Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21](F)=C[CH:19]=2)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=1)=[O:11].[N:26]1C=CC=C(B(O)O)C=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:19]=[N:26][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=1)=[O:11]
Reactant: OB(O)c1cccnc1
Reactant: Cc1ccc(-c2ccc(F)cc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-(4-fluorophenyl)-6-methylpyridin-2-yl)methanone in Example A73 using pyridin-3-ylboronic acid. ESI-MS (m/z): 325 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])=[CH:4][C:3]=1[OH:14].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[Si:24]([O:14][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:2]=1[F:1])[C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: CON(C)C(=O)c1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 48 h
Yield: 66.8 %

Procedure:
To a solution of 4-fluoro-3-hydroxy-N-methoxy-N-methylbenzamide (1.90 g, 9.55 mmol) in DMF (8 mL) was added imidazole (740 mg, 10.8 mmol) and TBDMSCl (1.62 g, 10.8 mmol) at room temperature. The reaction mixture was stirred for 48 h and quenched with saturated NaHCO3. The solution was extracted with ether (3×) and the combined ether portions washed with LiCl (10%), dried over Na2SO4, filtered and concentrated. The resulted colorless oil was purified by ISCO chromatography (120 g column) using hexanes/EtOAc (0-100% over 30 min) to give 3-(tert-butyldimethylsilyloxy)-4-fluoro-N-methoxy-N-methylbenzamide (RT=10-12 minutes) as a colorless oil (2.00 g, 67% yield). LCMS: RT=2.06 min [M+H] 314.22 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.26 ppm, 2H, m; 7.02 ppm, 1H, m; 3.50 ppm, 3H, s; 3.31 ppm, 3H, s; 0.97 ppm, 9H, s, 0.16 ppm, 6H, s.
Reaction SMILES: CO[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(N[C:36]2[CH:37]=C(CS(N)(=O)=O)C=C[CH:41]=2)N=1.C1(C2CCN2)C=CC=CC=1>>[C:9]1([CH:4]2[CH2:3][CH2:6][N:5]2[C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[N:11]=2)[CH:37]=[CH:36][CH:41]=[CH:7][CH:8]=1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Agent: c1ccc(C2CCN2)cc1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC3c3ccccc3)n2)c1

Procedure:
B37 was prepared following the general procedure reported for B4 using A1 and rac-2-phenylazetidine and obtained as white crystals; yield: 120 mg (34%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 2.05-2.20 (m, 1H), 2.69-2.90 (m, 1H), 3.88-4.29 (m, 4H), 5.42 (bs, 1H), 6.72-7.08 (m, 3H), 7.20-7.55 (m, 6H), 7.58-7.72 and 7.82-8.00 (2 m, 1H), 8.11 and 8.25 (2bs, 1H), 9.65 and 9.78 (2bs, 1H). MS (ES) C19H20N6O2S requires: 396. found: 397 (M+H)+.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=O.[C:17]([NH:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH3:18]>C(O)(=O)C>[C:13]1([CH3:16])[CH:12]=[CH:11][C:10]([C:8]2[N:23]([CH2:22][CH2:21][NH:20][C:17](=[O:19])[CH3:18])[CH:2]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)CCC2OCCO2)cc1
Reactant: CC(=O)NCCN
Solvent: CC(=O)O
Product: CC(=O)NCCn1cccc1-c1ccc(C)cc1
Yield: 69.5 %

Procedure:
3-(1,3-Dioxolan-2yl)-4'-methylpropiophenone (10.2 g) was dissolved in 20 ml of acetic acid and added under argon and while stirring to a solution of 9.4 g of N-acetylethylenediamine in 100 ml of acetic acid. The reaction mixture was heated to reflux overnight, the acetic acid was subsequently removed in a vacuum. The residue was taken up in 200 ml of methylene chloride and washed with a mixture of 100 ml of saturated sodium hydrogen carbonate solution and 150 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted twice with 100 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 14.0 g of dark brown oil were chromatographed on 550 g of silica gel with ethyl acetate/hexane (2:1) as the eluent. 7.8 g (70%) of N-[2-(2-p-tolylpyrrol-1-yl)ethyl]acetamide were isolated as a brown oil. MS: m/e=242 (M+).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:31])[NH:12][C:13]1[N:18]=[C:17]2[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:20](=[O:22])[NH:21][C:16]2=[CH:15][CH:14]=1)[CH3:10])C)(C)(C)C.Cl>C1COCC1.CCOC(C)=O>[ClH:30].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:19]2[C:17]3=[N:18][C:13]([NH:12][C:11](=[O:31])[CH:9]([NH:7][CH3:6])[CH3:10])=[CH:14][CH:15]=[C:16]3[NH:21][C:20]2=[O:22])=[CH:29][CH:28]=1
Reactant: CC(C(=O)Nc1ccc2[nH]c(=O)n(Cc3ccc(Cl)cc3)c2n1)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(C)C(=O)Nc1ccc2[nH]c(=O)n(Cc3ccc(Cl)cc3)c2n1
Reaction time: 2 h

Procedure:
The product from Step 4 was dissolved in THF (2 mL) and then added to a solution of saturated HCl in EtOAc. After 2 hours, the resulting precipitate was collected by filtration and washed with EtOAc to give the title compound as a white solid (30 mg). 1H NMR (400 MHz, DMSO-d6): 11.31-11.23 (1H, m), 10.87 (1H, s), 9.37 (1H, br), 8.99 (1H, br), 7.78 (1H, d), 7.47-7.35 (3H, m), 7.31 (2H, d), 5.00 (2H, s), 4.08-3.95 (1H, m), 2.57-2.53 (3H, m), 1.47 (3H, d). MS: [M+H]+ 360.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[NH:8][CH:7]=[CH:6]2.[N+:16]([O-])([OH:18])=[O:17].OS(O)(=O)=O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:16]([O-:18])=[O:17])[C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: O=[N+]([O-])O
Reactant: COc1cc2cc[nH]c(=O)c2cc1OC
Agent: O=S(=O)(O)O
Product: COc1cc2ccncc2c([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,7-Dimethoxy-isoquinolinone (2.88 g) in sulphuric acid (20 ml) at 5-10° C. was added 2 M HNO3—H2SO4-solution (8 ml) and the reaction mixture stirred overnight at ambient temperature. The reaction mixture was poured into ice water, pH adjusted to 12 and the product extracted in methylene chloride. The methylene chloride phase was extracted with 1 M HCl , the pH of the aqueous phase adjusted to 12 and extracted into methylene chloride, dried and evaporated. Yield: 2.5 g.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9]S(C(F)(F)F)(=O)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1([CH2:8][O:9][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH:21]=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(COS(=O)(=O)C(F)(F)F)CCCCC1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(COc2cccc(C=O)c2)CCCCC1
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of compound iii (0.5 mmol), 3-hydroxy-benzaldehyde (iv, 0.6 mmol) and K2CO3 (0.7 mmol) were dissolved in DMF (3 mL). The solution was heated to 80° C. for 4 hr. The solution was poured into water, extracted with ethyl acetate (10 mL) three times, and concentrated. The residue was purified by chromatography and resulted in 0.22 mmol of 3-(1-methyl-cyclohexylmethoxy)-benzaldehyde (v) with a 44% yield.
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:25][NH2:26])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>CO.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11](/[C:14](=[N:26]/[NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=2)/[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: NNC(=O)c1cccnc1
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Agent: Cl
Solvent: O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccnc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (215 mg, 0.93 mmol) was suspended in methanol (3 ml) and water (1 ml). Nicotinic acid hydrazide (137 mg, 1.0 mmol, 1.1 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with water to yield the product, one apparent isomer, as a white solid: 311 mg (95%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(S(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 125 mg) and pyridine (60 μL) in dry methylene chloride (1.9 mL) at 0° C. is treated with methanesulfonyl chloride (32 μL), and the resulting mixture was stirred at 0° C. for one hour and at ambient temperature for 16 hours. The reaction mixture is then diluted with methylene chloride (30 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 240-242° C.
Reaction SMILES: [C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)([OH:3])=O.[CH2:13]([CH:15](C(O)=O)C(O)=O)[CH3:14].O1C=CCCC1>>[C:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)(=[O:3])[CH2:14][CH2:13][CH3:15]
Reactant: CCC(C(=O)O)C(=O)O
Reactant: O=C(O)c1noc2ccccc12
Agent: C1=COCCC1
Product: CCCC(=O)c1noc2ccccc12

Procedure:
Using 3.7 g (23 mmol) of 3-carboxy-l,2-benzisoxazole prepared in accordance with a known process [J. Amer. Chem. Soc., 97, 7305 (1975)], 3.34 g (25 mmol) of ethylmalonic acid and 6.4 g of 3,4-dihydropyran, 3-butyryl-1,2-benzisoxazole was obtained as colorless crystals by similar treatment to Example 28-(4).
Reaction SMILES: NC1C=C(C)C=CC=1C(N)=[O:5].NC(C1C=CC(C)=CC=1N[C:23]([C:25]1[N:26]=[C:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:35]=2[C:36]([F:39])([F:38])[F:37])[S:28][CH:29]=1)=[O:24])=O>>[F:37][C:36]([F:39])([F:38])[C:35]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[C:27]1[S:28][CH:29]=[C:25]([C:23]([OH:24])=[O:5])[N:26]=1
Reactant: Cc1ccc(C(N)=O)c(NC(=O)c2csc(-c3cnccc3C(F)(F)F)n2)c1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Product: O=C(O)c1csc(-c2cnccc2C(F)(F)F)n1

Procedure:
Reaction of intermediate III.1 and 2-amino-4-methylbenzamide and subsequent purification by HPLC in analogy to the synthesis of Example 1.1 results in N-[2-(aminocarbonyl)-5-methylphenyl]-2-[4-(trifluoromethyl)-3-pyridinyl]-4-thiazolecarboxamide as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[Br:13]Br>C(Cl)Cl.CCOCC>[Br:13][CH:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Br:1])[C:7]1=[O:12]
Reactant: O=C1CCCc2c(Br)cccc21
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1c2cccc(Br)c2CCC1Br
Yield: 79.4 %

Procedure:
A clear yellow solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone (12.09 g, 53.7 mmol) in freshly opened Et2O (220 mL) under an N2 atmosphere was chilled to −5° C. HCl was bubbled in subsurface for 1 min, causing no visible change. The dropwise addition of a solution of Br2 (8.58 g, 53.7 mmol) in CH2Cl2 (20 mL) and Et2O (2 mL) to the vigorously stirring solution of 5-bromo-3,4-dihydro-1(2H)-naphthalenone over 2 h (each drop was allowed to fully decolorize before adding the next) produced a product mixture that assayed by HPLC. Peak area showed 79.4% title compound, 9.5% unreacted 5-bromo-3,4-dihydro-1(2H)-naphthalenone, 0.6% unidentified, and 9.4% 2,2,5-tribromo-1-tetralone. The addition of H2O produced a top light brown organic phase, and a clear, colorless bottom aqueous phase which was separated. After drying with MgSO4, the organic layer was concentrated under vacuum at room temperature to give the crude intermediate title compound as a light brown oil (16.08 g, 98.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[CH2:16][CH2:15]3)=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:22][C:9]1[O:8][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[CH2:16][CH2:15]3)[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2cc(-c3ccoc3-c3ccncc3)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(-c3cc(Br)oc3-c3ccncc3)ccc21
Temperature: 50 °C
Yield: 15.7 %

Procedure:
A solution of the product of Step 8 (1.0 g, 3.6 mmol) in dry dimethylformamide (10 ml) was treated with freshly recrystallised N-bromosuccinimide (1.42 g, 8.0 mmol) and heated at 50° C. for 1 hour. After cooling to room temperature, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, extracted into dichloromethane, washed twice with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to afford the title compound (0.2 g, 16%); 1H NMR (CDCl3) 8.52 (2H, d, J 8 Hz), 7.80 (1H, d, J 11 Hz), 7.49 (1H, s), 7.38 (1H, d, J 8 Hz), 7.32 (2H, d, J 8 Hz), 6.54 (1H, s), 3.17 (2H, t, J 5 Hz), 2.75 (2H, t, 5 Hz).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:15][CH2:16][N:17]=[C:18]=[S:19]>ClCCl>[OH:2][CH:3]1[CH2:6][N:5]([C:18]2[S:19][CH2:15][CH2:16][N:17]=2)[CH2:4]1
Reactant: S=C=NCCCl
Reactant: OC1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC1CN(C2=NCCS2)C1
Reaction time: 2 h
Yield: 95 %

Procedure:
A 1.5 ml solution of acetonitrile anhydride containing 219 mg of 3-hydroxyazetidine hydrochloride (5) was cooled to 0° C. in the stream of nitrogen, and, to this solution, there were added 0.31 ml of triethylamine and subsequently a 0.3 ml solution of acetonitrile anhydride containing 250 mg of chloroethylisothiocyanate dissolved therein, and the resultant solution was stirred for 30 minutes at the same temperature, and, after left still until it had a room temperature, the solution was further stirred for two hours. Next, dichloromethane was added to the reaction liquid, and the resultant solution was washed with a saturated aqueous solution of potassium carbonate, and, thereafter, the dichloromethane layer was dried with magnesium sulfate, and then was condensed under reduced pressure, and, thus, there was obtained 300 mg (yield: 95%) of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) in the form of colorless needle crystal.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9](C)C)(=[O:5])[C:2]([CH3:4])=[CH2:3].[Br:12]CC(OC(C)(C)C)=O.C(OCC)C>C(#N)C>[Br:12][C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH2:7][CH2:8][NH2:9])=[O:5]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=C(C)C(=O)OCCN(C)C
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(Br)C(=O)OCCN

Procedure:
5 g 2-(Dimethylamino)ethyl methacrylate and 8.68 g tert-butyl bromoacetate were reacted in 20 ml acetonitrile for 24 h at 50° C. under N2 protection. Upon addition of 250 ml ethyl ether to the reaction mixture, the formed white crystals were isolated and dried. The resulting CB-tBu monomers were immediately stored in a desiccator at −20° C. (yield 96%). 1H NMR (D2O) δ (ppm): 1.44 (s, 9H, —OC(CH3)3), 1.87 (s, 3H, CH2═C(CH3)COO—), 3.31 (s, 6H, —CH2N(CH3)2CH2COO—), 3.98 (t, J=3 Hz, 2H, CH2═C(CH3)COOCH2CH2N(CH3)2CH2—), 4.28 (s, 2H, —CH2N(CH3)2CH2COO—), 4.60 (t, J=3 Hz, 2H, CH2═C(CH3)COOCH2CH2N(CH3)2CH2—), 5.73 and 6.10 (s, 2H, CH2═C(CH3)COO—).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[CH:15]([CH3:16])[C:14]([O:18][CH3:19])=[O:17])=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2)co1
Reactant: C=CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(C)c1oc(=O)[nH]c1-c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
4-(4-Chlorophenyl)-2-oxo-4-oxazoline (3.0 g) was dissolved in methanol (30 mL) and methyl acrylate (1.66 mL) and triethylamine (2.14 mL) were added. The obtained mixture was stirred with reflux for 6 h, and the solvent was concentrated under reduced pressure. Isopropanol (9 mL) and isopropyl ether (21 mL) were added, and the mixture was allowed to stand at room temperature overnight and was cooled to not higher than 5° C. and stirred for 1 h. The precipitated crystals were collected by filtration and washed with isopropyl ether to give the title compound (2.81 g; yield 65.0%).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cu][C:18]#[N:19]>CN(C=O)C.O>[C:18]([C:2]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:19]
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Br)c1
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(C#N)c1
Temperature: 140 °C
Yield: 73.9 %

Procedure:
To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added copper(I) cyanide (CuCN; 0.23 g, 2.65 mmol), and the reaction mixture was heated at 140° C. for 3 h. The reaction mixture was cooled to 25° C., diluted with H2O, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 15% EtOAc in n-hexane) to afford the title compound as a white solid (0.3 g, 72%): mp 51-53° C.; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.93 (d, J=17.6 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 229.84 ([M+H]+); IR (thin film) 2370, 1709, 1142 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40][N:41]([CH2:51][CH2:52][O:53][CH3:54])[C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:47]3[CH2:48][CH2:49][N:44]([CH2:43][C:42]([N:41]([CH2:40][CH2:39][O:38][CH3:37])[CH2:51][CH2:52][O:53][CH3:54])=[O:50])[CH2:45][CH2:46]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: COCCN(CCOC)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CCOC)CCOC)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-bis-(2-methoxy-ethyl)-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N,N-bis-(2-methoxy-ethyl)-2-piperazin-1-yl-acetamide (example 16) in an analogous manner as described in example 25. LR-MS: 763.4 [(M+H)+]
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:23][C:24]=1[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:21][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccccc2)sc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccccc2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-(4-methyl-2-phenyl-thiazol-5-yl)-ethanol [U. H. Lindberg, G. Bexell, B. Ulff, Acta Pharmaceutica Suecica 1971, 8, 49-58] in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield {6-[2-(4-methyl-2-phenyl-thiazol-5-yl)-ethoxy]-indol-1-yl}-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:19][CH:20]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([C:29]#[N:30])[CH:23]=1)[OH:21])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl>[CH3:31][S:32]([O:21][CH:20]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([C:29]#[N:30])[CH:23]=1)[CH2:19][C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH2:10][NH:11][C:12]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:18])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC[C@@H](CC(O)c1cc(F)cc(C#N)c1)O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H](CC(OS(C)(=O)=O)c1cc(F)cc(C#N)c1)O[Si](C)(C)C(C)(C)C
Temperature: -60 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl ((2R)-2-((tert-butyldimethylsilyl)oxy)-4-(3-cyano-5-fluorophenyl)-4-hydroxybutyl)carbamate (I-10) (5.3 g, 12.1 mmol) in DCM (50 mL) at −60° C. was added TEA (5.1 mL, 36.3 mmol) and MsCl (0.98 mL, 12.2 mmol). The resulting mixture was stirred at −60° C. for 2 hours. The reaction was poured into water, diluted with DCM and washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield (3R)-4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-1-(3-cyano-5-fluorophenyl)butyl methanesulfonate (I-11). MS m/z 539.1 (M+23)+. Compound decomposed on standing. Used immediately in next reaction without delay.