuo gave the title compound (1.6 g) as an oil which solidified on standing.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].NCCCCS([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:41])[CH:25]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)=O.C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][S:5]([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:41])[CH:25]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:7])=[O:6]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCCC1CNS(=O)(=O)CCCCN
Reactant: O=S(=O)(Cl)CCCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCCC1CNS(=O)(=O)CCCBr
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
A solution of Part A 3-bromopropyl sulfonyl chloride (1.06 g, 4.8 mmol) in dichloromethane (5 mL) was added dropwise to a cooled (-10° C.) stirred solution of Example 6a, Part B amine (1.05 g, 3.02 mmol) and triethyl amine (1.44 mL, 9.6 mmol) in dichloromethane (15 mL). After a few minutes, a precipitate formed. The suspension was stirred at -10° C. for 2.5 hours, diluted with dichloromethane (35 mL) and washed with 1N HCl solution (2×15 mL). The dichloromethane solution was dried (MgSO4), filtered and the solvent was removed in vacuo. The crude oil was purified on silica gel (Merck, 150 mL) eluting with 50% ethyl acetate in hexane to give title compound as a white foam (1.160 g, 72%).
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH3:16][N:17]([CH3:32])[CH2:18][CH2:19][N:20]([CH3:31])[C:21]1[S:22][C:23]2[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:30][C:28]3[CH:27]=[CH:26][C:24]4[N:25]=[C:21]([N:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:32])[CH3:31])[S:22][C:23]=4[CH:29]=3)=[O:13])=[CH:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc(C2C=CCCC2)cc1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(C4C=CCCC4)cc3)cc2s1

Procedure:
The title compound is prepared by following General Method A, using 4-cyclohex-2-enyl-benzoic acid (0.079 g, 0.39 mmol), and N*2*-(2-Dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.73 g, 0.30 mmol) to give the product (0.041 g, 31%). LC/MS: Retention time=5.09 min; (m/z): calcd for C25H30N40S (M+H)+: 435.6; found: 435.0.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:49]([NH:51][C@H:52]([C:58]([OH:60])=[O:59])[CH2:53][CH2:54][C:55](=[O:57])[OH:56])=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH2:3][OH:4].C(O)(=O)C>CO.[Pd]>[NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:16]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:49]([NH:51][C@H:52]([C:58]([OH:60])=[O:59])[CH2:53][CH2:54][C:55](=[O:56])[OH:57])=[O:50])[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:22])[NH2:23])=[O:14])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:6])[CH2:3][OH:4]
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reaction time: 13 h

Procedure:
1.84 Grams of Z-Ser-Leu-Arg-Ser-Lys(Tos)-Glu-OH was suspended in a mixture of 30 ml of methanol with 30 ml of 10%-acetic acid, and a small amount of palladium black was added to the suspension and stirred for 13 hours under introducing hydrogen gas. After the reaction was completed, the catalyst was removed by suction filtration to obtain the filtrate. Then filtrate was distilled under a reduced pressure and the thus obtained residue was pured into water and then lyophilized to obtain the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[C:37]([CH2:39][CH2:40][N:41]([CH3:51])[C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)#[N:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][C:42]([N:41]([CH2:40][CH2:39][C:37]#[N:38])[CH3:51])=[O:50])[CH2:49][CH2:48]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(CCC#N)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)CCC#N)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-(2-cyano-ethyl)-N-methyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 16d) in an analogous manner as described in example 25. LR-MS: 714.3 [(M+H)+]
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:18][C:16]2[S:17][C:13]([CH3:12])=[CH:14][CH:15]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1ccc(C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(NCc2ccc(C)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a mixture of 200 mg (1.32 mmol) methyl 4-aminobenzoate and 167 mg (1.32 mmol) 5-methyl-2-thiophenecarboxaldehyde dissolved in 8 mL dichloromethane was added 420 mg (1.98 mmol) sodium triacetoxyborohydride. The mixture was stirred at room temperature overnight, then partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated. Column chromatography, eluting with 20% ethyl acetate/hexane, provided 316 mg (1.2 mmol) of 4-[(5-Methyl-thiophen-2-ylmethyl)-amino]-benzoic acid methyl ester. This product was then dissolved in 10 mL methanol and treated with 127 mg (3.0 mmol) of lithium hydroxide dissolved in 5 mL water. The mixture was stirred at room temperature overnight, then partitioned between ethyl acetate and 1 N HCl, dried over magnesium sulfate and concentrated to provide 276 mg (92% yield) of 4-[(5-methyl-thiophen-2-ylmethyl)-amino]-benzoic acid (used in preparation of compound 64 of Table 1) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(o1)CCCC2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2c(O)cccc2o1

Procedure:
To a suspension of methyl 4-oxo-4,5,6,7-tetrahydro-benzofuran-2-ylcarboxylate (5.60 g, 28.8 mmol) in CCl4 (200 ml) were added N-bromosuccinimide (5.18 g, 28.8 mmol) and 2,2′-azobisisobutyronitrile (0.483 g, 2.88 mmol). The reaction mixture was heated at reflux for 80 min and concentrated in vacuo. The residue was suspended in ethyl acetate (200 ml), washed with saturated sodium bicarbonate solution (2×50 ml), brine (50 ml), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography over silica gel with ethyl acetate/hexane (1/10) to yield methyl 4-hydroxy-benzofuran-2-ylcarboxylate as a while solid (4.21 g, 21.9 mmol).