Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[Cl:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[Cl:13]
Reactant: Cc1ccccc1-c1nc(CCl)c(C)o1
Reactant: CCO[C@@H](Cc1ccc(O)cc1Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1Cl)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-3-(2-chloro-4-hydroxy-phenyl)-2-ethoxy-propionic acid methyl ester (example 15 d]) was reacted with 4-chloromethyl-5-methyl-2-o-tolyl-oxazole (example 1 e]) in the presence of cesium carbonate and potassium iodide to yield (S)-3-[2-chloro-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:51])/[C:19](=[N:45]\[O:46][CH2:47][CH:48]3[CH2:50][CH2:49]3)/[C:20]3[N:21]=[C:22]([NH:25][C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:23][CH:24]=3)[C:15](=[O:52])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].[CH2:59]([O:61][C:62]([O:64][CH:65](Br)[CH3:66])=[O:63])[CH3:60]>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:51])/[C:19](=[N:45]\[O:46][CH2:47][CH:48]3[CH2:50][CH2:49]3)/[C:20]3[N:21]=[C:22]([NH:25][C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[S:23][CH:24]=3)[C:15](=[O:52])[N:10]2[C:11]=1[C:12]([O:14][CH:59]([O:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH3:60])=[O:13])(=[O:3])[NH2:2]
Reactant: CCOC(=O)OC(C)Br
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)C1=C(COC(N)=O)CS[C@@H]2[C@H](NC(=O)/C(=N\OCC3CC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6R,7R)-3-Carbamoyloxymethyl-7-[(Z)-2-cyclopropylmethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylic acid (1.1 g) was dissolved in N,N-dimethylformamide (5 ml) and stirred with potassium carbonate (105 mg) under nitrogen with ice-water cooling. After 10 minutes, 1-ethoxycarbonyloxy-1-ethyl bromide was added. After one hour, the mixtured was allowed to attain 21° and was stirred thus for three hours. The mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The aqueous layer was extracted with more ethyl acetate and the combined organic layers were washed twice with brine, dried with magnesium sulphate and concentrated. The residue was chromatographed on Sorbsil U30 (50 g) in ethyl acetate (10 to 60%) in petroleum ether (bp 40° to 60°) to give the title compound (930 mg); [α]D21 +44.0° (c 1.30, CHCl3); λmax (ethanol) 230 nm (E1 cm1% 312), λ infl 236 nm (ED1% 295) and λnm (E1 cm1% 226).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a ice cold solution of salicylic acid (10 g, 0.072 mol) in methanol (100 mL), was added drop wise SOCl2 (12.8 g, 0.1 mol). After the addition, the mixture was warmed to room temperature and heated to reflux for 12 h. After reaction is completed the reaction mixture was cooled to room temperature and the excess methanol was evaporated under reduced pressure to obtain 9 g of methyl 2-hydroxybenzoate as a white solid. (81%). A solution of methyl 2-hydroxybenzoate (9 g, 0.059 mol) in glacial acetic acid (90 mL) was cooled to 15° C., fuming nitric acid (11.2 mL) was added drop wise. The reaction mixture was warmed to room temperature and stirred for 4 h. When the reaction is completed, the reaction mixture was poured into crushed ice. The precipitate was collected by filtration and washed several times with chilled water, then dried in a vacuum oven to the required product as a yellow coloured solid.
Reaction SMILES: C(C1C=CC(C([NH:11][C@H:12]([C:20]2[NH:21][CH:22]=[C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=3)[N:24]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=C)=C(NCC)C=1)#N.C(C1C(NCC)=C(C=CC=1)C(O)=O)#N.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N[C@H](C(O)=O)CC1C=CC=CC=1)(OC(C)(C)C)=O.BrCC(C1C=CC(C#N)=CC=1)=O>C1COCC1.CCN(CC)CC>[NH2:11][C@H:12]([C:20]1[NH:21][CH:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH2:31])=[O:30])=[CH:32][CH:33]=2)[N:24]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=C(N[C@@H](Cc1ccccc1)c1nc(-c2ccc(C(N)=O)cc2)c[nH]1)c1ccc(C#N)cc1NCC
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCNc1c(C#N)cccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(-c2c[nH]c([C@@H](N)Cc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Part D: (S)-4-(2-(1-(1-(4-Cyano-2-(ethylamino)phenyl)vinylamino)-2-phenylethyl)-1H-imidazol-4-yl)benzamide: Cyano-2-(ethylamino)benzoic acid from Example 140 Part C (40 mg, 0.2 mmol), Bop reagent (108 mg, 0.24 mmol), and Et3N (0.28 mL) were added together with 5 mL of THF. The mixture was stirred at RT for 15 minutes and (S)-4-(2-(1-Amino-2-phenylethyl)-1H-imidazol-4-yl)benzamide (107 mg, 0.2 mmol), obtained from N-boc-(L)-phenylalanine and 4-(2-Bromo-acetyl)-benzonitrile by the sequential application of the procedures described for Example 1 Part A, Example 28 Part A and Example 1 Part B, was added. The resulting mixture was heated to reflux under N2 for 2 h. The solvent were removed. The residue was dissolved in EtOAc and washed with water and brine. It was dried over MgSO4, concentrated, and purified by ISCO flash chromatography (silica, EtOAc/hexane) to give 50 mg of the desired product. LC/MS: 479.3 (M+1)+.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])=[O:4]>CCO.C(Cl)Cl>[OH:4][CH2:3][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccccc1-n1ccc2c(C=O)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1ccccc1-n1ccc2c(CO)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
NaBH4 (50 mg, 1.35 mmol Eq: 0.4) was added to a solution of 2-(4-formyl-1H-indol-1-yl)benzonitrile (810 mg, 3.29 mmol, Eq: 1.00) in EtOH (30 mL) and DCM (15 mL) at 0° C. and the mixture warmed to RT. After 3 h., the mixture was concentrated to remove the DCM. The resulting mixture was diluted with sat. NH4Cl, extracted with DCM and the combined extracts concentrated. The residue was purified by silica gel chromatography to afford the title compound (810 mg, 99%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])#[N:2].[ClH:21]>CO.[Pd]>[ClH:21].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: N#Cc1cccc(C(=O)N2CCCc3ccccc32)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cccc(C(=O)N2CCCc3ccccc32)c1
Yield: 99 %

Procedure:
A solution of 1-(3-cyanobenzoyl)-1,2,3,4-tetrahydroquinoline (7.1 g, 27 mmol) and hydrochloric acid (2.2 ml) in methanol (100 ml) was hydrogenated at atmospheric pressure for 8 h over a catalytic amount of 10% palladium on carbon. The mixture was filtered through Celite® and reduced to yield 1-(3-aminomethylbenzoyl)-1,2,3,4-tetrahydroquinoline hydrochloride (8.1 g, 99%) as a white solid.
Reaction SMILES: Br[C:2]1[CH2:3][CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])(C)(C)C.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.Cl>C(OCC)C.CCCCC>[CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: BrC1=Cc2ccccc2CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: OB(O)C1=Cc2ccccc2CC1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of 3-bromo-1,2-dihydro-naphthalene (7.7 g, 37 mmol) (Adamczyk, M.; Watt, D. S.; Netzel, D. A. J. Org. Chem. 1984, 49, 4226-4237) in diethylether (370 ml) was cooled in a dry ice bath and tert.-butyllithium solution (50 ml of a 1.5 M solution in pentane) was added maintaining T<−65° C. At this temperature stirring was continued for 30 min, then triisopropylborate (17.3 ml, 75 mmol) was added. The reaction mixture was brought to rt and treated with 3N HCl (100 ml). After 15 min the organic phase was dried (Na2SO4), evaporated and precipitated with pentane to provide the title compound (3.83 g, 60%) as a white solid material. MS: m/e=173 (M−H−).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6](=[O:12])[N:5]3[CH:13]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[CH2:14][N:3]1[C:4]=23.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6](=[O:12])[N:5]3[CH:13]([CH2:15][N:16]4[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:20][CH2:21]4)[CH2:14][N:3]1[C:4]=23
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c4c(ccc3=O)CCC(=O)N42)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 57.2 %

Procedure:
A solution of 1,1-dimethylethyl {1-[(4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-1-yl)methyl]-4-piperidinyl}carbamate (194 mg, 0.0.483 mmol) (301 mg, 0.694 mmol) in 1,4-dioxane (5 ml) was treated with DDQ (164 mg, 0.724 mmol) and stirred at 60° C. for 24 h. Further DDQ (164 mg, 0.724 mmol) was added and the reaction was stirred for a further 2 h. The reaction was then treated with 5% aqueous potassium carbonate (100 ml), extracted with 20% methanol/DCM (3×200 ml). The organic extracts were dried (MgSO4) and evaporated to give the product as an orange oil (159 mg, 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH2:10])[C:5]([F:8])=[N:6][CH:7]=1>CO.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][CH3:10])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: C=Cc1cc(N)cnc1F
Agent: [Pd]
Solvent: CO
Product: CCc1cc(N)cnc1F
Reaction time: 48 h
Yield: 99 %

Procedure:
A solution of the 5-amino-2-fluoro-3-vinylpyridine from Step 126c above (2.30 g, 16.6 mmol) in MeOH (50 mL) was added to a suspension of 10% palladium on activated carbon (Aldrich, 0.10 g) in MeOH (75 ml). The mixture was placed under an atmosphere of H2 (balloon) for 48 h. The catalyst was removed by filtration and the solvent was evaporated to yield the title compound as a beige solid (2.31 g, 99%): 1H NMR (CDCl3, 300 MHz) δ 1.22 (t, J=7.5 Hz, 3H), 2.58 (q, J=7.5 Hz, 2H), 6.96 (dd, J=3.0, 5.1 Hz, 1H), 7.45 (m, 1H); MS (CI/NH3) m/z 141 (M+H)+, 158 (M+NH4)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20]>>[CH3:28][O:27][C:23]1[CH:22]=[C:18]([CH:17]=[C:16]([O:15][CH3:14])[C:24]=1[O:25][CH3:26])[C:19]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:12][CH:13]=1)=[O:20]
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc(C=CC(=O)O)cc2)cc(OC)c1OC

Procedure:
4-(3,4,5-Trimethoxybenzoylamino)-cinnamic acid was prepared as described in Example 3 from 5 g (0.0271 mol) of p-aminocinnamic acid hydrochloride and 3,4,5-trimethoxybenzoyl chloride.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([OH:10])=O)(=[O:3])[CH3:2].[CH2:17]([S:22]([NH2:25])(=[O:24])=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21].CCCCCCC=CCCC>CN(C)C=O>[CH2:17]([S:22]([NH:25][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=1)(=[O:24])=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCCCCS(N)(=O)=O
Agent: CCCC=CCCCCCC
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-carbonyldiimidazole (65.09 g) was added all at once to a solution (200 ml) of N,N-dimethylformamide containing 3-acetylamino-4-nitrobenzoic acid (60.22 g), and the reaction mixture was stirred at room temperature for 1 hour. 1-pentanesulfonamide (60.72 g) and 1,8-diazabicycle[5.4.0]undec-7-ene (61.12 g) were added thereto, and the mixture was stirred at 100° C. for 16 hours. The solvent was evaporated at 90° C. under reduced pressure using a vacuum pump. Chloroform and water were added to the resulting residue, and the pH of the aqueous layer was adjusted to 4 with diluted hydrochloric acid with stirring. The organic layer was separated, dried over sodium sulfate, and then concentrated to yield partially purified N-(n-pentanesulfonyl)-3-(acetylamino)-4-nitrobenzamide. The product was used immediately in the next reaction step.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[N:4]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]1=[O:16].C([N-]C(C)C)(C)C.[Li+].[C:25]([C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=[O:30])#[N:26].O>O1CCCC1>[NH:26]=[C:25]1[O:30][CH:29]([C:10]2[S:11][C:5]3[N:4]([CH2:12][CH:13]([CH3:14])[CH3:15])[C:3](=[O:16])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=3[CH:9]=2)[C:28]2[CH:31]=[CH:32][CH:33]=[CH:34][C:27]1=2
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Reactant: N#Cc1ccccc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C3OC(=N)c4ccccc43)sc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (500 mg) in tetrahydrofuran (10 ml) at −78° C. was added lithium diisopropylamide (1M, 3.1 ml). After 5 minutes a solution of o-cyanobenzaldehyde in tetrahydrofuran (2 ml) was added and the reaction was allowed to stir for 2 h. Water (10 ml) was the added and the mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate. The organic layer was separated and dried over magnesium sulfate, then concentrated in vacuo and purified by normal phase HPLC to yield the title compound (15 mg).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:14]2[CH:23]=[CH:24][C:25]([S:27]([N:30]3[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[N:31]3)(=[O:29])=[O:28])=[CH:26][C:13]=2[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C>[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:14]2[CH:23]=[CH:24][C:25]([S:27]([N:30]3[CH:34]=[C:33]([C:35]([OH:1])=[O:36])[CH:32]=[N:31]3)(=[O:29])=[O:28])=[CH:26][C:13]=2[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCOCC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Oxone (596 mg, 0.97 mmol) was added to a solution of 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carbaldehyde (380 mg, 0.88 mmol) (see example 23 for preparation) in DMF (15 mL). The resulting mixture was stirred overnight at room temperature and the solvent was concentrated. The residue was dissolved in DCM, washed with 10% HCl solution and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid Yield: 330 mg (74%); MS (ESI) (M+H)+=447.09.
Reaction SMILES: C12CC(CC1)C[C@@H]2NC1SC(CC2CCN(C(OC(C)(C)C)=O)CC2)(C)C(=O)N=1.[CH:30]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[CH2:32][CH:31]2[NH:37][C:38]1[S:39][CH:40]([CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[C:41](=[O:43])[N:42]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:63][CH2:64][O:65][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67]>>[CH:30]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[CH2:32][CH:31]2[NH:37][C:38]1[S:39][C:40]([CH2:63][CH2:64][O:65][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67])([CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[C:41](=[O:43])[N:42]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC1SC(NC2CC3CCC2C3)=NC1=O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: CC(C)(C)OC(=O)N1CCC(CC2(C)SC(N[C@H]3CC4CCC3C4)=NC2=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)(C)[Si](C)(C)OCCC1(CCO[Si](C)(C)C(C)(C)C)SC(NC2CC3CCC2C3)=NC1=O

Procedure:
The title compound was prepared according to the procedure described in the preparation of tert-butyl 4-((2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)methyl)piperidine-1-carboxylate by using 2-(bicyclo[2.2.1]heptan-2-ylamino)-5-(2-(tert-butyldimethylsilyloxy)ethyl)thiazol-4(5H)-one (630 mg, 1.71 mmol), lithium diisopropylamide (Aldrich, 2.0 M in heptane/THF/ethylbenzene, 4.27 mL, 8.55 mmol), and (2-bromoethoxy)(tert-butyl)dimethylsilane (Aldrich, 2.46 g, 10.25 mmol). The title compound was obtained as a sticky orange solid (771 mg). MS (ESI, pos. ion) m/z: 413 (M-TBDMS+2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3Br)[C:18]2=[O:27])=[CH:12][CH:11]=1.[C:29]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[CH:38]=[CH:37][C:36]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:24]=2[CH2:25][N:17]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[NH2:1])=[O:28])=[CH:11][CH:12]=2)[C:18]3=[O:27])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3c(Br)cccc3C2=O)cc1
Product: CC(C)(C)c1ccc(-c2cccc3c2CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)cc1
Yield: 58 %

Procedure:
The procedure of Example 2 was repeated except for using N-(2-aminophenyl)-4-((4-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 9 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 4-tert-butylphenyl boronic acid instead of phenyl boronic acid, to obtain the title compound (58%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14]([CH:16]1[CH2:20][N:19]([CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:18](=[O:34])[N:17]1[CH3:35])=[O:15].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][NH:13][C:14]([CH:16]1[CH2:20][N:19]([CH:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[C:18](=[O:34])[N:17]1[CH3:35])=[O:15]
Reactant: CN1C(=O)N(C2CCN(C(=O)OC(C)(C)C)CC2)CC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(=O)N(C2CCNCC2)CC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 160 %

Procedure:
A solution of 1,1-dimethylethyl 4-{4-[({[2-chloro-3-(trifluoromethyl)phenyl]methyl}amino)carbonyl]-3-methyl-2-oxo-1-imidazolidinyl}-1-piperidinecarboxylate (218 mg, 0.42 mmol) in 1,4-dioxane (3 ml) was treated with 4M hydrogen chloride in 1,4-dioxane (1 ml) and the reaction was stirred at room temperature for 4 hours. The solvent was evaporated and the gum was dissolved in methanol and the solvent evaporated. The residue was triturated with ether and the solid was collected and dried to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-2-oxo-1-(4-piperidinyl)-4-imidazolidinecarboxamide hydrochloride (153 mg, 80%), LC/MS [M+H]+=419, retention time=1.75 minutes.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:11][N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl>C[N+]([O-])=O>[N:1]1([C:7]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)N2CCOCC2)nc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: O=C(O)c1ccc(C(=O)N2CCOCC2)nc1
Reaction time: 0.33 h
Yield: 68.5 %

Procedure:
Into a solution of the compound of Example 11 (b) (0.606 g, 2.07 mmol) in CH3NO2 (5 mL) was bubbled HCl(g) for 20 min. After standing for 20 min, the solvent was removed in vacuo to give a pale yellow solid. Recrystallization (acetone) gave 0.335 g (68%) of the title compound as a white solid. Mp: 181-183° C. 1H NMR (CD3OD): δ9.26 (d, J=1.1 Hz, 1H), 8.78 (dd, J=8.1 Hz, 1H), 3.80 (s, 4H), 3.67 (m, 2H), 3.51 (m, 2H). IR (KBr): 2928, 2872, 1717, 1601, 1285, 1262, 1111 cm−1. MS (DCI/CH4): m/z (rel intensity) 277 (M +C3H7+), 265 (M+C2H5+), 238, 237 (MH+, 100). Anal. (C11H12N2O4): C, H, N.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:6]([O:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH3:7].[C:17]1([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C(Cl)Cl>ClC(Cl)C>[CH2:6]([O:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13](=[O:15])[C:27]1[CH:28]=[CH:29][C:24]([O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:25][CH:26]=1)[CH3:7]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: O
Product: CCOC(=O)CCCC(=O)c1ccc(Oc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
93 g aluminium chloride are added over 15 minutes at -10° C. to a solution of 52.0 g glutaric acid monoethyl ester chloride [Cl--CO--(CH2)3 --COOC2H5 ]. The mixture is stirred for 15 mins. at 0° to 10° C. and then added portion-wise over a period of 20 mins. at -5° to 10° C. to a pre-prepared solution of 50.0 g diphenylether in 150 ml dichloroethane. The reaction mixture is allowed to rise slowly to room temperature and is then stirred for 12 hours, poured onto ice and shaken well with H2O/methylene chloride. The organic phase is washed thouroughly with H2O and saturated NaHCO3 solution, dried over MgSO4 and the solvent evaporated off. The obtained light yellow oil is crystallised from hexane/ethyl ether on an ice bath: m.p.=61°-62° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:8][C:4]1[CH:3]=[C:2]([NH:1][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CNc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of m-toluidine (10 g), ethyl bromoacetate (10.3 ml), sodium acetate (7.6 g) and water (5 ml in ethanol (50 ml) was stirred at room temperature overnight. The product was filtered off as the hydrobromide salt. Yield 11.6 g.