Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:31]=[CH:30][C:18]2[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[N:21][C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:31]=[CH:30][C:18]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[CH:20]=[N:21][C:17]=3[CH:16]=2)[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: C[Si](C)(C)CCOCn1cnc2cc(Br)ccc21
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)ncn3COCC[Si](C)(C)C)C1=O
Yield: 75.2 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.8474 mmol) was reacted with 5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (332 mg, 1.0152 mmol), 1,4-dioxane (15 mL), copper iodide (16 mg, 0.0842 mmol), trans-1,2-diamino cyclohexane (28 mg, 0.2456 mmol) and potassium phosphate (538 mg, 2.5377 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 270 mg of 1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-5-yl]-imidazolidin-2-one (75.41% yield).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[S:12][CH:11]=[C:10]([C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH:9]=1)(C)(C)C.[F-].C([NH3+])(C)(C)C.C(O)(=O)C>O1CCCC1>[OH:6][CH2:7][C:8]1[S:12][CH:11]=[C:10]([C:13]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(C(=O)N2CCCCC2)cs1
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(c1csc(CO)c1)N1CCCCC1
Reaction time: 8 h
Yield: 64.3 %

Procedure:
[5-(tert-Butyl-dimethyl-silanyloxymethyl)-thiophen-3-yl]-piperidin-1-yl-methanone (0.96 g, 2.83 mmol) was dissolved in tetrahydrofuran (15 mL) and t-butylammonium fluoride (1 M in THF; 3.12 mL) and acetic acid (1 mL) were added. The reaction mixture was stirred overnight then partitioned between diethyl ether and saturated aqueous sodium hydrogen carbonate. The organic solution was separated and dried over magnesium sulphate, filtered and the solvent removed. The residue was purified by flash chromatography on silica, eluting with 30% ethyl acetate in pentane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a clear oil (0.41 g). LCMS m/z 226 [M+H]+ RT=6.15 min (Analytical Method 4).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][O:18][CH3:19]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][CH2:16][CH2:17][O:18][CH3:19])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCOc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 0.15 g, 3.75 mmol) was added, at room temperature, to a solution of 4-chloro-2-nitrophenol (0.5 g, 2.88 mmol) in anhydrous N,N-dimethylformamide (15 mL) and the resulting mixture was stirred for 5 minutes. 1-Bromo-3-methoxy-propane (0.485 g, 3.17 mmol) was then added and the reaction mixture was heated at 80° C. for 62 hours. The resulting mixture was partitioned between an aqueous solution of sodium hydroxide (3 M) and ethyl acetate, the organic layer was separated, washed twice with an aqueous solution of sodium hydroxide (3 M) and once with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 90/10 to 50/50) to give 0.455 g (64% yield) of 4-chloro-1-(3-methoxy-propoxy)-2-nitro-benzene as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.[CH3:39][C:40]1([CH3:57])[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([O:49][C:50]3[N:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=3)[CH:47]=2)[CH2:42][O:41]1>CN(C=O)C>[CH3:39][C:40]1([CH3:57])[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([O:49][C:50]3[N:55]=[CH:54][C:53]([NH:56][C:10]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12])=[CH:52][CH:51]=3)[CH:47]=2)[CH2:42][O:41]1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1(C)OCc2ccc(Oc3ccc(N)cn3)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc3c(c2)C(C)(C)OC3)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
To a solution of (2R)-2-(tert-butoxycarbonylamino)butanoic acid (19.8 mg, 0.097 mmol) in dry DMF (1 mL) N-ethyl-N-isopropyl-propan-2-amine (0.27 ml, 0.16 mmol) and then [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (35.60 mg, 0.094 mmol) were added and the reaction mixture was stirred for 15 minutes at room temperature. A solution of 6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]pyridin-3-amine (Intermediate 45, 20 mg, 0.0780 mmol) in DMF (0.5000 mL) was added and the reaction mixture was stirred overnight at the same temperature. The reaction was quenched with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and cyclohexane/ethyl acetate from 100:0 to 50:50 as eluent affording the title compound (25 mg) as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]([CH3:29])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2)#[N:2].[NH4+].[OH-]>CN(C=O)C.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]([CH3:29])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2
Reactant: CN(C(=O)c1ccc(-c2ccc(F)cc2)cc1)C1CCc2cc(C#N)ccc2C1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(-c2ccc(F)cc2)cc1)C1CCc2cc(CN)ccc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 4′-fluoro-biphenyl-4-carboxylic acid (6-cyano-1,2,3,4-tetrahydro-naphthalen-2-yl)-methyl-amide, 7, (0.200 g, 0.521 mmol), 28% NH4OH (2 mL) and Raney Ni (0.2 g) in DMF (5 mL) is stirred vigorously at room temperature under 1 atm of H2 for 18 hrs. The catalyst is removed by filtration and the filtrate is purified by directly loading to prep-HPLC column eluted with CH3CN—H2O (0.1% TFA) to afford 0.098 g of the desired product. 1H NMR (300 MHz, CD3OD) δ 7.42-7.78 (m, 6H), 7.03-7.16 (m, 5H), 4.83 (m, 1H), 3.91-4.07 (m, 3H), 2.60-3.31 (m, 6H), 2.01-2.20 (m, 2H); 13C NMR (75 MHz, CD3OD) δ 164.7, 161.4, 160.4, 141.7, 136.4, 135.5, 131.3, 130.0, 129.1, 128.8, 128.8, 127.0, 126.3, 115.7, 115.5, 56.0, 51.2, 42.9, 31.8, 29.0, 26.9; LRMS: 411.28 (M+Na), 388.27 (M+H), 372.25 (M+H−NH3).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.C([O-])(=O)C.[Na+].C(OCC)C>C(O)(=O)C.O>[Br:1][C:6]1[C:7]([O:10][CH3:11])=[N:8][CH:9]=[C:4]([Cl:3])[CH:5]=1
Reactant: COc1ccc(Cl)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: COc1ncc(Cl)cc1Br
Temperature: 80 °C
Reaction time: 6 h
Yield: 64.5 %

Procedure:
A solution of bromine (1.5 mL, 29.28 mmol) in glacial acetic acid (7 mL) was slowly added to a mixture of 5-chloro-2-methoxypyridine (2.1 g, 14.63 mmol) and sodium acetate (1.2 g, 14.63 mmol) in glacial acetic acid (7 mL) and the resulting mixture was stirred at 80° C. for 6 hours. The reaction was allowed to cool down to ambient temperature and then diethyl ether and water were added. The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide and a 4% aqueous solution of sodium bisulphite, dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was purified by flash chromatography (100% hexanes) to give the title compound (2.1 g, 64%) as a white solid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)\[C:4]#[N:5].Cl.Cl[CH2:16][C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.CN(C=O)C>[NH2:22][C:19]1[S:20][CH:21]=[C:17]([CH2:16][O:1]/[N:2]=[C:3](/[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)\[C:4]#[N:5])[N:18]=1
Reactant: Nc1nc(CCl)cs1
Reactant: COc1cccc(/C(C#N)=N/O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cccc(/C(C#N)=N/OCc2csc(N)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of (2Z)-(hydroxyimino)(3-methoxyphenyl)acetonitrile (2.57 g, 14.59 mmol, 1 eq.) in 70 ml of acetonitrile and 7 ml of DMF, was added 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (2.87 g, 16.05 mmol, 1.1 eq.) followed by potassium iodide (242 mg, 1.46 mmol, 0.1 eq.) and caesium carbonate (10.45 g, 32.09 mmol, 2.2 eq.). The reaction was stirred 8 h at room temperature. The solvent was then evaporated and the residue dissolved in EtOAc, subsequently washed with H2O and brine. Ater separation, the organic phase was dried over MgSO4 then concentrated to afford (2Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(3-methoxyphenyl)acetonitrile (4.03 g, 91% yield, only 1 oxime isomer) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][S:3]([N:6]([CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)(=[O:5])=[O:4].C(O)(C(F)(F)F)=O.N>C(Cl)Cl.O>[Cl:1][CH2:2][S:3]([N:6]([CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:4])=[O:5]
Reactant: CN(C)CCCN(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)CCl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCN(C1CCNCC1)S(=O)(=O)CCl
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a solution of the above carbamate (940 mg, 2.36 mmol) in CH2Cl2 (10 mL) was added TFA (5 mL). The reaction mixture was stirred for 1 hr. After being diluted with CH2Cl2 (10 mL) and H2O (10 mL), the mixture was made alkaline with aqueous NH3. The organic layer was separated and the aqueous layer was further extracted with CH2Cl2 (2×15 mL). The combined organic fractions were washed with H2O (2×20 mL) and dried (Na2SO4). Evaporation of the solvent gave chloro-N-[3-(dimethylamino)propyl]-N-(4-piperidinyl)methanesulfonamide (571 mg, 81%): 1H NMR (CDCl3) δ 4.46 (s, 2H), 3.76-3.68 (m, 1H), 3.35-3.31 (m, 2H), 3.16-3.14 (m, 2H), 2.70-2.63 (m, 2H), 2.28 (t, J=6.9 Hz, 2H), 2.22 (s, 6H), 1.88-1.68 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.27 (3, 9H), 7.41 (m, 3H), 7.50 (dd, 2H), J=4.8 Hz, 1.6 Hz), 7.67-72 (m, 4H), 8.85 (d, 2H, J=6 Hz), 10.19 (s, 1H). MS; m/z 473.9 (M30 +1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.C(OB(OC(C)C)OC(C)C)(C)C.C(NC(C)C)(C)C.[Li].C([O-])([O-])=O.[Na+].[Na+].[Cl:39][C:40]1[N:45]=[C:44](Cl)[C:43]([Cl:47])=[CH:42][N:41]=1>C1COCC1>[Cl:39][C:40]1[N:45]=[C:44]([C:9]2[S:8][C:7]3[CH:11]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)[C:43]([Cl:47])=[CH:42][N:41]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CSc1ccc2ccsc2c1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C([O-])[O-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1ccc2cc(-c3nc(Cl)ncc3Cl)sc2c1
Temperature: 25 °C
Yield: 7.4 %

Procedure:
To a stirred solution of 6-methylsulfanylbenzo[b]thiophene (1.41 g, 7.82 mmol) and triisopropylborate (1.80 mL, 7.82 mmol) in THF (20 mL) at −78° C. under nitrogen is added lithium diisopropylamine (4.3 mL, 2 M solution). The reaction is allowed to slowly warm to room temperature. An aqueous solution of Na2CO3 (2.50 g, 23.5 mmol, in 11 mL of water) is added, followed by the addition of 2,4,5-trichloropyrimidine (1.58 g, 8.60 mmol) and [1,1-bis(diphenylphospheno)ferrocene]palladium (II) chloride (0.32 g, 0.39 mmol). The reaction mixture is heated at 60° C. under nitrogen for 1 hour. After being cooled to room temperature, the suspension is filtered and the solid is washed with water and ethyl acetate then dried under vacuum. The crude product is purified by chromatography on silica gel, eluting with dichloromethane:hexanes 2:8 to 3:7, to give the title product as a light yellow solid (0.19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH3:13]
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1C(=O)C(=O)c2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-chloroisatin (CAS#6344-05-4, 3.64 g, 20.0 mmol) in acetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol) followed by iodomethane (2.75 mL, 44.0 mmol). The reaction was then placed at 60° C. and stirred for 40 minutes. The reaction was then cooled to room temperature, filtered and concentrated to 10% of the original volume. The reaction was then diluted with dichloromethane, water, and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate filtered, and concentrated to provide 4-chloro-1-methyl-1H-indole-2,3-dione as an orange solid without the need for further purification. The 4-chloro-1-methyl-1H-indole-2,3-dione (1.55 g, 7.92 mmol) was then treated with hydrazine hydrate (14.8 ml, 475 mmol). The reaction was then placed at 70° C. and heated to 130° C. over 20 minutes. The reaction was stirred at 130° C. for 45 minutes, at which time the reaction was placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were then separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 2%) to afford 4-chloro-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 182.0 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.N1C=CC=CC=1>C1COCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COCCOc1cc(N)ncc1C#N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCCOc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Phenyl chloroformate (4.93 ml, 39.3 mmol) was added drop wise to a mixture of 6-amino-4-(2-methoxyethoxy)nicotinonitrile (intermediate 20, 3.45 g, 17.86 mmol) and pyridine (6.35 ml, 79 mmol) in THF (100 ml) at room temperature. The reaction mixture was stirred for 5 h at room temperature and then partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer washed with saturated brine, dried over MgSO4 and evaporated. The residue was triturated with EtOAc and the product obtained by filtration as a white solid. (UPLC-MS 7) tR 0.97; ESI-MS 314.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:17]([O:24][CH2:25][C@H:26]([NH:30]C(OC(C)(C)C)=O)[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH2:30][C@@H:26]([CH2:25][O:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:27]([NH:12][C:11]1[CH:13]=[CH:14][C:8]([O:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)=[O:28]
Reactant: COc1ccc(Oc2ccc(N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: COc1ccc(Oc2ccc(NC(=O)[C@@H](N)COCc3ccccc3)cc2)cc1
Yield: 90 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-methoxyphenoxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(4-methoxyphenoxy)phenyl)propanamide (710 mg, 90%).
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:8][C:7]1=[O:15])(=[O:5])=[O:4].[H-].[Na+].Cl.[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([CH2:29][CH2:30][CH2:31][CH2:32][F:33])[C:25]([CH2:27]Cl)=[N:26][C:22]=2[CH:21]=1>CN(C=O)C.O>[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([CH2:29][CH2:30][CH2:31][CH2:32][F:33])[C:25]([CH2:27][N:8]3[C:9]4[CH:10]=[N:11][CH:12]=[CH:13][C:14]=4[N:6]([S:3]([CH3:2])(=[O:5])=[O:4])[C:7]3=[O:15])=[N:26][C:22]=2[CH:21]=1
Reactant: CS(=O)(=O)n1c(=O)[nH]c2cnccc21
Reactant: FCCCCn1c(CCl)nc2cc(Cl)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1c(=O)n(Cc2nc3cc(Cl)ccc3n2CCCCF)c2cnccc21
Reaction time: 0.33 h

Procedure:
To a solution of 1-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one hydrochloride 10 (720 mg, 2.626 mmoles) in 10 mL of extra dry DMF was added sodium hydride (210 mg, 5.253 mmoles, 60% dispersion in oil) portionwise at room temperature. After 20 minutes, a solution of 5-chloro-2-(chloromethyl)-1-(4-fluorobutyl)-1H-benzo[d]imidazole hydrochloride 9 (440 mg, 1.313 mmoles) in 5 mL of DMF was added dropwise. Stirring was continued overnight at room temperature. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The resulting slightly orange oil was triturated in DCM and the precipitate was filtered off. It was further washed with DCM, then isopropylether and dried under high vacuum, to provide the title product 3-((5-chloro-1-(4-fluorobutyl)-1H-benzo[d]imidazol-2-yl)methyl)-1-(methylsulfonyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one P34 as a white solid in 40% yield; m/z=452 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[NH:23]([C:24]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[S:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=C=Nc1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)N1CCN(C(=S)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Benzyloxycarbonylpiperazine (5.00 g) was dissolved in acetone (50 mL), and phenyl isothiocyanate (2.9 mL) was added thereto under ice-cooling. The mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration to give 1-(anilinocarbothioyl)-4-(benzyloxycarbonyl)piperazine (5.08 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[K]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[C:15]([OH:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[C:12]([F:11])([F:22])[F:23])[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: N#CCc1ccc(Cl)cc1
Agent: [K]
Solvent: C1CCOC1
Product: N#CC(=C(O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
A mixture comprising 45 g of 4-chlorobenzyl cyanide, 62 g of 2-trifluoromethylbenzoyl chloride and 210 ml of tetrahydrofuran, was dropwise added over a period of 1 hour at a temperature of not higher than 15° C. to the mixture comprising 70 g of potassium tertiary butyrate and 450 ml of tetrahydrofuran. After completion of the dropwise addition, the solution temperature was returned to room temperature, followed by the reaction for 1 hour. 500 ml of ice water was poured into the residue obtained by concentration under reduced pressure of the reaction mixture, followed by stirring for 15 minutes, whereupon the mixture was washed with 500 ml of methylene chloride. The aqueous layer was adjusted to pH 3 to 4 by concentrated hydrochloric acid and then extracted with 600 ml of methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 300 ml of n-hexane was added to the residue, followed by washing to obtain 87.6 g of the desired product. The NMR spectrum data of this product are as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.C(O)=O>O1CCOCC1.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[CH:3][CH:2]=1
Reactant: O=C(C=Cc1ccncc1)C=Cc1ccncc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=C(CCc1ccncc1)CCc1ccncc1
Temperature: 25 °C

Procedure:
To a slurry of Compound 1 (21.3 g, 67.4 mmol) in 1,4-dioxane (40 mL) was added triethylamine (48.1 mL, 0.346 mol), formic acid (6.54 mL, 0.145 mol) and 10% palladium on carbon (0.7 g) and the resulting mixture heated to reflux. After stirring at reflux for 1 hr, the reaction was cooled to room temperature filtered and concentrated in vacuo. The resulting residue was chromatographed over silica gel (elution with 5% methanol/methylene chloride) to provide the desired material.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:13])[CH2:9][C:10]([CH3:12])=[O:11])[CH:2]=1.[CH:15]([O-])([O-])OC>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:13])/[CH:9]=[C:10](\[O:11][CH3:15])/[CH3:12])[CH:2]=1
Reactant: COC([O-])[O-]
Reactant: CC(=O)CC(=O)Nc1cccc(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CO/C(C)=C\C(=O)Nc1cccc(C)c1
Temperature: 140 °C
Reaction time: 6 h
Yield: 46.6 %

Procedure:
A mixture of 80 g of N-(m-tolyl)-acetoacetamide, 80 g of methyl orthoformate, 100 ml of methanol and 1 g of p-toluene sulfonic acid was refluxed with stirring for 6 hours and the volatile material was distilled off under reduced pressure. 300 ml of toluene and 1.5 ml of quinoline were added and the mixture was heated to about 140° C for 3 hours and then the rest of the toluene was evaporated. The residue was chromatographed over silica gel with a mixture of 9-1 methylene chloride-ethyl acetate as eluant to obtain 40 g of N-(m-tolyl)-3-methoxy-crotonamide melting at 106° C.