Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][OH:17])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][O:56][C:57]1[CH:62]=[CH:61][C:60](O)=[CH:59][CH:58]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:34](=[O:35])[N:11]2[C:12]([C:18]([O:20][CH:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][O:17][C:60]3[CH:61]=[CH:62][C:57]([O:56][CH3:55])=[CH:58][CH:59]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)[C@H]3SC2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 21.2 %

Procedure:
5.00 g (10.1 mmol) of Diphenylmethyl 7-tert-butoxycarbonylamino-3-hydroxymethyl-3-cephem-4-carboxylate, 7.93 g (30.2 mmol) of triphenylphosphine, and 7.28 g (60.2 mmol) of p-methoxyphenol were dissolved in 25 ml of tetrahydrofuran under argon atmosphere, and the reaction solution was cooled to -40°-35° C., and 4.76 ml (30.2 mmol) of diethyl azodicarboxylate were added dropwise, and then the stirring was effected for 6 hrs. at the same temperature. This solution was added to a suspension of 300 ml of ice cold 1N hydrochloric acid and 300 ml of ethyl acetate, and stirred, and then separated, and the layer of ethyl acetate was washed with water and saturated saline solution, and dried over anhydrous magnesium sulfate. Benzene was added to a caramel obtained by evaporating off the solvent so that the insoluble material was removed by filtering off, and the residue obtained by evaporating off the benzene filtrate was dissolved in diethyl ether. This ether solution was washed with 20% potassium carbonate aqueous solution until unreacted p-methoxyphenol was removed, and further washed with saturated potassium dihydrogen phosphate aqueous solution, water, and saturated saline solution. The layer of ether was dried over anhydrous magnesium sulfate, and then, ether was evaporated off to give 2.80 g of a caramel. The caramel was column chromatographed on silica gel by eluting with benzene-acetone (V:V;100:1), and then, powdered with ether-hexane to give 1.29 g of diphenylmethyl 7-tert-butoxycarbonylamino-3-(4-methoxyphenoxymethyl)-3cephem-4-carboxylate.
Reaction SMILES: [C:1]([C:4]1([CH2:7][S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:15][Mg]Br>C(OCC)C>[C:9]1([S:8][CH2:7][C:4]2([C:1]([OH:3])([CH3:15])[CH3:2])[CH2:6][CH2:5]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[Mg]Br
Reactant: CC(=O)C1(CSc2ccccc2)CC1
Solvent: CCOCC
Product: CC(C)(O)C1(CSc2ccccc2)CC1

Procedure:
To a stirred and ice-cooled solution of 6 (6.16 g, 29.9 mmol) in diethyl ether (60 mL) was added a solution of methylmagnesium bromide (3.0M solution in diethyl ether, 12 mL) dropwise over 10 min under nitrogen. The mixture was stirred for 20 min. The reaction was quenched by an addition of ammonium chloride solution and the organic layer was separated. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with brine, and dried over sodium sulfate. Filtration and concentration gave 5.80 g of an oily material, which was purified by column chromatography (silica gel 60 g, 4-10% ethyl acetate in n-hexane) to give 4.83 g (71.2%) of 7, as a colorless oil.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[N:9][S:10][C:11]=1[O:12][CH3:13])(=O)=O.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[C:25]([CH3:36])[C:24]=1[CH3:37]>>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([C:8]2[C:7]([CH2:6][O:5][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[C:25]([CH3:36])[C:24]=3[CH3:37])=[C:11]([O:12][CH3:13])[S:10][N:9]=2)=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCc1ccc(-c2nsc(OC)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: CCc1ccc(-c2nsc(OC)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 2-6 by coupling of (3-(4-ethylphenyl)-5-methoxyisothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[BH3-]C#N.[Na+]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:8]2[C:7]3[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[O:11][CH2:10][CH2:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(CN2CCOc3cc([N+](=O)[O-])ccc32)cc1
Yield: 70.7 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (305 mg, 1.7 mmol), p-anisaldehyde (2.3 g, 17 mmol) and NaBH3CN (532 mg, 8.4 mmol) to afford 361 mg (70%) of 3,4-dihydro-4-(p-methoxybenzyl)-7-nitro-2H-1,4-benzoxazine, an yellow solid. Data for 3,4-dihydro-4-(p-methoxybenzyl)-7-nitro-2H-1,4-benzoxazine: Rf 0.79 (3:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, 1H, J=9.0, 2.6), 7.70 (d, 1H, J=2.5), 7.14 (d, 2H, J=8.6), 6.88 (d, 2H, J=8.6), 6.63 (d, 1H, J=9.1), 4.54 (s, 2H), 4.26 (t, 2H, J=4.5), 3.80 (s, 3H), 3.51 (t, 2H, J=4.6).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:28]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cccs1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccs3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 87.8 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (600 mg, 1.8 mmol) and thiophene-2-sulfonyl chloride (331 mg, 1.1 mmol) the title compound was obtained (760 mg, 87.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (d, J=5.3 Hz, 1H), 7.51-7.57 (m, 2H), 7.29-7.38 (m, 2H), 7.20-7.27 (m, 2H), 7.13-7.17 (br, 1H), 6.98-7.03 (m, 1H), 6.88 (d, J=5.3 Hz, 1H), 3.27-3.37 (m, 1H), 1.43 (d, J=7.1 Hz, 6H). MS (ES+): 477 [M+H]+.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:37])[C@H:15]([OH:36])[C@H:16]([C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)C1C=CC=CC=1.[OH:38]O.[Li+].[OH-]>C1COCC1.O>[C:29]([O:28][C:26]([C:25]1[CH:24]=[C:23]([C@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C@@H:15]([OH:36])[C:14]([OH:38])=[O:37])[CH:35]=[CH:34][CH:33]=1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1cccc([C@H](c2ccccn2)[C@@H](O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc([C@H](c2ccccn2)[C@@H](O)C(=O)O)c1
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-hydroxy-3-oxo-1-pyridin-2-ylpropyl}benzoate from the previous step (0.068 g, 0.135 mmol) in THF (2 mL), was added 35% hydrogen peroxide (0.061 mL, 0.541 mmol) dropwise, then 1.0M LiOH (0.271 mL, 0.271 mmol) in H2O (0.4 mL). The reaction was stirred for 1.5 hours, at which time HPLC indicated incomplete reaction so additional 35% hydrogen peroxide (0.030 mL, 0.271 mmol) and 1.0M LiOH (0.135 mL, 0.135 mmol) in H2O (0.2 mL) were added and stirring continued for 1 hour. HPLC analysis showed complete consumption of starting material. The mixture was quenched with 10% aqueous Na2SO3 (1 mL) and saturated aqueous NaHCO3 (1 mL), diluted with H2O (20 mL), and washed with 2×20 mL CH2Cl2. The aqueous layer was acidified with 10% aqueous citric acid, extracted with 2×30 mL CH2Cl2, dried over MgSO4, filtered, and the solvent removed under reduced pressure to give (2R,3R)-3-[3-(tert-butoxycarbonyl)phenyl]-2-hydroxy-3-pyridin-2-ylpropanoic acid as a yellow oil (0.020 g, 43%). TPLC RT=1.44 min, method B; M+H=344.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:15][N:16](C)C=O.C(N)CN>O>[C:15]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)#[N:16]
Reactant: O=c1ccc(-c2ccc(Br)cc2)n[nH]1
Reactant: CN(C)C=O
Solvent: NCCN
Solvent: O
Product: N#Cc1ccc(-c2ccc(=O)[nH]n2)cc1
Reaction time: 0.5 h

Procedure:
A 19.20 g. portion of 6-(p-bromophenyl)-3(2H)-pyridazinone is mixed with 9.10 g. of cuprous cyanide in 70 ml. of dimethylformamide and stirred at reflux temperature for 12 hours. The hot mixture is poured into a solution of 46 ml. of ethylenediamine in 230 ml. of water. The mixture is stirred at ice-bath temperature for 30 minutes and the solid is separated by filtration. A second crop forms in the filtrate which is collected and added to the first crop which is then washed with water yielding 6-(p-cyanophenyl)-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[N:6]([C:15]([N:19]=[C:20]=[O:21])([CH2:17][CH3:18])[CH3:16])=[N:7][C:8]([N:12]=[C:13]=[O:14])([CH2:10][CH3:11])[CH3:9]>CCCCC>[N:6]([C:15]([NH:19][C:20]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:21])([CH2:17][CH3:18])[CH3:16])=[N:7][C:8]([NH:12][C:13]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:14])([CH2:10][CH3:11])[CH3:9]
Reactant: CCNCC
Reactant: CCC(C)(N=C=O)N=NC(C)(CC)N=C=O
Solvent: CCCCC
Product: CCN(CC)C(=O)NC(C)(CC)N=NC(C)(CC)NC(=O)N(CC)CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3.95 grams (0.054 moles) of diethylamine in 30 ml pentane in a 50 ml erlenmeyer flask cooled in a water bath was added 6.05 grams (0.027 moles) of 2,2'-azobis(2-isocyanatobutane) (from Example XXXVI) dropwise over 20 minutes while holding the reaction temperature below 30° C. After the addition was complete, the reaction was stirred for an additional 60 minutes at room temperature and filtered. The filter cake was washed with pentane and dried. The dry white solid weighed 1.8 grams (18% crude yield) and melted at 215°-220° C. with decomposition. The product had a broad carbonyl band at 1650 cm-1 and a strong NH band at 3400 cm-1 in its infrared spectrum and the isocyanate band at 2200 cm-1 was absent.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12]SCl>>[CH:1]1([O:7][CH2:8][C:9]([Cl:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClSCl
Reactant: O=C(O)COC1CCCCC1
Product: O=C(Cl)COC1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 2-(cyclohexyloxy)acetic acid (0.90 g, 5.69 mmol) and dichlorosulfane (10 mL) was refluxed for 2 h. The mixture was cooled to rt and concentrated in vacuo to give the title compound as yellow oil, which was used for next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)COB([C:35]2[CH:36]=[CH:37][C:38]([NH:42]C(=O)OC(C)(C)C)=[N:39][C:40]=2[CH3:41])OC1>>[CH3:41][C:40]1[N:39]=[C:38]([NH2:42])[CH:37]=[CH:36][C:35]=1[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1B1OCC(C)(C)CO1
Product: Cc1nc(N)ccc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with tert-butyl 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-methylpyridin-2-ylcarbamate via General Procedure A. Purification on silica yielded 258. NMR (CDCl3): 2.60-2.63 (m, 4H, 2×CH2), 2.65 (s, 3H, CH3), 2.74 (s, 3H, CH3), 3.22-3.24 (m, 4H, 2×CH2), 3.78-3.81 (m, 6H, 3×CH2), 3.91-3.94 (m, 4H, 2×CH2), 4.43 (s, 2H, NH2), 6.36 (d, H, ArH, J=8.38 Hz), 7.22 (s, H, ArH), 7.98 (d, H, ArH, J=8.41 Hz). MS: (ESI+): MH+504.22
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:24])[CH2:15][C@@H:14]([C@@H:25]([OH:36])[CH2:26][C@H:27]([C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])[NH:13][C:12](=[O:37])[C@H:11]([CH3:38])[NH:10][C:9]1=[O:39])(C)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>Cl.O1CCOCC1>[C:41]([NH:7][C@@H:8]1[C:9](=[O:39])[NH:10][C@@H:11]([CH3:38])[C:12](=[O:37])[NH:13][C@H:14]([C@@H:25]([OH:36])[CH2:26][C@@H:27]([CH3:28])[C:29]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:35])[CH2:15][C@H:16]([CH3:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)(=[O:43])[CH3:42]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]1C[C@H](C)CCCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H]1C[C@H](C)CCCCCCC[C@H](NC(C)=O)C(=O)N[C@@H](C)C(=O)N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 45 mg (0.079 mmol) [(3S,6S,14R,16S)-16-((1S,3R)-3-butylcarbamoyl-1-hydroxy-butyl)-3,14-dimethyl-2,5-dioxo-1,4diaza-cyclohexadec-6-yl]-carbamic acid tert-butyl ester (example 6) in 1 ml 4N HCl/dioxane is kept for 3 h and then evaporated. The residue is taken up in 3 ml THF and 1 ml EtOH and 1 ml 10% aqueous sodium carbonate, cooled to 0° C. and stirred vigorously. 0.112 ml (1.6 mmol) acetyl chloride are added and stirring is continued for 1 h. The solvents are evaporated and the residue is stirred with water and TBME/hexane for 30 min. The mixture is filtered to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[C:24]1([CH3:27])[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH2:18][NH:17][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:7]3[CH:28]=[CH:29][C:4]([CH2:3][CH2:2][NH:1][CH2:58][C@H:56]([OH:57])[CH2:55][O:54][C:51]4[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=4)=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(CCCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CCCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 23 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[3-(4-methylphenyl)propyl]-1-piperidine-carboxamide foramte (0.44 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.40 g, 1.0 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.185 g, 0.23 mmol).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[F:25])[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Fc1ccccc1N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccccc2F)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(2-Fluorophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 7.02 (m, 4H), 5.00 (s, 2H), 3.80 (m, 2H), 3.70 (m, 2H), 3.53 (m, 2H), 3.25 (m, 2H), 2.30 (s, 3H) ppm; MS (ES) M+Na expected=427.0, found 427.0.
Reaction SMILES: [CH:1]1([P:7]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)([C@@H:9]2[CH2:13][NH:12][C@H:11]([CH2:14][P:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)[CH2:10]2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[SiH](Cl)Cl>C(#N)C>[CH:29]1([P:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C@@H:9]2[CH2:13][NH:12][C@H:11]([CH2:14][P:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:10]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=P(C[C@@H]1C[C@H](P(=O)(C2CCCCC2)C2CCCCC2)CN1)(c1ccccc1)c1ccccc1
Agent: Cl[SiH](Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: c1ccc(P(C[C@@H]2C[C@H](P(C3CCCCC3)C3CCCCC3)CN2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In 4 ml of acetonitrile were dissolved 50 mg (0.1 m-mol) of (2S,4S)-4-dicyclohexylphosphinyl-2-diphenylphosphinylmethylpyrrolidine [X] and 42 mg (0.42 m-mol) of triethylamine, and the air in the reaction vessel was satisfactorily replaced with nitrogen. A solution of 54 mg (0.4 m-mol) of trichlorosilane in 1 ml of acetonitrile was added dropwise to the above solution under ice-cooling. After refluxing the mixture for 3 hours, the mixture was concentrated under reduced pressure at a low temperature. The residual product was dissolved in 15 ml of benzene, and 10 ml of a 30% aqueous solution of caustic soda was added to the benzene solution under ice-cooling. The mixture was stirred in nitrogen atmosphere for 30 minutes at 50°60° C. The benzene phase was separated and the aqueous phase was extracted with 10 ml of benzene. The benzene phases are combined, washed with 10 ml of water, dried over magnesium sulfate and concentrated under reduced pressure whereby 44 mg (yield: 95%) of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:26])[C:6]=1[C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Br[CH2:28][C:29]1[CH:41]=[CH:40][C:32](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1>>[CH3:1][C:2]1[N:3]([CH2:28][C:29]2[CH:41]=[CH:40][C:32](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=2)[CH:4]=[C:5]([CH3:26])[C:6]=1[C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1c(C)c[nH]c1C
Reactant: CCOC(=O)/C=C/c1ccc(CBr)cc1
Product: CCCCCCCCCCCCCCCCCC(=O)c1c(C)cn(Cc2ccc(/C=C/C(=O)OCC)cc2)c1C

Procedure:
Preparation as in Example 2C with 362 mg (1 mmol) of 2,4-dimethyl-3-octadecanoylpyrrole (Lehr M., WO95/13266) in place of 3-dodecanoyl-2,4-dimethylpyrrole and with ethyl (E)-4-(bromomethyl)-cinnamate in place of ethyl (E)-3-(bromo-methyl)cinnamate.
Reaction SMILES: [CH:1]([C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:14]([OH:16])=[O:15])=[CH:8]2)=[O:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH:1]([C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[CH:8]2)=[O:2]
Reactant: O=Cc1c(O)ccc2cc(C(=O)O)ccc12
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(O)ccc2cc(C(=O)OCc3ccccc3)ccc12
Reaction time: 72 h

Procedure:
To a suspension of 5-formyl-6-hydroxy-2-naphthoic acid (1.12 g, 5.18 mmol) in 7.3 mL DMF at rt under N2 was added 569 mg (5.69 mmol) of KHCO3 and 1.11 mL (9.32 mmol) of benzyl bromide. The mixture was stirred for 3 days, at which point it was diluted with H2O and extracted with EtOAc. The extract was washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel, using 85:15 hexanes-EtOAc as the eluent, to give 410 mg (25%).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20]C)=[O:19])=[CH:9][CH:8]=1)[CH3:2].O.[OH-].[Li+]>C1COCC1>[CH2:1]([N:3]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])[C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][S:15][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([OH:20])=[O:19])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(CCSc2ccccc2C(=O)O)cc1
Yield: 96.9 %

Procedure:
Methyl 2-{[2-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}-benzoate was dissolved in a mixture of THF (freshly distilled)/water (2/1, 3 ml), Lithium hydroxide (0.015 g, 0.629 mmol) was added. The reaction was performed in a single node microwave oven (5 min, 150 deg). THF was removed by evaporation. Water was added (10 ml) and the basic water phase was washed with diethyl ether (2×10 ml). Addition of HCl (2 ml, 1 M, pH 1). The water phase was extracted with two portions of DCM (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.095 g of 2-{[2-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)ethyl]-thio}benzoic acid (yield 96.9%)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Cc1ccc(N)cn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
prepared by reaction of 6-methyl-pyridin-3-ylamine with 4-tert-butyl-benzene-sulfonyl chloride