Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:29]2[O:28][CH2:27][C:21]3([CH2:26][O:25][CH2:24][O:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:30][CH3:31])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:29]2[O:28][CH2:27][C:21]3([CH2:26][O:25][CH2:24][O:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:30][CH3:31])=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(COCOC1)CO2
Reactant: Cc1c(Cl)cncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(COCOC1)CO2

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (211 mg, 1.3 mmol) with compound 524 (310 mg, 1.0 mmol) in THF (6 mL) in the presence of LiHMDS (3 mL, 3.0 mmol) afforded compound 130 as a white solid material after purification by column chromatography (60-80% EtOAc in light petroleum). LC-MS: RT=3.64 min.; m/z 440.16, 442.17 (M+H)+, 438.27, 440.29 (M−H). 1H NMR (DMSO-d6): δ 8.65 (2H, s), 7.43 (1H, d, J 8.9), 6.89 (1H, d, J 8.9), 4.84 (1H, d, J 6.1), 4.79 (1H, d, J 6.1), 4.64 (2H, s), 4.34 (2H, s), 4.08 (2H, s), 3.90 (2H, d, J 11.4), 3.85 (3H, s), 3.82 (2H, d, J 11.2).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:16])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[CH3:18][Mg]Br.OS([O-])(=O)=O.[K+]>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:16])[CH3:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)CCCNC(=O)OC(C)(C)C
Reactant: C[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)CCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of 11-3 (10.0 g, 40.5 mmol) and THF (200 ml) at 0° C. was added methylmagnesium bromide (27.0 ml, 91.0 mmol; 3M in ether) dropwise over 20 minutes. After 2.0 hours, 10% KHSO4 was added slowly. The mixture was extracted with EtOAc. The organic portion was washed with sat. NaHCO3, brine, and dried over MgSO4. Evaporative removal of the solvent gave 11-4 as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12][C:8]1[C:3]([O:2][CH3:1])=[C:4]([OH:11])[C:5]([O:9][CH3:10])=[CH:6][CH:7]=1
Reactant: COc1cccc(OC)c1O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(OC)c1O
Reaction time: 2 h
Yield: 66.1 %

Procedure:
To a stirring solution of 2,6-dimethoxy-phenol (2 g, 12.98 mmol) in CCl4 (70 mL) at −10° C. was added bromine (2.07 g, 12.98 mmol) and stirred for 2 h. The reaction mixture was diluted with CCl4, washed with water and the combined CCl4 layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3-Bromo-2,6-dimethoxy-phenol as a solid (2 g, 66%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:19])[CH2:7][C:8](=[O:18])[CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)[CH3:4].Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>C1COCC1.[Cl-].[Na+].O>[CH2:3]([O:5][C:6](=[O:19])[CH:7]([C:8]([CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH3:17])[CH2:13][CH2:14]1)=[O:18])[CH2:21][C:22](=[O:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCC1CCC(C(=O)CC(=O)OCC)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCC(C(=O)C(CC(=O)c2ccccc2)C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 115.5 %

Procedure:
To a stirred slurry of 0.92 g (23 mmol) NaH, 60% dispersion in mineral oil, in 30 mL anhydrous THF, cooled 0° C. in ice, 5.12 g (21.3 mmol) 3-oxo-3-(4-propyl-cyclohexyl)-propionic acid ethyl ester from Step 2 was added dropwise over the course of 60 min. The reaction was stirred at 0° C. for 1 hr. 2-bromoacetophenone (5.57 g, 28 mmol) in 12 mL anhydrous THF was then added dropwise at 0° C. and the reaction was allowed to stir at room temperature over 5 days. The reaction was poured into brine, extracted with ethyl acetate, dried over MgSO4, and concentrated to afford 8.85 g (24.6 mmol, 115% yield) 4-oxo-4-phenyl-2-(4-propyl-cyclohexanecarbonyl)-butyric acid ethyl ester as an oil. The product was used in the next step without further purification.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 43 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 43% of theory, C35H42N6O5 (626.8) Rf value: 0.40 (silica gel; dichloromethane/ethanol=19:1) ##EQU68##
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:2]([O:20][C:14]1[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:13]=1[F:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Oc1ccc(Br)cc1F
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1ccc(Br)cc1F
Yield: 99.3 %

Procedure:
To a 50 ml round bottom flask was added 2.77 g (12.5 mmoles) 1-bromodecane and 2.39 g (12.5 mmoles) 2-fluoro-4-bromophenol (1) in 25 ml methyl ethyl ketone. 4.30 g anhydrous potassium carbonate was added and the heterogeneous mixture was refluxed for 48 hrs. The reaction mixture was partitioned between ethyl ether and water, washed with brine, dried, filtered through a 2 inch plug of silica, and solvent removed to afford 4.11 g (99%) of the 4-decyloxy-3-fluorophenyl bromide (2), where R=C10H21, as a pale yellow clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[N+]=[N-].[FH:11]>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:11])[CH:5]=[CH:4][C:3]=1[NH2:8]
Reactant: F
Reactant: [N-]=[N+]=Nc1ccccc1F
Solvent: C1CCCCC1
Product: Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4.11g. (0.03 mole) of 2-fluorophenylazide in 81 ml. of cyclohexane was treated with 20 ml. of hydrogen fluoride. The reaction mixture was then shaken at room temperature for 24 hours, then cooled, vented, and rinsed from the bomb with two successive applications of 100 ml. of dichloromethane and then 100 ml. of water. The reaction mixture was then blown down under nitrogen, quenched in 75g. of ice, and rendered basic with KOH pellets. The reaction mixture was extracted with dichloromethane to yield 2.2g. (57%) of a brown-red fluid after drying over MgSO4. The 2,4-difluoroaniline structure of the final product was confirmed by IR, and the product had a b.p. of 90°-92° C. at 40 mm. Hg.
Reaction SMILES: [OH:1][CH:2]1[C:19]([CH3:21])([CH3:20])[O:18][C:17]2[C:4](=[C:5]3[C:14](=[C:15]([O:22][CH3:23])[CH:16]=2)[C:13](=[O:24])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]4[CH:28]=[CH:27][CH:26]=[CH:25][C:11]4=2)[N:6]3[CH3:29])[C:3]1=[O:30].[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[C:31]([O:1][CH:2]1[C:19]([CH3:20])([CH3:21])[O:18][C:17]2[C:4](=[C:5]3[C:14](=[C:15]([O:22][CH3:23])[CH:16]=2)[C:13](=[O:24])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]4[CH:28]=[CH:27][CH:26]=[CH:25][C:11]4=2)[N:6]3[CH3:29])[C:3]1=[O:30])(=[O:33])[CH3:32]
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(=O)C(O)C(C)(C)O2
Reactant: CC(=O)OC(C)=O
Product: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(=O)C(OC(C)=O)C(C)(C)O2

Procedure:
The compound is obtained according to the procedure of Example 14, starting from the compound of Example 16, using acetic anhydride instead of the butyryl chloride.
Reaction SMILES: ClC1C=C2C(C)(C)/C(=C\C=C(/C3C=CC=C(CCCCC(O[N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=O)C=3)\C=C\C3C(C)(C)C4C5C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=5C=CC=4[N+]=3CCCCS([O-])(=O)=O)/N=C2N(CCCCS([O-])(=O)=O)C=1.[Na+:77].[Na+].[Na+].[C:80]([CH2:83][CH2:84][CH2:85][CH2:86][C:87]1[CH:88]=[C:89](/[C:93](=[CH:119]\[CH:120]=[C:121]2/[C:122]([CH3:140])([CH3:139])[C:123]3[C:124](=[N:138]/2)[N:125]([CH2:130][CH2:131][CH2:132][CH2:133][S:134]([O-:137])(=[O:136])=[O:135])[CH:126]=[C:127]([Cl:129])[CH:128]=3)/[CH:94]=[CH:95]/[C:96]2[C:104]([CH3:106])([CH3:105])[C:103]3[C:98](=[CH:99][CH:100]=[C:101]([S:107]([O-:110])(=[O:109])=[O:108])[CH:102]=3)[N+:97]=2[CH2:111][CH2:112][CH2:113][CH2:114][S:115]([O-:118])(=[O:117])=[O:116])[CH:90]=[CH:91][CH:92]=1)([OH:82])=[O:81].[Na+].[Na+]>>[Cl:129][C:127]1[CH:128]=[C:123]2[C:122]([CH3:140])([CH3:139])/[C:121](=[CH:120]\[CH:119]=[C:93](/[C:89]3[CH:90]=[CH:91][CH:92]=[C:87]([CH2:86][CH2:85][CH2:84][CH2:83][C:80]([O:82][N:70]4[C:74](=[O:75])[CH2:73][CH2:72][C:71]4=[O:76])=[O:81])[CH:88]=3)\[CH:94]=[CH:95]\[C:96]3[C:104]([CH3:105])([CH3:106])[C:103]4[C:98](=[CH:99][CH:100]=[C:101]([S:107]([O-:110])(=[O:108])=[O:109])[CH:102]=4)[N+:97]=3[CH2:111][CH2:112][CH2:113][CH2:114][S:115]([O-:118])(=[O:116])=[O:117])/[N:138]=[C:124]2[N:125]([CH2:130][CH2:131][CH2:132][CH2:133][S:134]([O-:137])(=[O:136])=[O:135])[CH:126]=1.[Na+:77].[Na+:77]
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C)c1cccc(CCCCC(=O)O)c1
Reactant: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1
Agent: [Na+]
Product: CC1(C)C2=CC(Cl)=CN(CCCCS(=O)(=O)[O-])C2=N/C1=C/C=C(/C=C/C1=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc2C1(C)C)c1cccc(CCCCC(=O)ON2C(=O)CCC2=O)c1

Procedure:
Compound 50 is prepared analogously to compound 29 (Example 38), except that compound 49 is used as a starting material.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=[O:18])=[CH:10][C:11]=2[O:13]C(=O)C)[C:6]([CH2:20][CH3:21])=[N:5]1)(=O)C.[H-].[Na+].[CH2:24](O)[CH3:25]>CCOC(C)=O>[CH2:20]([C:6]1[C:7]2[C:12](=[C:11]([OH:13])[CH:10]=[C:9]([C:17]([O:19][CH2:24][CH3:25])=[O:18])[CH:8]=2)[NH:4][N:5]=1)[CH3:21]
Reactant: CCc1nn(C(C)=O)c2c(OC(C)=O)cc(C(=O)[O-])cc12
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(O)c2[nH]nc(CC)c2c1
Yield: 87 %

Procedure:
To a solution of 1-acetyl-7-(acetyloxy)-3-ethyl-1H-indazole-5-carboxylate (4.0 g, 13 mmol) in ethanol (450 mL) was slowly added 60% NaH (0.50 g, 12.6 mmol). The mixture was stirred for 1 hour before concentration and removal of the majority of the ethanol. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3. The aqueous phase was back extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The solid was triturated with CH2Cl2 to provide ethyl 3-ethyl-7-hydroxy-1H-indazole-5-carboxylate as an off-white solid (2.9 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20](O)=[O:21])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:20](=[O:21])[CH2:19][CH:16]1[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:24])[CH:12]=2)[C:14](=[O:23])[NH:15]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Reactant: NCc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)NCc3ccccc3)C2=O)cn1
Yield: 30 %

Procedure:
Prepared as in Example 10-48 from 3-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) and benzyl amine. Yield: 30%. 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.41 (s, 3H), 2.56-2.52 (m, 1H, J=16 Hz), 2.56-2.52 (m, 1H), 3.00-2.96 (m, 1H), 4.45-4.44 (d, J=5.6 Hz, 2H), 5.04 (s, 2H), 5.96 (bs, 1H), 6.36 (bs, 1H), 7.36-7.25 (m, 5H), 7.90 (s, 1H, 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.3 μM.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH:25]([C:27]2[CH:39]=[CH:38][C:30]([O:31][C@@H:32]([CH3:37])[C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=2)[CH3:26])[C:20]([CH3:40])=[C:19]3[CH3:41])=[O:15])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.CN(C=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH:25]([C:27]2[CH:28]=[CH:29][C:30]([O:31][C@@H:32]([CH3:37])[C:33]([OH:35])=[O:34])=[CH:38][CH:39]=2)[CH3:26])[C:20]([CH3:40])=[C:19]3[CH3:41])=[O:15])[CH3:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)[C@H](C)Oc1ccc(C(C)n2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1c(C)n(C(C)c2ccc(O[C@@H](C)C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12

Procedure:
A solution of (2S)-methyl 2-(4-(1-(5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoate (˜0.07 mmol) and NaOH (2 M, 0.2 mL) in MeOH (2 mL) and DMF (1 mL) was stirred at rt for 5 h. It was neutralized and purified by preparative HPLC to yield the title compound as a white solid. ESI-MS (m/z): 541 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[I:10][C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=1)[C:14]([C:16](=[CH:19]NC1C=CC=CC=1)[C:17]#[N:18])=[O:15]>C(O)C.CCCCCC>[NH2:18][C:17]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:19][C:16]=1[C:14](=[O:15])[C:13]1[CH:27]=[CH:28][CH:29]=[C:11]([I:10])[CH:12]=1
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(I)c1
Reactant: NNc1ccc(F)cc1
Solvent: CCO
Solvent: CCCCCC
Product: Nc1c(C(=O)c2cccc(I)c2)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
A mixture of 4-fluorophenylhydrazine (26.6 g, 211 mmol) and 2-(3-iodobenzoyl)-3-phenylaminoacrylonitrile (79 g, 211 mmol) in ethanol (400 ml) was heated at reflux under a nitrogen atmosphere. After 30 minutes, the reaction mixture was cooled to room temperature, diluted with hexane to give 5-amino-4-(3-iodobenzoyl)-1-(4-fluorophenyl)pyrazole (75.1 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH2:14][C:15]23[CH2:24][CH:19]4[CH2:20][CH:21]([CH2:23][C:17]([CH2:25][OH:26])([CH2:18]4)[CH2:16]2)[CH2:22]3)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Si:31]([O:26][CH2:25][C:17]12[CH2:23][CH:21]3[CH2:20][CH:19]([CH2:24][C:15]([CH2:14][O:13][C:3]4[C:2]([Cl:1])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=4)([CH2:22]3)[CH2:16]1)[CH2:18]2)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OCC23CC4CC(C2)CC(CO[Si](C)(C)C(C)(C)C)(C4)C3)cc1F
Yield: 102 %

Procedure:
A solution of methyl 5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzoate (0.83 g, 2.17 mmol), tert-butylchlorodimethylsilane (0.36 g, 2.39 mmol), and imidazole (0.74 g, 10.90 mmol) in anhydrous dimethylformamide (12 mL) was stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), saturated ammonium chloride (2×50 mL) and brine (2×50 mL); dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (8:1 hexanes:ethyl acetate) to provide the title compound (1.10 g, quant): 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=7.6 Hz, 1H), 6.62 (d, J=12.1 Hz, 1H), 3.87 (s, 3H), 3.58 (s, 2H), 3.17 (s, 2H), 2.13-2.05 (m, 2H), 1.69-1.58 (m, 6H), 1.49-1.36 (m, 6H), 0.87 (s, 9H), −0.01 (s, 6H); MS (ES+) m/z 497.1, 499.1 (M+1).
Reaction SMILES: [CH3:1][O:2][P:3]([N:7]([CH3:9])[CH3:8])([O:5]C)=[O:4].[C-]#N.[Na+:12]>CS(C)=O>[CH3:1][O:2][P:3]([N:7]([CH3:9])[CH3:8])([O-:5])=[O:4].[Na+:12]
Reactant: COP(=O)(OC)N(C)C
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COP(=O)([O-])N(C)C
Reaction time: 8 h

Procedure:
There is reacted with stirring for several hours at 60°-70° C. a mixture of 153 parts dimethyldimethylamidophosphate, 50 parts sodium cyanide and 400 parts dimethylsulphoxide (DMSO). The preparation is left overnight at ambient temperature, the product separated off by filtration, washed with DMSO and then with acetone and dried under vacuum. 140 parts of a white solid, readily soluble in water, are obtained.
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[N:30]4[N:31]=[C:32]([CH2:34][OH:35])[N:33]=[C:29]4[N:28]=[C:27]([C:36](=[O:39])[NH:37][OH:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:42][O:43][C:44]([CH3:60])([CH3:59])[C:45]([NH:47][NH:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=1)=[O:46]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:42]/[O:43][C:44]([C:45](=[O:46])[NH:47][NH:48][C:49](=[O:58])[C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=2)([CH3:59])[CH3:60])/[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[N:30]4[N:31]=[C:32]([CH2:34][OH:35])[N:33]=[C:29]4[N:28]=[C:27]([C:36](=[O:39])[NH:37][OH:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(C(=O)NO)nc5nc(CO)nn45)CS[C@H]23)cs1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(C(=O)NO)nc4nc(CO)nn34)CS[C@H]12)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(hydroxycarbamoyl)-2-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (50 mg) (0.082 mmol) and 34 mg (0.11 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 4 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the solvent is removed at room temperature. The residue is treated with water. The precipitated product is filtered off under suction and washed in succession with water and diethyl ether. There are obtained 50 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[5-(hydroxycarbamoyl)-2-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonic acid chloride (0.41 ml, 6.5 mmol, 1.5 eq) was added to an ice-cooled (0° C.) solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (1.0 g, 4.37 mmol, 1 eq) and triethylamine (1.2 ml, 8.7 mmol, 2.0 eq) in dichloromethane (10 ml), and stirring was carried out for 1 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was diluted with dichloromethane (75 ml), washed with water and sat. NaCl solution (in each case 30 ml), dried over sodium sulfate and concentrated under reduced pressure. A yellow oil was obtained, which was used in the next step without being purified further.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:24])[CH2:19][CH2:18]1>CC1C=CC=CC=1>[C:4]([CH:5]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:24])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(C)=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 4 parts of a sodium hydride dispersion 60% in 180 parts of methylbenzene are added dropwise 12 parts of ethyl 3-oxobutanoate at room temperature. Then there is added 1 part of N,N,N-tridecylmethanammonium chloride and the whole is warmed to 40° C. At this temperature, a solution of 25 parts of [1-(3-chloropropyl)-4-piperidinyl](4-fluorophenyl)methanone in 45 parts of methylbenzene is added slowly. The whole is heated to reflux and stirring is continued overnight at reflux temperature. The reaction mixture is cooled to room temperature and filtered over Hyflo. The filtrate is evaporated, yielding 24 parts of ethyl α-acetyl-4-(4-fluorobenzoyl)-1-piperidinepentanoate as a residue.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[C:17]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)(=O)[CH3:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH3:18])=[CH:9][CH:10]=1
Reactant: CC(=O)c1cccnc1
Reactant: Nc1ccc(Oc2ccc(F)cc2F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(Nc1ccc(Oc2ccc(F)cc2F)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of N-(4-(2,4-difluorophenoxy)phenyl)amine (1.0 equiv.) in dichloromethane (0.2 M) was cooled to 0° C. and treated with 3-acetylpyridine (Aldrich; 1.4 equiv.), acetic acid (5.0 equiv.), and sodium triacetoxyborohydride (2.5 equiv.). The reaction was allowed to warm to ambient temperature and stirred an additional 22 hours. The reaction was cautiously quenched with saturated aqueous NaHCO3 then adjusted to pH=10 with 1 N NaOH. The mixture was stirred for 4 hours then the layers were separated. The aqueous layer was extracted twice with DCM. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified via radial chromatography eluting with 50:50 to 60:40 ethyl acetate/hexanes to give N-(4-(2,4-difluorophenoxy)phenyl)-1-pyrid-3-ylethylamine. 1H NMR (400 MHz) 1.54 (3H, d, J=6.7 Hz), 3.96 (1H, bs), 4.48 (1H, q, J=6.7 Hz), 6.44 (2H, m), 6.76 (2H, m), 6.83-6.93 (2H, m), 7.24 (1H, m), 7.44 (1H, m), 7.68 (1H, td, J=1.8, 7.9 Hz), 8.50 (1H, d, J=3.8 Hz), 8.64 (1H, bs). HRMS calcd 327.1309. Found 327.1308.