Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:38][C:39]([F:47])([F:46])[CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>N12CCCN=C1CCCCC2.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([N:43]3[CH2:44][CH2:45][CH:40]([C:39]([F:47])([F:46])[F:38])[CH2:41][CH2:42]3)=[N:20][CH:19]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1cc(F)ccc1-c1cc(N2CCC(C(F)(F)F)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C
Yield: 34.1 %

Procedure:
A mixture of 150 mg (0.28 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide and 0.16 g (0.84 mmol) 4-(trifluoromethyl)piperidine hydrochloride in 2 ml 1,8-diazabicyclo[5.4.0]undec-7-ene was heated at 140° C. for 20 h. After cooling to room temperature the reaction mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 62 mg (34%) of the title compound as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].N1(C2C=C[C:26]([CH:27]=[O:28])=CC=2)C=CC=N1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[CH:26]/[CH:27]=[O:28])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2ccc([N+](=O)[O-])cn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(5-nitro-2-pyridinyl)benzaldehyde (prepared as described in Reference Example 19) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 255 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Na].C1(C)C(C)=CC=CC=1.Br[C:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([CH3:31])[CH2:29][OH:30]>C(O)C>[S:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([CH3:31])[CH2:29][OH:30])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Oc1ccc(C2CCSc3ccccc32)cc1
Reactant: CC(Br)(CO)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CC(CO)(Oc1ccc(C2CCSc3ccccc32)cc1)c1ccccc1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A mixture of 2.42 g. of 4p-hydroxyphenyl-thiochromane and 0.23 g. of sodium in 50 ml. of xylene is boiled for 3 hours. The mixture is allowed to cool to 20° C., 2.15 g. of 2-bromo-2-phenylpropanol in 10 ml. of xylene are added and the suspension is stirred for 6 hours at the boil, cooled and treated with 2 ml. of ethanol. The inorganic precipitate is filtered off, the filtrate is evaporated, the residue is taken up in ether and the solution is washed with NaHCO3 solution and saturated NaCl solution, dried over MgSO4 and evaporated, to give 2-[4-(4-thiochromanyl)-phenoxy]-2-phenylpropanol, nD20 1.6172.
Reaction SMILES: C(C1C=CC(C#C)=CC=1)(C)(C)C.C[Si]([C:17]#[C:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=1)(C)C>>[CH3:32][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]#[CH:17])=[CH:24][CH:23]=1)([CH3:31])[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)CCC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: C#Cc1ccc(C(C)(C)C)cc1
Product: C#Cc1ccc(C(C)(C)CCC(C)C)cc1

Procedure:
Using the same general procedure as described for Compound 19, but using instead trimethylsilyl [4-(1,1,4-trimethylpentyl)] phenylethyne (Compound 34), the title compound was synthesized as a colorless oil. PMR (CDCl3): & 0.81 (6H, d, J~6.6 Hz), 0.85-0.96 (2H, m), 1.29 (6H, s), 1.32-1.48 (1H, m). 1.55-1.66 (2H, m)., 3.04 (1H, s), 7.29 (2H, d, J~8.4 Hz), 7.44 (2H, d, J~8.4 Hz).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.I[CH:21]([CH3:23])[CH3:22]>O.CC(O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH2:7][N:8]([CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccnc1)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CC(C)N1C=C(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)C=CC1
Temperature: 0 °C
Reaction time: 96 h
Yield: 78.3 %

Procedure:
Boc-D-Pal (4.0 g, 17.7 mmol) and Ag2O (8.0 g, 34.4 mmol) in 22 ml water was stirred at room temperature for 4 hours. The reaction vessel was cooled to 0° C., and 2-iodopropane (20.4 g, 120 mmol) in 40 ml 2-propanol was added. After addition was complete, the mixture was allowed to warm to room temperature and stirred for 4 days. Additional Ag2O (2 g) and 2-iodopropane (2 g) were added after 24 hours and again after 48 hours. The mixture was filtered, and the precipitate was washed with ethanol (2×15 ml). The filtrate was evaporated to yield 4.3 g of a yellow oil. Crystallization from ethanol/ethyl acetate gave light yellow crystals (3.0 g); Yield: 63%; m.p. 182–185° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C@@H:13]([CH2:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C[Si]([N:33]=[C:34]=[O:35])(C)C.O>ClCCl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([C@H:13]([C:14]([NH:16][C:17]3[S:18][C:19]([F:22])=[CH:20][N:21]=3)=[O:15])[CH2:23][C@H:24]3[CH2:28][CH2:27][N:26]([C:34]([NH2:33])=[O:35])[CH2:25]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=C(Nc1ncc(F)s1)[C@H](C[C@H]1CCNC1)c1ccc(S(=O)(=O)C2CC2)cc1
Solvent: O
Solvent: ClCCl
Product: NC(=O)N1CC[C@H](C[C@@H](C(=O)Nc2ncc(F)s2)c2ccc(S(=O)(=O)C3CC3)cc2)C1
Yield: 99.9 %

Procedure:
The (R)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-((S)-pyrrolidin-3-yl)propanamide (20.0 mg, 47.2 μmol) obtained in Step 1 of Example 2 was dissolved in dichloromethane (1 mL), and trimethylsilyl isocyanate (25.0 μL, 188 μmol) was then added to the obtained solution. The obtained mixture was stirred for hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated in vacuo. The obtained residue was purified by silica gel chromatography (chloroform/methanol=1%→20%) to obtain the captioned compound (22.0 mg, 99%) in the form of a white solid.
Reaction SMILES: Br[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][OH:12].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[C:2]1[S:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][OH:12]
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: OCc1c(C(F)(F)F)nsc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2snc(C(F)(F)F)c2CO)c(C)c1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [5-bromo-3-(trifluoromethyl)-1,2-thiazol-4-yl]methanol (100 mg, 0.38 mmol, 1.00 equiv), dioxane (3 mL), (2,4-dimethylphenyl)boronic acid (113 mg, 0.75 mmol, 1.97 equiv), Pd(PPh3)4 (44 mg, 0.04 mmol, 0.10 equiv), K3PO4 (402 mg, 1.89 mmol, 4.96 equiv). The resulting solution was stirred for 3 h at 90° C. in an oil bath. The solvent was removed and the residue was applied onto a TLC plate with ethyl acetate/petroleum ether (1:3). This resulted in 100 mg (crude) of [5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1,2-thiazol-4-yl]methanol as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][CH2:16][NH:17]2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].[I:26](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[I:26][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[NH:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=I(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCc1ccc2c(c1)NCCC2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1cc2c(cc1I)CCCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
To a mixed solution of 770 mg of t-butyl[2-(1,2,3,4-tetrahydroquinolin-7-yl)ethyl]carbamate in 15 ml of dichloromethane and 3 ml of MeOH were added 420 mg of calcium carbonate and 970 mg of benzyltrimethylammonium dichloroiodate, followed by stirring at room temperature for 2 hours. The insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 595 mg of t-butyl [2-(6-iodo-1,2,3,4-tetrahydroquinolin-7-yl)ethyl]carbamate as a reddish brown viscous substance.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]([CH:14]2[CH2:16][O:15]2)[C:10]([O:12][CH3:13])=[O:11])=[O:7])=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>CO>[F:23][C:24]1[CH:25]=[C:26]([S:30][CH2:16][CH:14]([OH:15])[CH:9]([NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][C:4]=2[C:19]([F:22])([F:21])[F:20])[C:10]([O:12][CH3:13])=[O:11])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C1CO1
Reactant: Fc1cccc(S)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)CSc1cccc(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
480 mg (1.5 mmol) of methyl (4-fluoro-2-trifluoromethylbenzoylamino)oxiranylacetate were dissolved in methanol, and 215 mg (1.5 mmol) of 3-fluorothiophenol and 280 mg (3.8 mmol) of triethylamine were then added. The mixture was then stirred at RT for 15 h, and the solvent was then removed. This gave 760 mg of diasteromerically pure crude product which was used for the next step without further purification.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1.C1(C)C=CC(S(O[CH2:22][CH2:23][O:24][CH2:25][CH3:26])(=O)=O)=CC=1>CO>[CH2:23]([O:24][CH2:25][CH2:26][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:22]
Reactant: CCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(O)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOCCOc1ccc(C)nc1
Reaction time: 0.08 h

Procedure:
A solution of 994 g (18.4 mmol) of sodium methylate in 20 ml of abs. methanol is added dropwise to a solution of 2 g (18.4 mmol) of 5-hydroxy-2-methylpyridine in 20 ml of abs. methanol. The mixture is stirred for 5 minutes and then a solution of 5.83 g (23.9 mmol) of (2-ethoxy)ethyl p-toluenesulphonate in 15 ml of abs. methanol is added. The mixture is heated under reflux for 72 hours. It is evaporated to dryness, the residue is taken up in ethyl acetate and washed with saturated NaCl solution. Drying over sodium sulphate and evaporation result in 2.1 g (70% of theory) of a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1.C(Cl)Cl>[N:16]1([CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=2[F:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNCC1
Reactant: Fc1ccc(Br)cc1COCCCCBr
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1COCCCCN1CCCCC1
Reaction time: 24 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (520 mg, 1.53 mmol) in tetrahydrofuran (8 ml) was treated with piperidine (1.5 ml, 15.3 mmol). The resulting reaction mixture was stirred for about 24 hours. The reaction mixture was then diluted with methylene chloride and washed with saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].C1(C)CCC(C(C)C)[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]3C(C(C)C)CCC(C)C3)[C:16]=2[OH:31])C1>>[CH3:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH3:8])[C:16]=1[O:31][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC1CCC(C(C)C)C(c2cccc(C3CC(C)CCC3C(C)C)c2O)C1
Reactant: CC(=O)CCl
Product: CC(=O)COc1c(C)cccc1C
Yield: 84 %

Procedure:
Prepared by 1-chloro-propan-2-one (50 mmol) and 2,6-dimenthylphenol (60 mmol); purified by silica gel/hexane:ethyl acetate (5:1) column chromatography as a colorless oil; yield 84% (7.5 g); H NMR (400 MHz, CDCl3): d 2.34 (s, 6H, CH3), 2.42 (s, 3H, CH3), 4.40 (s, 2H, OCH2), 7.02-7.10 (m, 3H, Ar); CNMR (100 MHz, CDCl3): δ 16.3, 26.6, 76.8, 124.5, 129.1, 130.6, 155.0, 205.4; GC-MS m/z 178.1 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:21]=[C:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[O:19][N:18]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[C:20]1[O:19][N:18]=[C:17]([CH3:16])[N:21]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccccc2C(=O)N2CCCC[C@H]2CNC(=O)OC(C)(C)C)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.0 g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (1.9) in dimethylformamide (10 ml containing diisopropylethylamine (2.4 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (3.55 g) and stirred at 90° C. for 16 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, diethyl ether eluant) to give the title compound (3.4 g).
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][C:4]#[CH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][CH:2]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH2:3][C:4]#[CH:5]
Reactant: C1=COCCC1
Reactant: C#CCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCC(C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(+/−)-4-Pentyn-2-ol (5.58 ml, 59.4 mmol) and 3,4-dihydro-2H-pyran (8.08 ml, 89 mmol) were dissolved in DCM (100 ml). 4-Toluenesulfonic acid pyridine salt (1.494 g, 5.94 mmol) was added and the resulting mixture was stirred for 4 h at RT with CaCl2-tube. The mixture was concentrated. 50 ml of diethyl ether was added, extracted with brine and dried with MgSO, filtered and evaporated. The product was used in the subsequent steps without further purifications. LC-MS: [M+1]=169.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[NH:10][N:9]=1.[CH2:23](Br)[CH3:24]>>[CH2:23]([N:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:10]1)[CH3:24]
Reactant: CCBr
Reactant: FC(F)(F)c1ccccc1-c1nc(-c2ccccc2Cl)n[nH]1
Product: CCn1nc(-c2ccccc2C(F)(F)F)nc1-c1ccccc1Cl

Procedure:
starting from 3-(o-chlorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole and ethyl bromide there is obtained a mixture of isomeric N-ethyltriazoles and therefrom there are obtained pure 1-ethyl-5-(o-chlorophenyl)-3-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole as a resinous product, 1H-NMR(CDCl3): 1.47 (t, CH2CH3), 4.10 (q, CH2CH3); and pure 1-ethyl-3-(o-chlorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, likewise as a resinous product, 1H-NMR(CDCl3): 1.45 (t, CH2CH3), 4.04 (q, CH2CH3);
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:28]4[N:35]=[CH:36][C:37]([C:38](=[O:40])[NH2:39])=[C:27]4[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[O:42]([CH2:44][S:45]([C:48]1[CH:49]=[C:50]([OH:55])[C:51](=[CH:53][CH:54]=1)[OH:52])(=[O:47])=[O:46])[NH2:43]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:42][CH2:44][S:45]([C:48]2[CH:54]=[CH:53][C:51]([OH:52])=[C:50]([OH:55])[CH:49]=2)(=[O:46])=[O:47])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[CH:30]=[C:29]([C:31]([F:33])([F:32])[F:34])[N:28]4[N:35]=[CH:36][C:37]([C:38](=[O:40])[NH2:39])=[C:27]4[N:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NC(=O)c1cnn2c(C(F)(F)F)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)nc12
Reactant: NOCS(=O)(=O)c1ccc(O)c(O)c1
Product: NC(=O)c1cnn2c(C(F)(F)F)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c5ccc(O)c(O)c5)c5csc(N)n5)[C@H]4SC3)nc12

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was reacted with 4-[[(aminoxy)methyl]sulphonyl]pyrocatechol according to the procedure described in Example 7. After purification of the product with the chromatographic procedure in Example 7 and lyophilization of the product, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)-sulphonyl]methoxy]imino]acetamido]-3-[[(3-carbamoyl-7-(tri-fluoromethyl)pyrazolo[1,5-a]pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a pale yellow powder.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:7]=[C:8]([C:20]([O:23]C)=[CH:21][N:22]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:10].CO>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]([C:20]([OH:23])=[CH:21][N:22]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)=[O:10]
Reactant: COc1cnc(Br)cc1C(=O)NCc1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1cc(Br)ncc1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.8 %

Procedure:
BBr3 (20 mL) was added dropwise to a mixture of 2-bromo-N-(4-fluorobenzyl)-5-methoxyisonicotinamide (2.0 g, 5.9 mmol) in DCM (10 mL) at −78° C. The mixture was stirred at RT for 10 h, and then MeOH (20 mL) was added to quench the reaction. The mixture was concentrated in vacuum to give the product of compound 2-bromo-N-(4-fluorobenzyl)-5-hydroxyisonicotinamide (1.8 g, yield: 95%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.9 (s, 1H), 9.35 (s, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.38 (t, J=6.0 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 4.78 (s, 2H). MS (M+H)+: 325/327.
Reaction SMILES: CN1CCOCC1.[CH2:8]([O:15][C:16](=[O:31])[CH:17]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:19][C:20]([OH:22])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN([C:35]([O:39][N:40]1N=NC2C=CC=N[C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC>CN(C)C=O>[CH2:8]([O:15][C:16](=[O:31])[CH:17]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:19][C:20](=[O:22])[N:40]([O:39][CH3:35])[CH3:41])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC(CCC(=O)O)C(=O)OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CON(C)C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 100.6 %

Procedure:
4-Methylmorpholine (9.77 mL, 88.9 mmol) was added to a suspension of 2-tert-butoxycarbonylamino-pentanedioic acid 1-benzyl ester (6 g, 17.7 mmol), and HATU (8.11 g, 21.3 mmol) in dimethylformamide (20 mL). After 5 minutes N,O-dimethylhydroxylamine hydrochloride (2.60 g, 26.7 mmol), was added to the solution. After 1 hour the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (150 mL), and washed with water (100 mL), aqueous hydrogen chloride (0.5 N, 2×100 mL), saturated sodium bicarbonate (100 mL), and saturated sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of ethyl acetate and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 2-tert-butoxycarbonylamino-4-(methoxy-methyl-carbamoyl)-butyric acid benzyl ester (6.8 g, 17.8 mmol, 99%). C19H28N2O6 calculated 380.2 observed [M+1]+ 381.2; rt=2.48 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([Cl:10])[N:3]=1.[CH:11](O)=[O:12].C1(C)C=CC=CC=1.O>>[NH2:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([NH:1][CH:11]=[O:12])=[N:7][C:6]=1[Cl:8]
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1c(Cl)nc(NC=O)nc1Cl
Temperature: 2.5 °C
Yield: 1000 %

Procedure:
A solution of 2,5-diamino-4,6-dichloro-pyrimidine (0.001 mol; 2.0 g) and 98% strength formic acid (0.5 mol, 22.96 g, 18.8 ml) was stirred overnight at room temperature. Toluene (0.94 mol, 86.76 g, 18.82 ml) was then added and the reaction was cooled to 0-5° C. The product was filtered off and washed with water (1.11 mol, 20.0 g, 20.0 ml). The product was subsequently dried at 50° C. in vacuo. N-(5-Amino-4,6-dichloropyrimidin-2-yl)formamide was detected in the 1H NMR as a single product. 0.01 mol (1.62 g) of the abovementioned product was obtained, corresponding to a yield of about 70%.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[Br:15]Br>C(O)(=O)C.O>[Br:15][C:8]1[C:7]2[N:2]([CH3:1])[C:3](=[O:14])[N:4]([CH3:13])[C:5](=[O:12])[C:6]=2[NH:10][CH:9]=1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)c2[nH]cc(Br)c2n(C)c1=O
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of Intermediate 1 (500 mg, 2.800 mmol) in acetic acid (5 mL) was added a solution of bromine (430 mg, 2.700 mmol) in acetic acid (5 mL) dropwise with stirring, after which water (1.2 mL) was added. The reaction mixture was stirred for another 20 min and diluted with two volumes of cold water. After 3 h, the precipitate was filtered off and washed with diethyl ether to afford 400 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.23 (s, 3H), 3.65 (s, 3H), 7.42 (s, 1H), 12.59 (br s, 1H); APCI-MS (m/z) 258.19 (M+H)+.