Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][CH2:9][CH:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:26][F:27].O>CN(C=O)C>[NH2:2][C@@H:3]([CH2:8][CH2:9][CH:10]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:26][F:27])=[CH:20][CH:21]=1)[C:11]([O:13][CH3:14])=[O:12])[C:4]([O:6][CH3:7])=[O:5]
Reactant: FCBr
Reactant: COC(=O)C(CC[C@H](N)C(=O)OC)Cc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(CC[C@H](N)C(=O)OC)Cc1ccc(OCF)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
Dimethyl (2S)-2-amino-5-(4-hydroxybenzyl)hexanedioate hydrochloride (200 mg, 0.54 mmol) were solved in DMF (5 ml) and at 0° C. sodium hydride (34 mg, 1.14 mmol) were added. After 30 min, bromofluoromethane (1.35 mmol) were added and the resulting mixture was stirred at 0° C. for one hour. The mixture was then poured into water and extracted three times with methylene chloride. The organic phase was dried with sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography to yield 37 mg (20.8%) of the product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[NH2:12][OH:13]>[OH-].[Na+]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[N:12][OH:13])([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cccc(C=NO)c1
Yield: 78.7 %

Procedure:
3-Nitrobenzaldehyde (6 g, 40 mmol) was added to a solution of hydroxylamine (15 g, 216 mmol) in 5% aqueous sodium hydroxide solution (120 ml). Filtration and drying afforded the title compound as a white solid (5.23 g, 79%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:24])[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=4)[N:13]=3)[CH:3]=2)[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example E.47) (0.39 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.4 g, 76%). MS (ISP) 526.3 [(M+H)+]; mp 163° C.
Reaction SMILES: [Li+].[Cl-].[CH:3](NC(C)C)([CH3:5])[CH3:4].[Li]CCCC.[Cl:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([N:22]([C@@H:24]([CH3:33])[C@@H:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])=[O:21].C(Br)C=C.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.O>[Cl:15][CH2:16][CH2:17][CH2:18][C@H:19]([CH2:5][CH:3]=[CH2:4])[C:20]([N:22]([C@@H:24]([CH3:33])[C@@H:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])=[O:21]
Reactant: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)CCCCCl
Reactant: CC(C)NC(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: O
Product: C=CC[C@@H](CCCCl)C(=O)N(C)[C@@H](C)[C@@H](O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
To a magnetically stirred suspension of LiCl (83 g, 1.96 mol) in THF (700 mL) at room temperature was added diisopropylamine (104 mL, 736 mmol) in one portion. nBuLi (2.5M in hexane, 281 mL, 703 mmol) was added dropwise over 30 min using an addition funnel. The light yellow mixture stirred at −78° C. for 20 min and then was warmed to 0° C. for 15 min. The mixture was then cooled to −78° C. and 5-chloro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpentanamide (92.8 g, 327 mmol) in THF (330 mL) was added dropwise over 30 min using an addition funnel. The mixture was stirred at −78° C. for 1 h and then was warmed to 0° C. for 25 min. Allylbromide (41.5 mL, 490 mmol) was then added slowly over 2 min via syringe and then the reaction was warmed to room temperature. The reaction stirred at room temperature for 50 min and was judged complete by LC/MS. The mixture was cooled to 0° C. and saturated aqueous NaHCO3 (400 mL) and H2O (200 mL) were added. EtOAc was added, the phases were separated and the aqueous phase was extracted with EtOAc (1500 mL total). The combined with organic layers were washed with 1N HCl (4×150 mL), brine, dried over MgSO4, filtered, and concentrated under reduced pressure to furnish (R)-2-(3-chloropropyl)-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpent-4-enamide as an orange oil (101.2 g, 312 mmol, 95%). The crude material was carried on without further purification. LC/MS (m/z=306.0).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=2)[CH:5]=[CH:6][CH:7]=1.N>CO.C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:18][CH:19]=3)[C@@H:11]3[CH2:12][CH2:13][CH2:14][N:10]3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1CCCC1c1cccc(OCCCN2CCCCC2)c1)c1cccc(I)c1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Ic1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 54 %

Procedure:
1-(3-Iodo-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.46 mmol scale, to give 1.0 g (54%) of the desired product as an orange semi-solid after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C26H33IN2O2, 532.2; m/z found, 533.4 [M+H]+. 1H NMR (CDCl3): 8.20 (m, 1H), 7.82 (m, 2H), 7.24 (t, J=7.9, 1H), 7.12 (t, J=7.9, 1H), 6.97 (d, J=7.6, 1H), 6.93 (m, 1H), 6.78 (m, 1H), 3.97 (m, 2H), 3.42 (t, J=8.7, 1H), 3.35 (m, 2H), 2.61 (m, 6H), 2.34 (m, 1H), 2.18 (m, 1H), 2.05 (m, 4H), 1.85 (m, 2H), 1.68 (m, 4h), 1.48 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C:12]([C:13]3[CH2:14][CH2:15][CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18](O)[CH2:17]4)=[CH:11][CH2:10]1)[CH3:8])[CH3:3].C(N(S(F)(F)[F:35])CC)C.O>C(Cl)Cl>[F:35][C@@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([CH2:15][CH2:14][C:13]3[C:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:10][CH:11]=4)[CH2:17]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)CC1CC3
Solvent: O
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@@H](F)CC1CC3
Temperature: -78 °C

Procedure:
Cholesta-8,14-diene-3β-ol (1.17 g, 3 mmol) was dissolved in 10 ml of methylenechloride and cooled to −78° C. Over 10 min a solution of diethylaminosulfur trifluoride (1.4 g, 8.7 mmol) in 10 ml of methylenechloride was added at −78° C. The mixture was stirred for 1½ hour at −78° C. and was then slowly heated to room temperature. To the reaction mixture was added 15 ml of water while stirring was continued. The organic phase was separated and washed with 30 ml of 5% NaHCO3 and then with water. The organic phase was dried with MgSO4 and evaporated to dryness. The residue was purified by column chromatography using heptane for a first fraction and heptane/acetone, 95:5 (w/w) for a second fraction containing 3α-fluorocholesta-8,14 diene, 0.14 g (12%). Melting point: 98.6° C. Elementary analysis: Cal C: 83.88; H: 11.21; F: 4.91. Found C: 83.92; H: 11.75. 19F-NMR: d 181.0 and 181.2 (JHCF 45.2 Hz, C3-aF).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH:10]([OH:13])[C:11]#[N:12])=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:13][CH:10]([C:11]#[N:12])[CH2:9][NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: N#CC(O)CNc1ccc(Br)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC(C#N)CNc2ccc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
7.2 g of 3-(5-bromo-2-pyridinylamino)-2-hydroxypropionitrile was dissolved in 60 mL dichloromethane, and 7.8 mL diisopropyl ethylamine and 6.3 g of 4-toluenesulfonic acid chloride were added thereto, and while the temperature of the mixture was gradually increased to room temperature, the mixture was stirred for 2 hours. An aqueous saturated sodium bicarbonate solution was poured into the reaction mixture which was then extracted with ethyl acetate and washed with brine, then the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) to give 7.64 g of the title compound (yellow oil).
Reaction SMILES: [C:1]([C:3]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40].O>CN(C)C=O>[C:1]([C:3]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])#[N:2]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(C#N)cc2F)c1=O
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2C#N)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
72 mg of 3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (described later, produced in Intermediate Production Example 9) was dissolved in 1.0 ml of N,N-dimethylformamide, and to this was added 31 mg of anhydrous potassium carbonate, and 31 mg of methyl 2-bromopropionate was added with stirring at room temperature, then, the mixtures was stirred for 1 hours at 70° C. The reaction solution was cooled to room temperature, then, the reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 80 mg of methyl 2-[3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [Compound 5-7 of the present invention].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>ClCCl>[CH:12]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
Oxalyl chloride (3.2 mL, 0.04 mol) and dimethyl sulfoxide (4.3 mL, 0.06 mol) were dissolved in 100 mL of dichloromethane in a dry ice bath. After stirring for 30 minutes, a solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate 2b (2 g, 0.01 mol) in 20 mL of dichloromethane was added dropwise. The reaction mixture was stirred for 45 minutes, and triethylamine (7.08 g, 0.07 mol) was added dropwise. After stirring for another 1 hours at 0° C., the reaction mixture was added with 500 mL of dichloromethane. The combined organic layers were washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate 2c (1.10 g, yield 55.4%) as a light yellow oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([S:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)=[O:19])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.Cl>CO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([S:18]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=1)=[O:19])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: COC(=O)c1ccc(S(=O)C(Cn2ccnc2)c2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C(Cn1ccnc1)S(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 68.5 %

Procedure:
1.22 ml of a 1N aqueous solution of sodium hydroxide was added to a solution of 235 mg of methyl 4-[1-(2-methoxyphenyl)-2-(imidazol-1-yl)ethylsulfinyl]benzoate (prepared as described in Example 39) in 3 ml of methanol, and the resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was then neutralized with 1.22 ml of 1N aqueous hydrochloric acid, and then treated and purified by the same method as described in Example 34, to give 155 mg of the title compound as a colorless powdery substance, melting at 157°-159° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](Cl)[C:5]2[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[OH:15][CH2:16][CH:17]([NH2:20])[CH2:18][CH3:19]>>[OH:15][CH2:16][CH:17]([NH:20][C:4]1[C:5]2[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:20][CH:17]([CH2:16][OH:15])[CH2:18][CH3:19])[N:3]=1)[CH2:18][CH3:19]
Reactant: CC(C)c1n[nH]c2c(Cl)nc(Cl)nc12
Reactant: CCC(N)CO
Product: CCC(CO)Nc1nc(NC(CC)CO)c2[nH]nc(C(C)C)c2n1
Temperature: 120 °C
Yield: 80 %

Procedure:
The mixture of 5,7-dichloro-3-isopropylpyrazolo[4,3-d]pyrimidine (100 mg; 0.331 mmol) and 2 mL 1-(R,S)-(hydroxymethyl)propylamine was heated at 120° C. for 6 hours. The reaction mixture was evaporated to dryness in vacuo. The product was purified by column chromatography on silica gel. The mixture of chloroform/methanol (96/4) was used as a mobile phase. Yield=80%; white syrupy; MS (ES+): 337.4 (100%, M+H+). 1H-NMR (300 MHz, CDCl3): 0.90-1.03 m (6H), 1.26 d (6H), 1.50-1.71 m (4H), 2.48 bs (1H), 3.07 m (1H), 3.40 m (1H), 3.59-3.90 m (4H).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[Br:9]N1C(=O)C(C)(C)N(Br)C1=O.BrBr>C(Cl)(Cl)(Cl)Cl>[C:1](=[O:8])([O:5][CH:6]([Br:9])[CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCOC(=O)OCC
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)OC(C)Br
Yield: 163.9 %

Procedure:
A mixture of diethyl carbonate (35 g, 0.3 m) in carbon tetrachloride (50 ml) and alpha-azo-isobutyronitrile (AIBN) (0.1 g) was heated to gentle reflux and dibromodimethyl hydantoin (28.6 g, 0.1 m) was added in small aliquots over a period of 8 hours together with further additions of AIBN (8×0.05 g): care being taken to ensure that free bromine did not accumulate in the reaction mixture. At the end of the reaction the mixture was subjected to vacuum fractional distillation to afford pure ethyl alpha-bromoethyl carbonate (32.3 g, 82% yield) identical in all respects with the product of Examples 3 and 4.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH2:6][CH:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=2)[CH2:3][CH2:2]1.C1C(C(OOC(C)(C)C)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C1COC(C2CC2)=N1
Agent: CC(C)(C)OOC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1coc(C2CC2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
Into a 10000-mL 3-necked round-bottom flask were placed methyl 2-cyclopropyl-4,5-dihydrooxazole-4-carboxylate (294 g, 1.74 mol, 1.00 equiv.), CuBr (274 g, 1.92 mol, 1.10 equiv.) and toluene (3000 mL). This was followed by the addition of tert-butyl perbenzoate (506 g, 2.61 mol, 1.50 equiv.) dropwise with stirring at 60° C. over 60 minutes. The resulting solution was stirred overnight at 80° C. in an oil bath. The reaction mixture was cooled to room temperature, then quenched by the addition of 2000 mL of 10% NH4OH. The resulting solution was extracted with 3×2000 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20). This resulted in 200 g (69% yield) of methyl 2-cyclopropyloxazole-4-carboxylate as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[NH2:25][C:26]1[N:31]=[C:30]([NH2:32])[C:29]([CH2:33][C:34]2[CH:35]=[C:36]([O:49][CH2:50][CH3:51])[C:37](I)=[C:38]([O:40][S:41]([CH2:44][CH:45]([CH3:47])[CH3:46])(=[O:43])=[O:42])[CH:39]=2)=[CH:28][N:27]=1>>[NH2:25][C:26]1[N:31]=[C:30]([NH2:32])[C:29]([CH2:33][C:34]2[CH:35]=[C:36]([O:49][CH2:50][CH3:51])[C:37]([C:2]3[CH:3]=[CH:4][C:5]([NH:8][CH2:15][CH2:16][OH:17])=[CH:6][CH:7]=3)=[C:38]([O:40][S:41]([CH2:44][CH:45]([CH3:46])[CH3:47])(=[O:43])=[O:42])[CH:39]=2)=[CH:28][N:27]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1I
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)CC(C)C)c1-c1ccc(NCCO)cc1
Yield: 68.1 %

Procedure:
Starting from 397 mg (0.93 mmol) N-(4-bromo-phenyl)-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2,2,2-trifluoro-acetamide and 220 mg (0.47 mmol) 2-methyl-propane-1-sulphonic acid 5-(2,4-diamino-pyrimidin-5-ylmethyl)-3-ethoxy-2-iodo-phenyl ester, 165 mg of the title compound are obtained as a pale beige foam after splitting off of the tert-butyl-dimethylsilanyl protective group under acid conditions (HCl/MeOH).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40]/[CH:41]=[CH:42]/[CH3:43].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:40][C@H:41]1[C@H:42]([CH3:43])[C@H:16]2[C:15]1=[C:14]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:27])[N:13]1[C@H:12]([S:17]2)[C@H:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:38]1=[O:39]
Reactant: C/C=C/C
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C3[C@@H](C)[C@H](C)[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethyl-sulphonyloxy)ceph-3-em-4-carboxylate (40 mg, 0.0682 mmol) in dichloromethane (5.0 ml) was cooled to -20° C. Trans-2-butene (ca. 5 ml) was condensed into the solution. Diisopropylethylamine (12 μl, 0.068 mmol) was added and the mixture allowed to warm to room temperature over 1 h. The mixture was chromatographed to give the title compound (29.7 mg, 88%), m.p. 172°-173° C. (EtOAc) (Found: C, 65.6; H, 5.5; N, 5.6; S, 6.2; M+, 492.1724. C27H28N2O5S requires C, 65.8; H, 5.7; N, 5.7; S, 6.5%; M, 492.1719; νmax (CH2Cl2) 1786, 1721, 1687 cm-1 ; δH (CDCl3) 1.03 (3H, d, J 7.1), 1.25 (3H, d, J 7.3), 2.41 (1H, ddq, J 9.5, 7.1, 3.0), 3.04 (1H, ddq, J 7.3, 3.2, 3.0), 3.63 (2H, ABq, J 16.0), 3.79 (3H, s), 4.47 (1H, dd, J 9.5, 3.2), 4.90 (1H, d, J 4.9), 5.08 (1H, d, J 11.9), 5.26 (1H, d, J 11.9), 5.76 (1H, dd, J 9.0, 4.9), 6.07 (1H, d, J .9.0), 6.87 (2H, d, J 8.7), 7.30 (7H, m); δc (CDCl3), 15.9, 17.9, 37.2, 43.1, 43.4, 47.0, 55.3, 58.3, 59.8, 67.0, 114.0 (2c), 130.5 (2c) 121.7, 127.4, 127.7, 129.1 (2c), 129.5 (2c), 130.5 (2c), 133.8, 142.9, 159.8, 160.8, 164.2, 171.2
Reaction SMILES: [CH3:1][N:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH3:3].BrC#[N:16].C(Cl)Cl>CCOCC>[CH3:3][N:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[C:1]#[N:16]
Reactant: N#CBr
Reactant: CN(C)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C#N)c1cccc2ccccc12
Yield: 48 %

Procedure:
In a 2 neck round bottom flask, equipped with a magnetic stir bar and reflux condenser, was placed N,N-dimethyl-1-naphthylamine (4.35 g, 25.4 mmol, and BrCN (2.99 g, 28.2 mmol) in a single portion. This suspension was placed in an oil bath (preheated, 90° C.) and allowed to stir and reflux under N2 for 21 hours. During this time a gas was given off, detected by bubbler placed over the reflux condenser. The reaction was followed by TLC, using methylene chloride as the solvent and viewed under UV. After the 21 hours, the mixture was cooled, 100 ml of ether was added and the insoluble quaternary salt (669 mg) was filtered off. The ether filtrate was extracted with an aqueous 5M HCl solution (4×, 30 ml) and washed with water (5×, 20 ml). The ether was dried over anhydrous granular K2CO3, filtered, then concentrated to dryness, then distilled by bulb to bulb distillation at reduced pressure to afford the yellow oil of the N-methyl-N-(1-naphthyl)cyanamide (2.22 g, 48%. b.p. 180° C./1.5 mm Hg (Cressman, Homer, W. J., Org. Synth. collective vol.3, 608), 170°-171° C./1 mm Hg).
Reaction SMILES: C[O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].Cl>C(O)(=O)C>[C:19]1([CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][C:11]3([CH2:10][C:9](=[O:29])[C:8]4[C:26](=[CH:27][CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:30])=[O:2])[CH:7]=4)[O:25]3)[CH2:16][CH2:15]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2
Temperature: 85 °C
Yield: 105.5 %

Procedure:
(E)-3-{1′-(2-Phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (1.70 g, 4.19 mmol) was dissolved in acetic acid (20 ml). 6 M HCl (20 ml) was added and the resulting suspension was heated at 85° C. for 4 h, then the solvents were evaporated and the residue was dried under vacuum, giving (E)-3-{1′-(2-phenyl-ethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (1.73 g) as a light yellow solid (hydrochloride salt).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>C(Cl)Cl.CO>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][C:2]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][N:25]3[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]3)=[CH:35][CH:34]=2)=[N:3][CH:4]=1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)N(C)C)n3)cc2)CC1
Yield: 32 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2,5-dichloropyrimidin-4-yl)amino)-N,N-dimethylbenzamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 32% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.07 (s, 1H), 8.35 (d, 1H J=8.2 Hz), 8.05 (s, 1H), 7.46 (s, 2H, J=8.2 Hz), 7.38 (t, 1H, J=7.8 Hz), 7.29 (d, 1H, J=7.5 Hz), 7.21 (d, 2H, J=8.2 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.01 (s, 1H), 3.45 (s, 2H), 3.11 (s, 3H), 3.04 (s, 3H), 2.43 (bs, 8H), 2.27 (s, 3H); MS (ESI): 480.1 [M+H]+.