Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[F:13][C:14]([F:35])([F:34])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([C:15]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:14]([F:35])([F:13])[F:34])=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: COc1cc(C(=O)O)ccc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)ccc1N
Reaction time: 1 h
Yield: 112.4 %

Procedure:
4-Amino-3-methoxybenzoic acid (2.045 mmol, 0.342 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.700 g) and triethylamine (6.14 mmol, 0.853 mL, 0.621 g) were combined and stirred at room temperature in dichloro-methane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 1 hour. The reaction mixture was diluted with dichloromethane and saturated sodium hydrogen carbonate solution and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (1.13 g). MS (ESI) m/z 492.1 [M+H]+
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH2:21][C@@H:20]2[C@@H:16]([CH2:17][C:18]3(OCC[O:22]3)[CH2:19]2)[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH2:21][C@@H:20]2[C@@H:16]([CH2:17][C:18](=[O:22])[CH2:19]2)[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=C(CCCCCOCc2ccccc2)C[C@H]2CC3(C[C@@H]12)OCCO3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1C[C@@H]2CC(CCCCCOCc3ccccc3)=C[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.5 %

Procedure:
6.65 g of 3-(5-benzyloxypentyl)-7,7-ethylenedioxy-cis-bicyclo[3,3,0]oct-2-ene (prepared as described in Preparation 4 or 10) were added to a mixture of 120 ml of acetone, 45 ml of water and 1.0 ml of concentrated hydrochloric acid, and the mixture was stirred for 2 hours at room temperature. After completion of the reaction, sodium bicarbonate was added to the reaction mixture for neutralization, and acetone was distilled off under reduced pressure. A saturated aqueous solution of sodium chloride was added to the residue, and then the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract under reduced pressure, giving 6.00 g of residue. On purifying this residues by silica gel column chromatography, 5.33 g of the title compound were obtained from the fractions eluted with hexane containing 7-10% by volume of ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl>CO.[Fe]>[F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([NH2:10])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: Nc1cc(F)c(F)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of 5.55 g (31.876 mmole) of 4,5-difluoro-2-nitroaniline in 50 mL of MeOH, were added 100 mL of 2 N HCl and 8.90 g (159.380 mmole) of iron powder. The reaction mixture was stirred at room temperature for 2 hr and then filtered. The filtrate was neutralized with conc. NH4OH to ~pH 8. The resulting suspension was filtered again and the filter cake was washed thoroughly with MeOH. The filtrate and washings were combined, concentrated to ~100 mL, and extracted with CHCl3 (100 mL×3). The CHCl3 solution was washed with a sat. NaCl solution (100 mL×2), dried (Na2SO4), and evaporated. The residue was coevaporated with CHCl3 to give 3.515 g (77%) of 10. This material was used in the next reaction without further purification. A brown crystalline sample of 10 was obtained by recrystallization from CCl4. 1H NMR (DMSO-d6): d6.44 (t, 2,3-H and 6-H, JF-H =10.5 H), 4.59 (br. s, 4,2×NH2).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].COC1C=CC(C[S:16][C@@H:17]2[CH2:21][N:20]([CH3:22])[C@H:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([N+:31]([O-:33])=[O:32])[CH2:27][CH:26]3[C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[O:24])[CH2:18]2)=CC=1>C1(OC)C=CC=CC=1>[F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[SH:16][C@@H:17]1[CH2:21][N:20]([CH3:22])[C@H:19]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([N+:31]([O-:33])=[O:32])[CH2:27][CH:26]2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[O:24])[CH2:18]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN([N+](=O)[O-])CC3C(=O)OCc3ccccc3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CCN([N+](=O)[O-])CC1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
130 ml of trifluorocacetic acid and 4.6 ml of trifluoromethanesulfonic acid were added dropwise to a solution of 13.8 g of (2S,4S)-4-(4-methoxybenzylthio)-2-(4-nitrobenzyloxycarbonyl-1-piperazinylcarbonyl)-1-methylpyrrolidine [prepared as described in step (i) above] in 28.3 ml of anisole, and the resulting mixture was stirred for 30 minutes, whilst ice-cooling. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was washed with hexane and ether, in that order, by decantation to give 13.9 g of the title compound as a powder.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[N:10]=1)[CH2:2]2.CC1(C)C(C)(C)OB([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)O1>>[NH2:39][C:38]1[CH:40]=[CH:41][C:35]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[N:12]=2)=[CH:36][CH:37]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)cc1
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 49 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 4 using 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2.8 g, 49% yield.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH2:10][O:11][CH2:12][C:13](=[O:14])[C:8]=2[S:7]/[C:6]/1=[N:15]\[C:16](=[O:26])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>O1CCCC1>[CH2:1]([N:5]1[C:9]2[CH2:10][O:11][CH2:12][CH:13]([OH:14])[C:8]=2[S:7]/[C:6]/1=[N:15]\[C:16](=[O:26])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)C(=O)COC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)C(O)COC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.8 %

Procedure:
To a solution of Example 10 (50 mg, 0.13 mmol) in tetrahydrofuran (5 mL) was added sodium borohydride (5.8 mg, 0.15 mmol, Aldrich). The reaction mixture was stirred at room temperature for 6 h and then quenched with saturated aqueous NH4Cl solution. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-5% methanol in methylene chloride) to afford 20 mg (40%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3H), 1.24-1.45 (m, 2H), 1.59-1.77 (m, 2H), 3.72 (dd, J=11.7, 4.2 Hz, 1H), 3.80 (s, 3H), 3.84-3.93 (m, 1H), 3.99-4.10 (m, J=7.1 Hz, 2H), 4.56 (d, J=5.2 Hz, 1H), 4.58-4.84 (m, 2H), 5.70 (d, J=5.9 Hz, 1H), 7.12 (d, J=8.7 Hz, 1H), 7.44-7.50 (m, 1H), 7.75 (d, J=2.8 Hz, 1H); MS (ESI+) m/z 397 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:29])[CH3:9])=[CH:4][CH:3]=1.[O:30]=[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][NH:32]1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][C:24]([CH3:28])([CH3:27])[C:25]#[N:26])[O:12][C:11](=[O:29])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[CH:36][C:31](=[O:30])[NH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: O=c1ccc(B(O)O)c[nH]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 2-oxo-1,2-dihydropyridin-5-ylboronic acid following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.37 min, m/z=474 (M+1); 1H NMR (CDCl3) 7.97, (dd, 1H), 7.73 (s, 1H), 7.33 (m, 2H), 7.20 (d, 2H), 7.17 (t, 2H), 6.98 (m, 3H), 5.67 (q, 1H), 3.00 (dt, 1H), 2.49 (m, 2H), 2.30 (m, 1H), 2.13 (s, 2H), 1.55 (d, 3H), 1.45 (s, 3H), 1.34 (s, 3H).
Reaction SMILES: C([N:5]1[C:12]([NH2:13])=[C:11]([NH:14][CH:15]=O)[C:9](=[O:10])[NH:8][C:6]1=[O:7])CCC.BrCCCC(OCC)=O.[OH-].[Na+]>CN(C=O)C>[NH:8]1[C:9](=[O:10])[C:11]2[NH:14][CH:15]=[N:13][C:12]=2[NH:5][C:6]1=[O:7]
Reactant: CCCCn1c(N)c(NC=O)c(=O)[nH]c1=O
Agent: CCOC(=O)CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Reaction time: 1 h

Procedure:
11.3 g (0 . 05 mole) of 1-butyl-5-formylamino-6-aminouracil (II) (R1 =butyl, R8 =H) are dissolved under nitrogen in 200 ml of DMF. 10.6 ml (0.075 mole) of ethyl 4-bromobutyrate are added, after which 2 g (0.05 mole) of solid powder-form NaOH is added with thorough stirring in portions of 0.5 g at intervals of 1 hour. On completion of the addition, the mixture is left to react overnight. The solvent is then evaporated and the oily residue of (IV) (substituent in the 1-position=(CH2)3COOEt) is dissolved in 100 ml of 10% NaOH. This solution is then heated under reflux for 0.5 hour and then cooled, neutralized to pH 5 with acetic acid and filtered. The precipitate formed is dried. Yield: 9.2 g (60%) of crude xanthine (V) (substituent in the 1-position=(CH2)3COOH, R3 =butyl, R8 =H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(OC)nc(Cl)n1
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
A mixture of 2-chloro-4,6-dimethoxy-pyrimidine (3.35 g, 19.19 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 24.94 mmol, 1.3 equiv; commercially available) in anhydrous DMF (100 mL) was heated to 100° C. for 48 h. The organic phase was concentrated under reduced pressure and the residue extracted with ethyl acetate (3×50 mL) from a solution of 1 M NaOH (100 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.97 g (30%) of the title compound. MS (ISP): 339.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:12]=[CH:13][C:14]=1[CH:15]=[CH:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:38]=[O:39].O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:12]=[CH:13][C:14]=1[CH:15]=[CH:16][C:17]1[S:18][C:19]([CH:38]=[O:39])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OCc2ccccc2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Temperature: -72.5 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
In a stream of argon, in 35 ml of tetrahydrofuran was dissolved 2.6 g (6.2 mmol) of [3-benzyloxy-4-[2-(thiophene-2-yl)vinyl]phenyl]dibutylamine, and 5.8 ml of n-butyllithium (1.6 mol solution in hexane) (9.28 mmol) was added dropwise thereto under cooling at −71 to −74° C. The mixture was stirred for 1 hour. Next, 0.59 g (8.07 mmol) of N,N-dimethylformamide was added dropwise. The reaction mixture was stirred for 1 hour and the temperature was allowed to rise. To this mixture, 10 ml of water was added dropwise. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was dissolved in 300 ml of ether and 130 mg of iodine pieces were added thereto. After stirred at room temperature, the mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. After drying over anhydrous magnesium sulfate and concentration, the residue was crystallized from ethyl acetate/hexane (⅙) and the precipitate was separated by filtration to give 1.76 g of a reddish orange crystal. Further, the mother liquor was purified by silica gel column chromatography and the residue was crystallized in the same manner as described above to further give 0.12 g of the crystal (In total: 1.88 g; yield: 67.8%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([Cl:18])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(O)c1cccs1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCC(Cl)c1cccs1

Procedure:
Following the procedure described in Example 42(b), 15 g of 2-t-butoxycarbonylamino-1-(2-thienyl)ethanol were chlorinated using phosphorus pentachloride to afford 13.6 g of the title product as crystals melting at 40°-43° C. This substance was used for next step without purification because it was decomposed by silica gel column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[SH:18]>>[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[S:18][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Cn1ccnc1S
Product: Cn1ccnc1Sc1ccc([N+](=O)[O-])cc1Cl
Yield: 87 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 1-methyl-2-imidazolethiol to give 2-chloro-4-nitrophenyl 1-methylimidazol-2-yl sulphide in 87% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:36]2[C:31]([CH:32]=[N:33][C:34](OS(C(F)(F)F)(=O)=O)=[N:35]2)=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:34]3[N:33]=[CH:32][C:31]4=[CH:30][CH:29]=[C:28]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[O:21][CH3:20])[N:36]4[N:35]=3)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)C4)cc3)nn12

Procedure:
Prepared by following a procedure analagous to Example 1220c by using 3-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester. 1H-NMR (DMSO) δ 9.4 (s, 1H), 8.9 (s, 1H), 7.8 (d, J=7.5 Hz, 1H), 7.6 (d, J=8.5 Hz, 2H), 7.45 (t, 1H), 7.2 (d, J=8.5 Hz, 1H), 7.1 (m, 3H), 6.9 (dd, J1=J2=4.6 Hz, 2H), 3.8 (s, 3H), 3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m, 2H), 3.2 (t, 1H), 2.1 (m, 1H), 1.9 (m, 1H), 1.4 (s, 9H).
Reaction SMILES: S(Cl)(C)(=O)=O.Cl.[CH3:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:17][CH:18]=1)\[C:11](O)=[O:12].C(N(CC)C(C)C)(C)C.[NH2:48][C@@H:49]1[C:69](=[O:70])[N:51]2[C:52]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[C:53]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][O:57]3)[CH2:54][S:55][C@H:50]12>CN(C=O)C.N1C=CC=CC=1>[CH3:7][O:8]/[N:9]=[C:10](/[C:14]1[N:15]=[C:16]([NH:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:17][CH:18]=1)\[C:11]([NH:48][C@@H:49]1[C:69](=[O:70])[N:51]2[C:52]([C:62]([O:64][C:65]([CH3:66])([CH3:68])[CH3:67])=[O:63])=[C:53]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][O:57]3)[CH2:54][S:55][C@H:50]12)=[O:12]
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)C1=C(C2CCCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(C3CCCCO3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -50 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
Mesyl chloride (121mg, 82μl) was added to 2-(Z)-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid hydrochloride (466mg) and N,N-diisopropylethylamine (252mg, 340μl) in dry DMF (10ml) at -50° C. under argon and stirred at -50° C. for 1h. Then t-butyl (6R,7R)-7amino-3-(tetrahydropyran-2-yl)-ceph-3-em-4-carboxylate (Isomer A, 300mg) in dry DMF (5ml) followed by pyridine (70mg, 72μl) were added and reaction mixture left for a further 1h whilst warming to ambient temperature. The reaction mixture was partitioned between ethyl acetate and water, reextracted with ethyl acetate, organic extracts washed with water (x3) and brine, dried, concentrated and flash chromatography (eluting with 30,40,50,60% ethyl acetate in hexane) to afford the title compound as a pale yellow foam (420mg, 62%); vmax (CH2Cl2) 3420, 1784, 1732 (shoulder), 1717, 1685cm-1 ; δH (CDCl3), 1.53 (9H, s) overlapping 1.4-1.7 (4H, m), 1.73-1.94 (2H, m), 3.38-3.58 (3H, m), 3.95-4.00 (1H, m), 4.07 (3H, s), 4.54-4.59 (1H, m), 5.02 (1H, d, J4.8Hz), 5.90 (1H, dd, J4.5, 9.1Hz) 6.74 (1H, s), 6.86 (1H, d, J8.8Hz), 7.04 (1H, s) and 7.30 (15H, s). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (788)].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(N(CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)C1=Cc2ccc(O)cc21
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1=Cc2ccc(OC(=O)c3ccccc3)cc21
Reaction time: 0.08 h

Procedure:
27 g of 5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester are dissolved in 2000 ml of dichloromethane and then 18 g of triethylamine are added. Over a period of 5 minutes, while stirring at 10°-20°, 25 g of benzoyl chloride are added in portions, stirring is carried out for 5 hours at room temperature, 200 ml of water are added and the organic phase is separated off, dried over magnesium sulphate and concentrated to dryness by evaporation. 5-benzoyloxybenzocyclobutene-1-carboxylic acid methyl ester is obtained in the form of a colourless, viscous oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OS(C)(=O)=O)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(CO)cc1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
4-Methanesulfonyloxy-benzoic acid methyl ester (330 mg, 1.43 mmol) was dissolved in anhydrous THF (10 mL) and LiAlH4 (109 mg, 2.86 mmol) was added. The resulting suspension was stirred at room temperature until no starting material was left. Excess LiAlH4 was hydrolyzed with aq. HCl (2N) and the remaining suspension was extracted with EtOAc. The organic layer was separated, dried (MgSO4) and evaporated and the remaining crude product was purified by flash chromatography using n-heptane/EtOAc 3:7 as the eluent to afford the title compound as an oil (202 mg, 93%). 1H NMR (400 MHz, CDCl3): δ 7.37-7.40 (d, 2H), 7.23-7.25 (d, 2H), 4.67 (s br, 2H), 3.10 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])[CH:10]=2)[NH:5][CH2:4][CH2:3]1.[CH:21](=O)[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:21]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:8][CH:7]=2)[C:2]([CH3:20])([CH3:1])[CH2:3][CH2:4]1)[CH3:22]
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCN2
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCN2CC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.5 g of (RS)-2-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptanol, dissolved in 25 ml of methylene chloride, were treated at 0° C. with 0.46 ml of acetaldehyde and 3.46 g of sodium triacetoxyborohydride, then 0.62 ml of acetic acid was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with the addition of one portion of 25 ml of water and then, was extracted with two portions of 25 ml of methylene chloride. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 25% ethyl acetate/hexanes). 1H NMR (CDCl3): 6.98 (d, J=2.2 Hz, 1H), 6.85 (dd, J=8.4, 2.2 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 3.75-3.55 (m, 2H), 3.33 (q, J=7.1 Hz, 2H), 3.30-3.20 (m, 2H), 2.70-2.55 (m, 1H), 1.80-1.70 (m, 2H), 1.70-1.45 (m, 2H), 1.45-1.20 (m, 6H), 1.26 (s, 6H), 1.14 (t, J=7.1 Hz, 3H), 0.84 (t, J=6.5 Hz, 3H).