Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([N:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)(C)C)(C)C)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([N:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(O)cc2)n1
Reaction time: 1 h
Yield: 17.5 %

Procedure:
A mixture of Intermediate 70a (124 mg, 169 μmol) and TBAF (1M in THF, 0.34 mL, 0.34 mmol) in THF (5 mL) was stirred for 1 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine, and concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, then further purified by HPLC (30-98% MeCN in H2O, 0.1% HCO2H) to give the title compound as an off-white solid (18.4 mg, 18%). LCMS (Method 5) Rt 4.22 min, m/z 621 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.25 (9H, s), 1.61 (2H, m), 1.72 (4H, m), 1.79-1.98 (2H, m), 1.99-2.15 (2H, m), 3.13 (4H, m), 4.81 (1H, m), 5.54 (1H, t, J 4.5), 6.29 (1H, s), 6.85 (2H, m), 7.09 (1H, d, J 8.7), 7.14 (1H, dd, J 9.7, 2.0), 7.20-7.39 (6H, m), 7.59-7.64 (2H, m), 7.95 (1H, s), 9.77 (1H, br s).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:11])([CH3:10])[C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH3:9].[I-:12].[Na+]>CC(=O)CC>[I:12][CH2:2][Si:3]([CH3:11])([CH3:10])[C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: [I-]
Reactant: Cc1ccoc1[Si](C)(C)CCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cc1ccoc1[Si](C)(C)CI

Procedure:
Reflux chloromethyl(dimethyl)(3-methyl-2-furyl)silane (114.5 mmol) in butanone (200 mL) containing sodium iodide (116 mmol) for 4 h, according to the procedure described in Example 1, step b to provide the title compound.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:10]([NH:12][C@@H:13]1[C:20](=[O:21])[N:19]2[C@@H:14]1[S:15][CH2:16][C:17](/[CH:25]=[C:26]1\[CH2:27][CH2:28][N:29]([CH2:32][C:33]([F:36])([F:35])[F:34])[C:30]\1=[O:31])=[C:18]2[C:22]([OH:24])=[O:23])=[O:11])=O)(C)(C)C.C(OCC)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[NH2:8][C@H:9]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:10]([NH:12][C@@H:13]1[C:20](=[O:21])[N:19]2[C@@H:14]1[S:15][CH2:16][C:17](/[CH:25]=[C:26]1\[CH2:27][CH2:28][N:29]([CH2:32][C:33]([F:34])([F:36])[F:35])[C:30]\1=[O:31])=[C:18]2[C:22]([OH:24])=[O:23])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC(F)(F)F)C3=O)CS[C@H]12)c1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC(F)(F)F)C3=O)CS[C@H]12)c1ccccc1
Reaction time: 0.5 h

Procedure:
1.0 g (1.64 mmol) (6R,7R)-7-[(R)-2-t-butoxycarbonylamino-2-phenyl-acetylamino]-8-oxo-3-[(E)-5-oxo-1-(2,2,2-trifluoro-ethyl)-pyrrolidin-4-ylidenemethyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid were dissolved in 5 ml trifluoroacetic acid and stirred for 30 min at 0°-5° C. The solution was then poured on 100 ml diethyl ether and the separated material was filtered off. It was then stirred for 2 hours in 25 ml ethyl acetate; the crystals separated were filtered off and dried.
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([NH2:15])=[O:14])=[C:6]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>C(#N)C>[ClH:1].[Cl:1][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)=[C:7]([C:13]([NH2:15])=[O:14])[CH:8]=[N:9]2)=[CH:4][C:3]=1[I:2]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3ccc(I)cc23)c1
Agent: Cl
Solvent: CC#N
Product: COc1cccc(Nc2c(C(N)=O)cnc3cc(Cl)c(I)cc23)c1

Procedure:
Intermediate 63 was prepared from Intermediate 67 in a similar manner to Intermediate 14, using acetonitrile as solvent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:15])C2C=CC=CC=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][N+:22]([O-:25])=[CH:21][CH:20]=1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:15][C:19]2[CH:24]=[CH:23][N+:22]([O-:25])=[CH:21][CH:20]=2)=[N:6][CH:7]=1
Reactant: [O-][n+]1ccc(Cl)cc1
Reactant: OC(c1ccccc1)c1ccc(F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [O-][n+]1ccc(OCc2ccc(F)cn2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) was dissolved in DMF (20 mL), and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (2.03 g, 15.7 mmol) was added, and the reaction mixture was heated for 1 h at 120° C. Upon cooling, the mixture was diluted with methylene chloride, washed with 5% lithium chloride solution (5×), dried, and concentrated. Purification by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) provided the title compound (1.76 g, 50%) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.12 (d, J=7.7 Hz, 2H), 7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:22]([O:21][CH2:20][CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCCOCc1ccccc1
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCOCc2ccccc2)c(C=O)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
To a vigorously stirred solution of 15,2 g (100 mmol) 2-hydroxy-5-methoxy-benzaldehyde and 42.4 g (130 mmol) caesium carbonate in 350 ml DMF at 0° C. was added 26.9 g (125 mmol) (2-Bromo-ethoxymethyl)-benzene (Adrich) in 50 ml DMF dropwisely. The reaction mixture was stirred vigorously at 70° C. for 6 h. The solvent was evaporated. 200 ml water and 200 ml ethyl acetate were added. The organic phase was separated. The aqueous phase was extracted three times with 100 ml ethyl acetate each. The combined organic phases were washed with 50 ml water and 50 ml brine. The organic phase was dried with magnesium sulphate and evaporated. The crude product was purified by silica column chromatography (gradient ethylacetate:hexane 1:3→1:2). The desired product 2a was obtained in 86% yield (24.6 g, 86 mmol) as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C1(C)C=CC(S(O[CH2:19][C:20]([I:24])=[C:21]([I:23])[I:22])(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[I:24][C:20](=[C:21]([I:23])[I:22])[CH2:19][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1nccn1CC(I)=C(I)I
Temperature: 60 °C

Procedure:
To a solution of 57 mg (0.5 mmoles) of 2-nitroimidazole and 300 mg (0.5 mmoles) of 3-p-toluenesulfonyloxy-1,1,2-triiodo-1-propene in 30 ml of dry DMF was added 0.07 ml (0.05 mmoles) of triethylamine and the resulting mixture was heated at 60° C. for one hour. After cooling, the reaction mixture was poured into 10 ml of ice-water, the brown crystalline substance thus separated was recovered by filtration, washed with water and then dried. Yield 246 mg (92%), mp 156°-158° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5](Br)=[CH:4][C:3]=1[F:12].[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[C:2]([F:1])=[C:3]([F:12])[CH:4]=2)[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cc(Br)c2occc2c1F
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Product: CC1CN(Cc2ccccc2)CCC1(O)c1cc(F)c(F)c2ccoc12
Yield: 42.4 %

Procedure:
Beginning with 4.0 gm (17.17 mMol) 4,5-difluoro-7-bromobenzofuran and 3.8 gm (18.88 mMol) 1-benzyl-3-methyl-4-oxopiperidine, 2.6 gm (43%) of the desired compound were recovered as a yellow oil essentially as described in EXAMPLE 3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23]O)=[C:21]([CH3:25])[C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[C:21]=3[CH3:25])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(C)c1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3c(C)c(-c4ccc(C(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with [2,4-dimethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[2,4-dimethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as yellow oil.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[C].[Pd]>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([N:10]1[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:9]1[CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:17]
Reactant: CC1(C)C(=O)N(C2CCCCCCC2)N1C(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)N(C2CCCCCCC2)N1C(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 2-cyclooctyl-4,4-dimethyl-1-[(2-nitrophenyl)carbonyl]-1,2-diazetidin-3-one (22.3 mg, 0.0620 mmol) in methanol was added with 10% palladium carbon (catalyst amount), and under a hydrogen atmosphere, the resultant was stirred at room temperature for 30 minutes. The reaction solution was filtered using celite, concentrated in vacuo, and the obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (14.7 mg, 72.1%) was obtained as a colorless oil.
Reaction SMILES: [Br: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.[CH3:12][NH:13][CH3:14]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7]([N:13]([CH3:14])[CH3:12])=[O:9])=[C:4]([OH:8])[CH:3]=1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Reactant: CNC
Solvent: CO
Product: CN(C)C(=O)Nc1ccc(Br)cc1O

Procedure:
6-Bromobenzoxazolinone (35.1 g) was stirred with 55 ml of a 38% solution of dimethylamine in methanol at 60° C. for 21/2 hours. The mixture was cooled and filtered, and the precipitate was washed with cold methanol to give the desired urea (17.9 g), m.pt. 178° C. (decomp.).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1.[F:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[C:39]1[C:40]([C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[N:41][C:42]([NH2:46])=[C:43]([NH2:45])[CH:44]=1>CN(C=O)C>[NH2:46][C:42]1[N:41]=[C:40]([C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[C:39]([C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[F:32])=[CH:44][C:43]=1[NH:45][C:7]([C:5]1[CH:4]=[N:3][CH:2]=[N:1][CH:6]=1)=[O:9]
Reactant: O=C(O)c1cncnc1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1NC(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of pyrimidine-5-carboxylic acid (0.088 g, 0.709 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.136 g, 0.709 mmol) and 1H-1,2,3-benzotriazol-1-ol (0.072 g, 0.534 mmol) in DMF (4 mL) was heated at 40° C. for 15 minutes. Finally, 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.15 g, 0.534 mmol) in DMF (4 mL) was added and the mixture was stirred at room temperature overnight. The crude mixture was extracted between ethyl acetate and water. The organic layer was washed with 4% sodium bicarbonate aqueous solution and water, dried (MgSO4) and evaporated. The residue (0.2 g) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:22])=[C:12]3[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:18][C:17]([CH2:19][OH:20])=[C:16]([CH3:21])[C:13]=3[N:14]([CH3:25])[CH:15]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(CO)sc2c(O)c(C(=O)NCc3ccc(F)cc3)cnc12
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(F)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95 %

Procedure:
To a slurry of 3.34 g (9.64 mmol) N-(4-fluorobenzyl)-7-hydroxy-2-(hydroxymethyl)-3-methylthieno[3,2-b]pyridine-6-carboxamide and 1.99 g (14.4 mmol) potassium carbonate in 50 mL anhydrous DMF, was added 0.89 mL (14.3 mmol) iodomethane. The mixture was stirred at room temperature. After 40 minutes the slurry became homogeneous and then cloudy. After another 15 minutes the mixture became a thick slurry that stopped stirring. An additional 30 mL of anhydrous DMF was added and the thick slurry was stirred at room temperature over night. Then, 150 mL of water was added to the slurry and the solids were collected by vacuum filtration and dried in a vacuum oven at 60° C. to provide 3.30 g of title compound as a tan solid.
Reaction SMILES: C[O:2][C:3](=O)[N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Br:20])[CH:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Br:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH2:13][CH2:12][N:4]([CH:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])[C:3]2=[O:2]
Reactant: CCCC(CCC)N(CCc1ccccc1Br)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCCC(CCC)N1CCc2c(Br)cccc2C1=O
Reaction time: 20 h
Yield: 87.7 %

Procedure:
5.8 g of methyl[2-(2-bromophenyl)ethyl](1-propylbutyl)carbamate are dissolved, under an inert atmosphere, in 250 cm3 of dichloromethane, at a temperature close to 20° C. 5.43 g of 4-dimethylaminopyridine are added to the reaction mixture. This is cooled to a temperature close to 0° C. 13 cm3 of trifluoromethanesulfonic anhydride in solution in 250 cm3 of anhydrous dichloromethane are poured into the reaction mixture over 45 min. The suspension is kept stirring for 20 h at a temperature close to 20° C. 300 cm3 of a saturated aqueous solution of sodium carbonate are added to the reaction mixture. The stirring is continued for 30 min. The organic phase is washed with 100 cm3 of a 20% aqueous solution of acetic acid, 100 cm3 of a saturated aqueous solution of sodium carbonate, and 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered through a pellet (50 g) of silica (particle size: 40-63 μm), rinsed with 500 cm3 of dichloromethane and concentrated using a rotary evaporator under reduced pressure (5 kPa). 4.63 g of 5-bromo-2-(1-propylbutyl)-3,4-dihydroisoquinolin-1(2H)-one are obtained in the form of a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]([CH2:8][CH3:9])[N:6]=[C:5]([C:10]2[CH:15]=[C:14](OC)[C:13](OC)=[C:12](OC)[CH:11]=2)[CH:4]=1.CC(C1C=CC([C:31]([F:34])([F:33])[F:32])=CC=1)=O.C(NN)C>>[Cl:1][CH2:2][C:3]1[N:7]([CH2:8][CH3:9])[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:31]([F:34])([F:33])[F:32])=[CH:12][CH:11]=2)[CH:4]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCn1nc(-c2cc(OC)c(OC)c(OC)c2)cc1CCl
Agent: CCNN
Product: CCn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCl

Procedure:
5-chloromethyl-1-ethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole was prepared in analogy to the prepaparation of 5-chloromethyl-1-ethyl-3-(3,4,5-trimethoxy-phenyl)-1H-pyrazole described by Kodama et al. (U.S. Pat. No. 6,472,386), but starting from 4-trifluoromethylacetophenone instead of 3′4′5′-trimethoxyacetophenone and using ethyl hydrazine instead of methylhydrazine.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]([F:25])([F:24])[C:5]([F:23])([F:22])[O:6][C:7]([F:21])([F:20])[C:8]([F:19])([F:18])[C:9]([F:17])([F:16])[CH2:10][O:11][CH2:12][CH2:13][CH2:14]Cl.FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)COCCCBr.[CH2:55]([C:63]1[CH:64]=[N:65][C:66]([C:69]2[CH:74]=[CH:73][C:72]([OH:75])=[CH:71][CH:70]=2)=[N:67][CH:68]=1)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]>>[CH2:55]([C:63]1[CH:68]=[N:67][C:66]([C:69]2[CH:74]=[CH:73][C:72]([O:75][CH2:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([F:17])([F:16])[C:8]([F:19])([F:18])[C:7]([O:6][C:5]([F:23])([F:22])[C:4]([F:25])([F:24])[O:3][C:2]([F:27])([F:26])[F:1])([F:21])[F:20])=[CH:71][CH:70]=2)=[N:65][CH:64]=1)[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)COCCCCl
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: FC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)COCCCBr
Product: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining a mixture of 3-(4-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2,3,3,4,4-hexafluorobutoxy)propyl chloride (1.92 g, 4.2 mmol) and 3-(4-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2,3,3,4,4-hexafluorobutoxy)propyl bromide (4:1 mole ratio, total 0.87 g, 1.7 mmol, prepared from 1-bromo-3-chloropropane and 4-(2-(trifluoromethoxy)tetrafluoroethoxy)-2,2,3,3,4,4-hexafluorobutanol) with 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.6 g, 5.9 mmol). The resulting crude product was isolated essentially as described in Example 3 and purified by chromatography on silica gel, eluting with 10 vol. % ethyl acetate in hexane, followed by Kugelrohr distillation (230° C. at 0.4 torr) to provide a yield of 2 g.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH:22]1[C:30]2[C:25](=[C:26]([C:31]3[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.[OH2:38]>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[NH2:37][C:34]1[N:35]=[CH:36][C:31]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:25]=2[CH2:24][C:23](=[O:38])[NH:22]3)=[CH:32][N:33]=1
Reactant: O
Reactant: Nc1ncc(-c2cccc3[nH]ccc23)cn1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(C)(C)O
Product: Nc1ncc(-c2cccc3c2CC(=O)N3)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pyridinium tribromide (90% purity from Aldrich, 7.1 g, 19.98 mmol) was added in portions over 10 minutes to a suspension of 5-(1H-indol-4-yl)-pyrimidin-2-ylamine (1.4 g, 6.66 mmol) in 2-methyl-2-propanol (50 mL), ethanol (30 mL) and acetic acid (18 mL). The mixture was stirred at room temperature for 2 hours, and then acetic acid (72 mL), water (1 mL) and zinc (6.5 g, 100 mmol) were added. Stirring was continued for 1.5 hours. The unreacted zinc dust was filtered off and washed with methanol. The filtrate was concentrated and the syrupy residue was suspended in water (100 mL) overnight. The solid which formed was filtered off. The filtrate was basified with aqueous sodium bicarbonate and extracted with ethanol:dichloromethane (5:95) to give 4-(2-amino-pyrimidin-5-yl)-1,3-dihydro-indol-2-one. 1H NMR (360 MHz, DMSO-d6) δ 10.46 (s, 1H, NH), 8.47 (s, 2H), 7.24 (t, J=7.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.78 (s, 2H, NH2), 3.64 (s, 2H)
Reaction SMILES: [NH2:1][C@H:2]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:29][CH:28]=1)[C:3]([NH:5][C@@H:6]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=1)=[O:8])=[O:4].C(N(C(C)C)CC)(C)C.[O:51]=[C:52](Cl)OC(Cl)(Cl)Cl>O1CCCC1>[O:51]=[C:52]1[NH:1][CH:2]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[CH:31][CH:32]=2)[C:3](=[O:4])[N:5]1[C@@H:6]([C@H:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:18])[CH2:16][CH3:17])[N:14]=1)=[O:8]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](N)c2ccc(OCCN3CCCCC3)cc2)[C@@H](C)c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)NC(c3ccc(OCCN4CCCCC4)cc3)C2=O)n1
Reaction time: 0.33 h
Yield: 35.9 %

Procedure:
Crude (2S,3S)-2-{(R)-2-amino-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-acetylamino}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide (≈0.16 mmol) was dissolved in tetrahydrofuran (10 mL) that contained diisopropylethylamine (142 μL, 105 mg, 0.81 mmol) and was transferred via cannula to a solution of diphosgene (14 μL, 23 mg, 0.12 mmol) in tetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred for 20 minutes and then partitioned between ethyl acetate and water. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel eluted first with ethyl acetate and then gradient eluted with dichloromethane containing from 0 to 10% methanol. Precipitation of the isolated product from dichloromethane with an excess of hexanes gave (2S,3S)-2-{2,5-dioxo-4-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-imidazolidin-1-yl}-3-phenyl-N-(4-propionyl-thiazol-2-yl)-butyramide as a white solid (26 mg, 27%).