Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+:4].[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)[CH3:6].C(O)(=O)C>[Ir].CO>[CH3:6][CH:5]([NH2:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [NH4+]
Reactant: CC(=O)c1ccccc1
Agent: [Ir]
Agent: O=C[O-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)c1ccccc1
Temperature: 60 °C

Procedure:
946 mg (15.0 mmol) of ammonium formate (MW: 63.06) was introduced in a 20-mL Schlenk tube and subjected to argon-gas replacement. To this, 5 mL of dehydrated methanol, 582 μL (5.0 mmol) of acetophenone (MW: 120.15), 582 μL (5.0 mmol) of acetic acid, and 12.1 mg (0.025 mmol, S/C=200) of the iridium catalyst Ir-1 (MW: 484.01) were added, and the mixture was stirred while heating at 60° C. for 5 hr. After distillation of the solvent, a saturated sodium hydrogen carbonate solution was added, then a product was extracted with methylene chloride, the organic layer was washed with water, and the product was dried with sodium sulfate. The drying agent was removed by filtration and the methylene chloride was distilled away to give a crude product DL-1-phenylethylamine. Its conversion rate was 100% based on NMR measurement, with 92.8% of DL-1-phenylethylamine, 0.4% of 1-phenylethanol, and 6.8% of other by-products.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:5][CH:4]=1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=4[N:18]([CH3:27])[S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])=[N:5][CH:4]=2)[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CCl)s3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2cnc(-c3cc4c(C)ccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.15 g) and N-acetylpiperazine (90 mg) in N,N-dimethylformamide (10 ml) was added potassium carbonate (120 mg) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-7:3), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (95 mg, yield 52%) as colorless crystals. melting point 171-172° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-])=O.BrC1C2C(Cl)=NC=NC=2N(C2CCCC2)C=1.[NH2:29][C:30]1[C:31]2[C:38](C(C3C=CC=C(N)C=3)=O)=[CH:37][N:36]([CH:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)[C:32]=2[N:33]=[CH:34][N:35]=1>>[NH2:29][C:30]1[C:31]2[C:38]([C:8]([C:7]3[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=3)=[O:9])=[CH:37][N:36]([CH:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)[C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Agent: Clc1ncnc2c1c(Br)cn2C1CCCC1
Product: Nc1ccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)cc1

Procedure:
The title compound was prepared from 4-Nitrobenzoyl chloride and 5-Bromo-4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine by procedures analogous to those described for the preparation of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone. MS: 322.3 (MH+); HPLC Rf: 4.45 min. (HPLC method 4).
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>CN(C=O)C.CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: C#CC[C@@H](C)O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-pent-4-yn-2-ol (68 mg, 0.82 mmol) (see Example 78 below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (31 mg, 0.03 mmol) and Cul (6 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was concentrated and the residue was chromatographed on a silica gel column with neat CH3CN then THF and finally MeOH as elution solvent. The resulting (R)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was triturated with Et2O and then recrystalized from superheated EtOH. (Yield 18 mg, 20%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[N+:6]([CH:9]([CH3:11])[CH3:10])([O-:8])=[O:7].[CH2:12]=O>C(O)(C)C>[N+:6]([C:9]([CH3:12])([CH3:11])[CH2:10][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])([O-:8])=[O:7]
Reactant: CC(O)CN
Reactant: C=O
Reactant: CC(C)[N+](=O)[O-]
Solvent: CC(C)O
Product: CC(O)CNCC(C)(C)[N+](=O)[O-]

Procedure:
Following the procedure described below in EXAMPLE 4A, step 1, 526.3 g (6.66 mol) of 1-amino-2-propanol (95%) are reacted with 561.6 g (6.05 mol) of 2-nitropropane (96%) and 181.7 g (6.05 mol) of paraformaldehyde in 100 ml of isopropanol to give the product which is used in the following reaction without any isolation.
Reaction SMILES: CCN(CC)CC.[NH2:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:14][CH2:13]1)=[O:11].[C:30]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl.O>[O:11]=[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:26])[F:27])[CH2:16][CH2:17]1)[CH2:9][NH:8][S:36]([C:33]1[CH:32]=[CH:31][C:30]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:35][CH:34]=1)(=[O:38])=[O:37]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNS(=O)(=O)c1ccc(-c2ccccc2)cc1)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 32.7 %

Procedure:
Et3N (42 mg, 0.42 mmol) was added to a stirred solution of 2-amino-1[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone (80 mg, 0.19 mmol) in DCM (4 mL) at 0-5° C. 4-biphenylsulfonyl chloride (47 mg, 0.19 mmol) was then added and the mixture was stirred at 0-5° C. for 4 hrs. The reaction was then diluted with cold water and the product was extracted with DCM, washed with 5% NaHCO3, 5% HCl, then saturated brine solution. The DCM layer was dried over sodium sulphate and concentrated. The residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in hexane as eluent) to afford 33 mg (33.4% yield) of biphenyl-4-sulfonicacid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LC-MS purity: 90.35%. 1H-NMR (CDCl3) δ 7.9 (m, 2H), 7.7 (d, 3H,), 7.6-7.5 (m 4H), 7.5-7.4 (m, 3H), 7.3 (m, 1H), 5.6 (s, 1H), 4.0-3.7 (m, 5H), 3.7-3.5 (m, 3H), 3.4-3.3 (m, 2H), 3.25-3.1 (m, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N+:9]([O-:24])[CH:10]=1
Reactant: COCOc1ccc(CC(C)(C)C)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCOc1ccc(CC(C)(C)C)[n+]([O-])c1
Reaction time: 4 h
Yield: 99.6 %

Procedure:
5-(Methoxymethoxy)-2-neopentylpyridine (11.0 g, 52.6 mmol) was dissolved in CH2Cl2 (200 mL) to which mCPBA (18.1 g, 105 mmol) was added, and the mixture was stirred under N2 for about 4 h. The mixture was quenched with 1M NaOH (200 mL) and stirring was continued vigorously for 10 min. The mixture was extracted with CH2Cl2 (2×200 mL), the combined organic layers were washed with saturated NaCl, dried (Na2SO4), and evaporated to give 5-(methoxymethoxy)-2-neopentylpyridine-N-oxide (11.8 g, 99.7% yield) as a brown oil which was used without purification in the next step.
Reaction SMILES: [CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[N:5]1)([CH3:3])[CH3:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH:1]([C:4]1([CH3:22])[N:5]2[C:12](=[O:13])[C:11]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[C:10]=3[C:6]2=[N:7][C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)C1(C)N=C(c2c(C(=O)O)ccc3c2OCO3)NC1=O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)C1(C)C(=O)N=C2c3c(ccc4c3OCO4)C(=O)N21
Reaction time: 8 h

Procedure:
A mixture of 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3,4-(methylenedioxy) benzoic acid (4.11 g, 13.5 mmol) and acetic anhydride (100 mL, 1.06 mol) is stirred overnight at reflux temperature and concentrated in vacuo to give a residue which is chased twice with toluene to give a pale yellow solid. Recrystallization from ethyl acetate affords the title product as a pale yellow solid, 2.77 g (69.9%), mp 158°-160° C., identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C(NC(C)C)(C)C.C1C(=O)N([Br:27])C(=O)C1.Cl>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:27])[C:6]=1[OH:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccccc1O
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cccc(Br)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl(2-hydroxyphenyl)acetate (14.0 g, 84.3 mmol) in 100 mL of DCM was added diisopropyl-amine (1.70 g, 16.8 mmol) and NBS (15 g, 84.2 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was poured into 1N HCl, extracted with DCM, and concentrated to give crude methyl(3-bromo-2-hydroxyphenyl)acetate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([I:1])[CH:3]=1)=[O:22]
Reactant: Cc1ccc(N)cc1I
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Iodo-4-methylaniline (2.42 g, 10.4 mmol) was dissolved in DCM (20.00 mL) and triethylamine (TEA) (1.70 mL, 12.2 mmol) was added and the resulting mixture was cooled to 0° C. To the mixture was added dropwise 3-fluoro-5-(trifluoromethyl)benzoyl chloride (1.60 mL, 10.5 mmol) and the resulting mixture was stirred at 0° C. for 45 minutes and at 25° C. for 16 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water sat. Na2CO3, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The reaction product was used in the next reaction without purification. 1H NMR (CDCl3): 8.98 (d, 1H), 7.78 (s, 1H), 7.72 (m, 2H), 7.55 (m, 2H), 7.23 (d, 1H), 2.42 (s, 3H). MS (EI) m/z=424 (M+H).
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]=[C:22](Br)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([CH3:36])[CH:35]=1>>[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]=[C:22]([C:32]4[CH:33]=[C:34]([CH3:36])[CH:35]=[C:30]([CH3:29])[CH:31]=4)[CH:23]=3)[C:18]2=[O:27])=[CH:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(CN2Cc3cc(Br)ccc3C2=O)cc1
Reactant: Cc1cc(C)cc(B(O)O)c1
Product: Cc1cc(C)cc(-c2ccc3c(c2)CN(Cc2ccc(C(=O)Nc4ccccc4N)cc2)C3=O)c1
Reaction time: 0.33 h
Yield: 46 %

Procedure:
The procedure of Example 2 was repeated except that N-(2-aminophenyl)-4-((5-bromo-1-oxoisoindolin-2-yl)methyl)benzamide obtained in Example 56 instead of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide, and 3,5-dimethylphenyl boronic acid instead of phenyl boronic acid were used, and the reaction was performed for 20 mins, to obtain the title compound (46%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:61]=[CH:60][C:15]2[NH:16][C:17]([CH2:19][CH2:20][CH:21]3[CH2:24][CH:23]([N:25]([CH2:28][C@@H:29]4[C@H:33]5[O:34]C(C)(C)[O:36][C@H:32]5[C@H:31]([N:39]5[C:43]6[N:44]=[CH:45][N:46]=[C:47]([NH:48]CC7C=CC(OC)=CC=7OC)[C:42]=6[CH:41]=[CH:40]5)[CH2:30]4)[CH2:26][CH3:27])[CH2:22]3)=[N:18][C:14]=2[CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:48][C:47]1[C:42]2[CH:41]=[CH:40][N:39]([C@@H:31]3[CH2:30][C@H:29]([CH2:28][N:25]([CH:23]4[CH2:22][CH:21]([CH2:20][CH2:19][C:17]5[NH:16][C:15]6[CH:60]=[CH:61][C:12]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:13][C:14]=6[N:18]=5)[CH2:24]4)[CH2:26][CH3:27])[C@@H:33]([OH:34])[C@H:32]3[OH:36])[C:43]=2[N:44]=[CH:45][N:46]=1
Reactant: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
Trifluoroacetic Acid (20 mL) was added to a mixture of Water (2 mL) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(ethyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.85 g, 1.2 mmol) at RT. The reaction was allowed to proceed for one hour at which time Triethylsilane (0.37 mL, 2.3 mmol) was added. The volatiles were removed in vacuo and resulting residue was taken up in MeOH (3 mls), 1 ml of K2CO3 (saturated) was added and reaction stirred at RT for 1 hour. The mixture was partitioned between H2O and DCM/MeOH (9:1). The aqueous layer was extracted (3×) and the combined organics dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to yield the desired product (0.150 g) as an off white foam. MS (ESL+) for C31H43N7O2 m/z 546.3 [M+H]+; MS (ESI−) for C31H43N7O2 m/z 544.3 [M−H]−; HPLC purity >91% (ret. time, 2.734 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.081 (s, 1H), 7.493 (s, 1H), 7.414-7.393 (m, 1H), 7.291-7.266 (m, 1H), 7.215-7.202 (m, 1H), 6.619-6.609 (d, J=4.0 Hz, 1H), 4.345-4.312 (m, 1H), 3.923-3.885 (m, 1H), 2.994-2.915 (m, 0.5; H (methine of trans isomer)), 2.860-2.793 (m, 2H), 2.701-2.578 (m, 3H), 2.501-2.380 (m, 2H), 2.259-2.234 (m, 2H), 2.109-2.008 (m, 3H), 1.920-1.880 (m, 3H), 1.658-1.499 (m, 2H), 1.364 (s, 9H), 1.036-0.991 (m, 3H). Retention time: 2.734 minutes. HPLC Conditions: Agilent Zorbax Exlipse XDB-C18 column, 4.6×50 mm (1.8 um packing), Solvent A—Water (0.1% TFA), Solvent B—Acetonitrile (0.07% TFA). 6 min gradient from 5 to 95% B; 1 min hold; then recycle
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][O:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:43]3[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][O:37][CH3:36])[CH2:41][CH2:42]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCOC)CC1
Product: Cl

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methoxy-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 1-(2-methoxy-ethyl)-piperazine in an analogous manner as described in example 25. LR-MS: 637.4 [(M+H)+]
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].CO[CH2:15][N:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([N:16]1[CH2:15][CH2:3][CH:2]([C:1]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
A solution of 10.0 g (61.6 mmol) of benzyl acrylate and 19 mL (74.2 mmol) of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in 75 mL of CH2Cl2 at 0° C. was treated with 0.5 mL (6.5 mmol) of TFA while maintaining the internal temperature at less than 3° C. The reaction was warmed to rt and stirred for 2.5 h. The reaction mixture was washed with 250 mL of 1N NaHCO3 and 250 mL of sat'd NaCl. The organic layer was dried over Na2SO4 and concentrated. The residue was purified on a 40L Biotage column using 19:1 v/v hexane/acetone as the eluant to afford 18 g (99%) of the title compound as a light yellow oil: RF: 0.28 (9:1 v/v hexane/acetone); 1H-NMR (500 MHz) δ 2.15-2.20 (m, 2H), 2.60 (m, 1H), 2.73-2.77 (m, 2H), 3.02 (m, 1H), 3.13 (m, 1H), 3.66-3.73 (m, 2H), 5.17 (s, 2H), 7.28-7.42 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][Si:19]([CH2:22][CH2:23][O:24][CH2:25]Cl)([CH3:21])[CH3:20]>CN(C=O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:25][O:24][CH2:23][CH2:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]c2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.5 %

Procedure:
To a solution of 6-hydroxybenzo[d]oxazol-2(3H)-one (3 g, 19.85 mmol) in dry DMF (30 mL), K2CO3 (5.54 g, 40.1 mmol) and SEM-Cl (4.79 mL, 27.0 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. Solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by flash chromatography on silica gel using 10 to 50% ethyl acetate in hexane to give 6-hydroxy-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one as an white solid (1.2 g, 21%). 1HNMR 400 MHz, DMSO-d6: δ ppm −0.055 (s, 9H), 0.86 (t, J=8.00 Hz, 2H), 3.58 (t, J=8.00 Hz, 2H), 5.19 (s, 2H), 6.64 (dd, J=2.40, 8.40 Hz, 1H), 6.78 (d, J=2.00 Hz, 1H), 7.10 (d, J=8.40 Hz, 1H), 9.52 (s, 1H). LCMS: R.T. 1.845 min; 280.1 [M−H].
Reaction SMILES: O1CC1C[CH:4]([O:13][CH:14]([CH2:23][CH:24]1OC1)C1C=CC(OC)=CC=1)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.[O:33]1CCCC1>>[OH:33][CH:23]([CH2:14][O:13][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH2:24][N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: c1c[nH]cn1
Reactant: C1CCOC1
Reactant: COc1ccc(C(CC2CO2)OC(CC2CO2)c2ccc(OC)cc2)cc1
Product: COc1ccc(COCC(O)Cn2ccnc2)cc1

Procedure:
2,3-Epoxypropyl-4-methoxybenzyl ether (100 g, 0.725M) in dry tetrahydrofuran (200 ml) was treated with imidazole (44.4 g, 0.765M) and heated under reflux for 16 hours. The solution was filtered and the solvent was evaporated off under reduced pressure to give a brown solid which was recrystallised from 10% water-propan-1-ol to give 1-[2-Hydroxy-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (83 g) as a colourless crystalline solid, m.p. 96°-98° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1.O>CN(C=O)C>[O:1]([C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCC[C@H](O)CC(=O)OC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCC[C@@H](CC(=O)OC)O[Si](C)(C)C(C)(C)C
Reaction time: 17 h

Procedure:
12.9 g of methyl (S)-3-hydroxytetradecanoate are dissolved in 50 ml of DMF under argon 9.0 g of t-butyldimethylchlorosilane are added thereto, 8.5 g of imidazole are then added portionwise and the mixture is left to stir for 17 hours. The reaction mixture is poured into 300 ml of water and extracted three times with 50 ml of diethyl ether. The combined organic phases are dried, filtered and evaporated. By distillation at 140°-145° C./0.07 mm there is obtained methyl (S)-3-(t-butyldimethylsiloxy)tetradecanoate as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-chloro-2-oxindole (167 mg), 3-methylindole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 5-chloro-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH:8]1([CH2:11][C@H:12]([NH:18]C(=O)OC(C)(C)C)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH2:10][CH2:9]1>C(O)C>[ClH:1].[NH2:18][C@@H:12]([CH2:11][CH:8]1[CH2:10][CH2:9]1)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: CN(C)C(=O)[C@H](CC1CC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)C(=O)[C@@H](N)CC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A 4M solution of HCl in dioxane (4.68 mL, 18.7 mmol) was added to a solution of (S)-tert-butyl 3-cyclopropyl-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (1.2 g, 4.68 mmol) in ethanol (10 mL). After 16 h stirring at ambient temperature the solvent was removed under reduced pressure. The remaining solid was digerated with diethyl ether (10 mL), filtered off, washed with diethyl ether (3×5 mL) and dried for 3 h in vacuo at 40° C. to give the title compound as off-white solid (820 mg, 91%). MS (EI): m/e=157.1 [M+H]+.