Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][CH2:28][CH2:29][N:30]([CH2:34][CH2:35][Cl:36])[C:31](Cl)=[O:32]>N1C=CC=CC=1>[Cl:27][CH2:28][CH2:29][N:30]([CH2:34][CH2:35][Cl:36])[C:31]([O:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:26])=[C:19]([CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH:24]=1)=[O:32]
Reactant: Cc1ccc(O)cc1C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: O=C(Cl)N(CCCl)CCCl
Solvent: c1ccncc1
Product: Cc1ccc(OC(=O)N(CCCl)CCCl)cc1C(CNC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Adapting a literature known protocol (U.S. Pat. No. 3,299,104), tert-butyl 3-[5-[bis(2-chloroethyl)carbamoyloxy]-2-methyl-phenyl]-4-(tert-butoxycarbonylamino)butanoate (23e) is prepared through carbamoylation of tert-butyl 4-(tert-butoxycarbonylamino)-3-(5-hydroxy-2-methyl-phenyl)butanoate (23d) (731 mg, 2.0 mmol) with commercial N,N-bis(2-chloroethyl)carbamoyl chloride (439 μL, 614 mg, 3.0 mmol) in anhydrous pyridine (15 mL) at about 0° C. The reaction mixture is stirred with gradual warming to room temperature. The reaction is monitored by TLC and/or LC/MS to completion. Excess of the carbamoyl chloride is destroyed with crushed ice. Aqueous work-up followed by purification through silica gel column chromatography afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:20])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.I[CH2:22][C:23]([CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:22]=[C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:20]=[C:9]2[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])([CH3:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C(=N)Nc1ccc(Br)cc1)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)CI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC1c1cn(-c2ccc(Br)cc2)c(C(C)(C)c2ccccc2Cl)n1
Reaction time: 48 h
Yield: 5.5 %

Procedure:
To a solution of N-(4-bromophenyl)-2-(2-chlorophenyl)-2-methylpropanimidamide (3.51 g, 10 mmol) in 60 mL dioxane was added tert-butyl 2-(2-iodoacetyl)pyrrolidine-1-carboxylate (3.38 g, 10 mmol) and NaHCO3 (2.5 g, 30 mmol). The mixture was heated to reflux with stirring for 2 days. The reaction was monitored by LC/MS. The reaction mixture was cooled and filtered over celite. The crude mixture was initially purified by silica gel column chromatography. The fraction containing the desired product was further purified by prep HPLC, affording 300 mg (5.5%) of tert-butyl 2-(1-(4-bromophenyl)-2-(2-(2-chlorophenyl)propan-2-yl)-1H-imidazol-4-yl)pyrrolidine-1-carboxylate. 1H NMR (CD3OD): δ 1.4 (m, 10H), 1.6 (m, 3H,), 1.8 (m, 1H), 1.9-2.3 (m, 5H), 3.4 (m, 1H), 3.6 (m, 1H) 4.6 (m, 1H), 6.9 (m, 3H), 7.05 (m, 1H), 7.2 (m, 2H), 7.25 (m, 1H), 7.50 (m, 2H); LC/MS M+H 544 (observed).
Reaction SMILES: [CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH2:19])[C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=2[F:18])[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH:19][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:8]2[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=2[F:18])[CH2:3][CH2:2]1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: NC(=NOCC1CC1)c1c(F)cccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)NC(=NOCC2CC2)c2c(F)cccc2C(F)(F)F)cc1

Procedure:
In 200 ml of benzene was dissolved 20.0 g of N'-cyclopropylmethyloxy-2-fluoro-6-trifluoromethylbenzamidine, and to the solution was added 16. 0 g of 4-methoxyphenylacetylchloride. The solution was heated under refluxing for 10 hours. After cooling, ethyl acetate was added to the solution, followed by washing with water and drying over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain 23.6 g of the objective compound.m.p. 75-76° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[SH:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+].O>C(O)C>[CH:12]([C:11]1[C:3]([CH2:2][S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1)([CH3:14])[CH3:13]
Reactant: O=C(O)CS
Reactant: CC(C)c1cc2c(cc1CCl)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1cc2c(cc1CSCC(=O)O)OCO2
Yield: 58.8 %

Procedure:
A suspension of 3.3 g of 5-chloromethyl-6-isopropyl-1,3-benzodioxole (crude oil) in 10 ml of ethanol was added to a liquid mixture comprising 2.1 g of mercaptoacetic acid, 3 g of sodium hydroxide, 25 ml of ethanol and 25 ml of water to carry out the reaction at 80° C. for 40 minutes. The reaction mixture was concentrated, followed by the addition of water. The obtained mixture was washed with ethyl acetate. Concentrated hydrochloric acid was added to the mixture to acidify the aqueous layer, followed by the extraction with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by column chromatography to obtain 2.45 g of the title compound as a colorless prismatic crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:21][CH3:22])=[C:13]([O:16]C(OC)=O)[CH:14]=2)[C@H:9]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:8][C@@H:7]1[CH3:43])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:21][CH3:22])=[C:13]([OH:16])[CH:14]=2)[C@H:9]([N:23]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:41])([F:40])[F:42])[CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH2:8][C@@H:7]1[CH3:43])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC(=O)OC)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1c2cc(O)c(OC)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 12 h
Yield: 50.3 %

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-7-methoxycarbonyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (5.0 g, 8.0 mmol) and potassium carbonate (2.2 g, 16 mmol) in methanol (45 mL) was stirred at room temperature. After 12 hours, water (100 mL) was added, and the volatiles were removed in vacuo. The mixture was then extracted with ethyl acetate (3×100 mL), the combined organic extracts were washed with saturated sodium bicarbonate solution (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give 4.67 g of crude product. Purification by silica gel chromatography using 0-25% ethyl acetate/hexanes as eluent afforded 2.27 g of the title compound (50%). MS m/z 566 (M+ +2), 583 (M+ +19); 1H NMR (CDCl3) δ 7.07 (C8, s, 1H), 6.36 (C5, s, 1H).
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]=3[CH:22]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>N1C=CC=CC=1>[Br:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:9]([CH2:8][CH2:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[O:19])[O:17][C:16]([CH3:20])([CH3:21])[O:15][C:14]=3[CH:22]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC1(C)OC(=O)c2ccc(NCCCC3CCCC3)cc2O1
Solvent: c1ccncc1
Product: CC1(C)OC(=O)c2ccc(N(CCCC3CCCC3)C(=O)c3ccc(Br)cc3)cc2O1
Temperature: 60 °C
Reaction time: 7 h
Yield: 58.7 %

Procedure:
To a cold (0° C.) solution of 7-[(3-cyclopentylpropyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (1.70 g, 5.60 mmol) in pyridine (10 mL) was added 4-bromobenzoyl-chloride (Aldrich, 1.47 g, 6.72 mmol) and the resulting reaction mixture was stirred 10 min at 0° C., 30 min at rt and 7 hrs at 60° C. The solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (15/85)) gave 1.6 g (59%) of the title compound as a white solid. HPLC, Rt: 5.2 min (purity: 99.5%). 1H NMR (CDCl3) δ: 7.81 (d, J=7.3 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.18 (d, J=8.7 Hz, 2H), 6.76 (dd, J=1.9 Hz, J=8.3 Hz, 1H), 6.56 (d, J=1.9 Hz, 1H), 3.91 (t, J=7.9 Hz, 2H), 1.80-1.25 (m, 17H), 1.12-0.95 (m, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]2[NH:23][C:24](=[O:26])[CH2:25][N:17]2[CH2:16]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]2[N:23]([CH2:30][CH2:31][CH2:32][CH3:33])[C:24](=[O:26])[CH2:25][N:17]2[CH2:16]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CN2Cc3cc(OCCCCCCn4ccnc4)ccc3N=C2N1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)CN2Cc3cc(OCCCCCCn4ccnc4)ccc3N=C21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-(6-(N-imidazolyl)hexyl)oxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one in dry dimethylformamide is added sodium hydride (1.05 equivalents). The mixture is stirred at 60° C. for 30 minutes to give a homogeneous solution. 1-bromobutane (1.1 equivalents) is added via a syringe after which the mixture is stirred at 60° C. for 2 hours. The solvent is evaporated and the residue taken up in ethyl acetate which is washed with saturated brine, dried and filtered. Evaporation of the solvent affords 7-(6-(N-imidazolyl)hexyl)oxy-1-butyl-1,2,3,5-tetrahydroimidazo[2,1-b]-quinazolin-2-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CCCCO>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([NH:30][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=2)[CH3:29])=[CH:24][CH:23]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Reactant: C[C@H](N)c1ccc(F)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 165 °C
Yield: 97.6 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method 28, 0.33 g, 1.1 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.16 g, 1.2 mmol) and DIEA (0.21 ml, 1.2 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 165° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.43 g, 97%). 1H NMR (400 MHz) δ 12.09, 12.05 & 11.64 (s, 1H), 10.94, 10.87 & 10.72 (s, 1H), 8.98, 8.76 & 8.70 (d, J=7.6 Hz, 1H), 8.16 & 8.11 (d, J=9.6 Hz, 1H), 7.40-7.33 (m, 2H), 7.22-7.10 (m, 2H), 6.25 & 6.04 (d, J=9.6 Hz, 1H), 6.23 & 5.86 (d, J=13.6 Hz, 1H), 5.31, 5.21 & 4.89 (m, 1H), 4.71, 4.59 & 4.27 (m, 1H), 1.52 (m, 3H), 1.26 (m, 6H). MS: Calcd.: 400. Found: [M+H]+ 401.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].CO[CH:9](OC)[CH2:10][NH2:11]>C1COCC1>[Cl:1][C:2]([Cl:6])([Cl:5])[C:3]1[NH:11][CH:10]=[CH:9][N:4]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: COC(CN)OC
Solvent: C1CCOC1
Product: ClC(Cl)(Cl)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of trichloroacetonitrile (28.8 g, 200 mmol, 1 eq) in anhydrous THF (70 mL) at −60° C. under an argon atmosphere, 2,2-dimethoxyethanamine (C-1) (21.8 mL, 200 mmol, 1.0 eq) is added dropwise over 5 min. The resulting mixture is allowed to warm to RT and stirred at RT for 4 h. The mixture is concentrated in vacuo and the residue is added in portions to a stirred solution of trifluoroacetic acid (100 mL) at −30° C. under argon. The resulting mixture is then stirred from −30° C. to RT overnight. The reaction mixture is concentrated in vacuo to afford the product, 2-(trichloromethyl)-1H-imidazole (C-2). The product is used in the next step without further purification.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH2:22]([CH2:24][NH2:25])[OH:23]>>[OH:23][CH2:22][CH2:24][NH:25][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: NCCO
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)[nH]n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NCCO)[nH]n1
Yield: 91 %

Procedure:
As described for example 27, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (110 mg, 0.38 mmol) was converted, using ethanolamine instead of L-alaninol, to the title compound (110 mg, 91%) which was obtained as a colorless oil. MS: m/e=323.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[CH2:6][C:7]([OH:9])=[O:8].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(O)C[C@@H]1C[C@H]1CO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1C[C@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of trans-2-(2-(hydroxymethyl)cyclopropyl)acetic acid (50 mg, 0.38 mmol), benzyl bromide (0.050 mL, 0.42 mmol), potassium carbonate (58.4 mg, 0.42 mmol) and DMF (2 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→80% ethyl acetate/hexane) to give benzyl trans-2-(2-(hydroxymethyl)cyclopropyl)acetate (44.0 mg, 0.200 mmol, 52%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10](F)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[F:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O.C(O)(=O)C>C1(C)C=CC=CC=1>[F:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH:17]=[N:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Reactant: COc1ccc(C=O)c(F)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(C=Nc2cccc3[nH]c(=O)ccc23)c(F)c1

Procedure:
To 600 mg (3.9 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 624 mg (3.9 mmol) 2-fluoro-4-methoxybenzaldehyde in 12 ml toluene are added 18 μl acetic acid and 2 g molecular sieve. The mixture is heated over 25 hours under reflux and filtrated through a path of cellites after cooling. The solvent is evaporated and the residue is two times azeotrophed with small portions of toluene to obtain 5-{[1-(2-fluoro-4-methoxyphenyl)-methylidene]amino}-1H-quinolin-2-one are quantitatively. 0.81 ml (11.6 mmol) 1,1,1-trifluoroepoxypropane in 12 ml THF and 3.5 ml hexane are cooled to −100° C. and 3.75 ml of a 2.5 M n-butyl lithium solution (9.4 mmol) in hexane are added over 10 minutes while the temperature does not exceed −95° C. 10 Minutes after complete addition 1.11 g (12 mmol) 5-{[1-(2-fluoro-4-methoxyphenyl)-methylidene]amino}-1H-quinolin-2-one in 10 ml THF are added over 15 minutes while the temperature does not exceed −95° C. After tree hours at −100° C. 3.75 ml diethyl ether are added and the reaction mixture is warmed to −10° C. over one hour. The reaction is quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer is extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated. Flash chromatography on silica gel (acetone in hexane 0 to 80%) yields 410 mg of 5-{[(2-Fluoro-4-methoxyphenyl)(2-trifluoromethyl-oxiranyl)methyl]amino}-1H-quinolin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CO[C:61](=O)[NH:62]C(C(N1CCCC1C1NC(C2C=CC3C(=CC=C(B4OC(C)(C)C(C)(C)O4)C=3)C=2)=CN=1)=O)C(C)C>>[CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:61]#[N:62])[CH2:44][N:43]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for [2-methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester. 1H-NMR: 400 MHz, (DMSO-d6) δ 11.98 (s, 1H), 11.82 (s, 1H), 8.22 (m, 2H), 7.92-7.77 (m, 6H), 7.62 (m, 2H), 7.44 (d, J=7.6 Hz, 1H), 7.31 (d, J=8.0, 1H), 5.24 (t, J=5.2 Hz, 1H), 5.12 (d, J=4.0, 1H), 4.22-4.19 (m, 1H), 4.09-4.0 (m, 4H), 3.89-3.83 (m, 4H), 3.56 (d, J=5.6 Hz, 6H), 2.17 (brs, 2H), 2.06-1.90 (m, 4H), 0.95-0.84 (m, 14H); MS (ESI) m/z 814 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10].Cl[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)c1cc(O)ccc1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Yield: 86.8 %

Procedure:
A solution of 4-bromo-3-isopropyl-phenol (Intermediate 144, 1.13 g, 5.25 mmols), chloro-tert-butyl-dimethylsilane (0.95 g, 6.30 mmols), and imidazole (428.0 mg, 6.3 mmols) in 10 mL DMF was stirred at 25° C. for 3 hours. The solution was diluted with H2O and extracted with Et2O and the combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (MgSO4) before being concentrated under reduced pressure. Column chromatography (1-2% EtOAc-hexanes) afforded 1.50 g (87%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17](=[O:24])[NH:18][C@@H:19]([CH2:22][SH:23])[CH2:20][OH:21])([CH3:15])([CH3:14])[CH3:13]>CCO>[C:12]([O:16][C:17](=[O:24])[NH:18][C@@H:19]([CH2:22][S:23][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10])[CH2:20][OH:21])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CS
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)CSc1cc[nH]c(=O)c1[N+](=O)[O-]
Yield: 69.2 %

Procedure:
A solution of 4-chloro-3-nitropyridin-2(1H)-one (1.61 g, 9.2 mmol) (or any other suitable activated aromatic compound) and TEA (2 ml, 14.4 mmol) in etanol (15 mL) stirred at 0° C., was treated with a solution of tert-butyl[(2R)-1-hydroxy-3-sulfanylpropan-2-yl]carbamate (42, 2.073 g, 10 mmol) in ethanol (10 mL+5 ml rinse) added from syringe. The final mixture was stirred at room temperature for 22 h (became a thick yellow suspension). Filtered, the cake washed with pentane and dried under vacuum, to afford the title compound (2.20 g, 69% yield) as a yellow solid, MS: m/z=368.1 (MNa+).
Reaction SMILES: [OH-].C[N+](C)(C)CC1C=CC=CC=1.[CH2:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]([N:22]2[CH2:27][C:26]3([CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][OH:43])=[CH:37][CH:36]=4)[CH2:29][CH2:28]3)[O:25][CH2:24][CH2:23]2)=[O:21])[N:19]=1)[CH3:14].[C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:47])[CH:45]=[CH2:46]>C(#N)C>[CH2:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]([N:22]2[CH2:27][C:26]3([CH2:32][CH2:31][N:30]([CH2:33][CH2:34][C:35]4[CH:36]=[CH:37][C:38]([CH2:41][CH2:42][O:43][CH2:46][CH2:45][C:44]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:39][CH:40]=4)[CH2:29][CH2:28]3)[O:25][CH2:24][CH2:23]2)=[O:21])[N:19]=1)[CH3:14]
Reactant: CCc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO)cc4)CC3)C2)cs1
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC#N
Product: CCc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCOCCC(=O)OC(C)(C)C)cc4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N,N-Trimethyl-1-phenylmethanaminium hydroxide (40% in water, 0.51 mL) was added to a solution of (2-ethylthiazol-4-yl)(9-(4-(2-hydroxyethyl)phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone [Example 3, step c] (1.9 g) and tert-butyl acrylate (1.32 mL) in acetonitrile (1.5 mL) and the mixture stirred at ambient temperature for 4 hours. The mixture was concentrated in vacuo and the crude product purified by flash silica chromatography, elution gradient 50 to 75% ethyl acetate in isohexane with 5% triethylamine. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a colourless oil. Yield 2.19 g.