Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:28][C:29]([CH2:32][O:33][CH3:34])=[CH:30][N:31]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:35])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:37]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:28][C:29]([CH2:32][O:33][CH3:34])=[CH:30][N:31]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)([F:37])[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:35])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: COCc1cnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: COCc1cnc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for preparation of 4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 246), using 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2 HCl salt) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5). m/z (ES+) 487 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 7.79-7.67 (m, 2H), 7.66 (d, 3H), 7.53-7.39 (m, 2H), 4.99-4.93 (m, 1H), 4.85 (s, 2H), 3.76-3.56 (m, 3H), 3.50 (s, 3H), 2.42 and 2.34 (2 singlets, amide rotamers, ArCH3, 3H), 2.27-1.97 (m, 8H), 1.92-1.81 (m, 2H), 1.35-1.26 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][CH2:20][C:19]=3[CH:23]=2)[S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)CCO3)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)CCO3)S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-(3-{[(2,3-dihydro-benzofuran-5-ylmethyl)-amino]methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 12w, and 4-fluorobenzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ7.79 (m, 2H), 7.14 (m, 3H), 7.03 (d, 1H), 6.88 (m, 2H), 6.79 (s, 1H), 6.71 (d, 1H), 6.58 (d, 1H), 4.51 (t, 2H), 4.25 (s, 2H), 4.21 (s, 2H), 3.64 (s, 3H), 3.08 (t, 2H), 2.80 (t, 2H), 2.50 (t, 2H).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(=O)([O-])[O-].[Na+].[Na+]>[C:13]([N:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7]1)(=[O:15])[CH3:14]
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)C1CN(C(C)=O)CCC1=O
Temperature: 0 °C

Procedure:
To a vigorously stirred, ice-water cooled suspension of 2.0 g of 3-carbethoxy-4-piperidone in 20 ml of aqueous sodium carbonate is added 1 ml of acetic anhydride. The mixture is stirred in the cold for 30 minutes then extracted with ether. The organic layer is dried and evaporated to afford 1.5 g of colorless solid, m.p. 53°-55° C.
Reaction SMILES: [O:1]=[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[C:3]1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]O)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)[Cl:25].S(Cl)(Cl)=O>O>[Cl:25][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:3]2[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1
Reactant: ClC(Cl)Cl
Reactant: O=c1cccccc1N1CCN(CCO)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=c1cccccc1N1CCN(CCCl)CC1

Procedure:
A mixture of 4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanol (10.0 g, described in Example 7), potassium carbonate (26 g) and chloroform (150 ml) was stirred and cooled in an ice-bath. Thionyl chloride (11.7 g) was added dropwise over a period of 30 min and allowed to react with stirring at room temperature for 16 hr. Water (50 ml) was added and extracted with chloroform. After drying over magnesium sulfate, the extract was evaporated and the residue (11.0 g) was chromatographed on 500 g silica gel with ethyl acetate to yield 6.2 g of 2-[4-(2-chloroethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one mp 71°-73° C.; ir(CHCl3) 1560 cm-1 ; uv max(MeOH) 352 (ε=9730) and 255 nm(ε=14300); nmr(CDCl3) δ2.75 (m, 6H), 3.5 (m, 6H) and 7.0 (m, 5H) and Anal. Calcd for C13H17 --ClN2O: C, 61.77% H, 6.78% N, 11.08% and Found: C, 61.60% H, 6.79% N, 10.98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)=[C:5]([O:18][CH2:19][CH2:20][CH2:21][Cl:22])[CH:4]=1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[ClH:22].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)=[C:5]([O:18][CH2:19][CH2:20][CH2:21][NH:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:4]=1
Reactant: COc1ccc(-c2nc3cnccc3[nH]2)c(OCCCCl)c1
Reactant: CC(C)(C)N
Solvent: CCO
Product: COc1ccc(-c2nc3cnccc3[nH]2)c(OCCCNC(C)(C)C)c1
Product: Cl

Procedure:
The above compound was prepared by reacting the product of stage (a) of Example 43 and tert-butylamine in ethanol at 100° C. for 8 hours as described in stage (b) in Example 43, m.p. 252°-253° C. (hydrate).
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][CH:6]([OH:8])[CH3:7].C[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[C:5]1([CH:6]([OH:8])[C:7]#[C:14][CH2:13][CH2:12][CH2:11][CH3:10])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCCC
Reactant: CC(C)O
Solvent: ClC(Cl)Cl
Product: CCCCC#CC(O)c1ccccc1

Procedure:
A colorless oil. [α]D25−18.1 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.54-7.52 (m, 2H), 7.38-7.28 (m, 3H), 5.43 (d, J=5.6 Hz, 1H), 2.26 (td, J=7.2, 2.0 Hz, 2H), 2.13 (d, J=5.6 Hz, 1H), 1.55-1.36 (m, 4H), 0.898 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 141.2 (C), 128.3 (CH×2), 127.9 (CH), 126.5 (CH×2), 87.3 (C), 79.9 (C), 64.5 (CH), 30.5 (CH2), 21.8 (CH2), 18.3 (CH2), 13.4 (CH3); IR (neat) 3397, 3031, 2958, 2933, 2873, 2227, 1950, 1884, 1809, 1603, 1494, 1455, 1135, 1002, 698 cm−1; HRMS calculated for C13H16O 188.1201, found 188.1192. Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/hexane (10:90), 1.0 mL/min, uv 254 nm; tR=11.0 min (87.5%), 13.8 min (12.5%), 75% ee.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:5][CH3:6].Cl[CH2:16][C:17]#[N:18].CCOCC>CN(C=O)C>[CH3:3][CH:4]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:16][C:17]#[N:18])=[CH:12][CH:13]=1)[CH2:5][CH3:6]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCC#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To prewashed sodium hydride (1.01 g, 42.0 mmol) in 60 ml of DMF at 20° is added 4-(1-methylpropoxy)phenol (7.0 g, 42.0 mmol) in 5 ml of DMF over 30 min. After 1 hour at RT, chloroacetonitrile (3.80 g, 50.4 mmol) in 5 ml of DMF is added dropwise to the mixture at 5°-8° over 15 min. After addition, the reaction is warmed slowly to RT and stirred at RT for 18 hours. The mixture is then poured into ice water and ether and extracted with ether (3×) The combined organic phases are washed with 10% NaOH, with water until neutral and with brine, dried, filtered and solvent removed in vacuo to give 4-(1-methylpropoxy)phenoxyacetonitrile.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:16][CH2:17][C@@H:18]1[O:22][C@H:21]([N:23]2[CH:30]=[C:29]([F:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@H:20]([OH:32])[CH2:19]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>N1C=CC=CC=1>[C:1]([O:32][C@@H:20]1[CH2:19][C@H:18]([CH2:17][O:16][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:22][C@@H:21]1[N:23]1[CH:30]=[C:29]([F:31])[C:27](=[O:28])[NH:26][C:24]1=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(OC[C@H]1C[C@@H](O)[C@@H](n2cc(F)c(=O)[nH]c2=O)O1)c1ccccc1
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)O[C@@H]1C[C@H](COC(=O)c2ccccc2)O[C@@H]1n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 96 %

Procedure:
Acetic anhydride (0.88 mL, 9.28 mmol) was added under argon to a solution of 15 (2.50 g, 7.14 mmol) in dry pyridine (50 mL) and the resulting mnixture was stirred at room temperature for 22 h. Then, ethanol was added and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-2%) in methylene chloride] to give pure 16 (2.69 g, 96%) as a white foam; mp=68-70° C. (foam); UV (ethanol): λmax239 nm (ε=15000) 267 nm (ε=8800), λmin=248 nm (ε=5600); 1H NMR (DMSO-d6): δ ppm 11.9 (br s, 1H, NH), 8.1-7.5 (m, 6H, C6H5CO and H-6), 6.10 (d, 1H, H-1′, J1′-2′=4.3 Hz), 5.4 (m, 1H, H-2′), 4.6-4.4 (m, 3H, H-4′, H-5′ and H-5″), 2.6 (m, 1H, H-3′), 2.03 (m, 1H, H-3″), 1,86 (s, 3H, CH3CO); MS (matrix GT): FAB>0 m/z 785 (2M+H)+, 393 (M+H)+, 263 (S)+, 131 (BH2)+, 105 (C6H5CO)+, 43 (CH3CO)+; FAB<0 m/z 391 (M−H)−, 129 (B)−, 121 (C6H5CO2)−, 59 (CH3CO2)−; [α]D20=−81 (c, 0.95 DMSO).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=[O:6])[CH3:2].[CH3:8][CH:9]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[CH2:10][O:11][CH3:12]>C1(C)C=CC=CC=1>[CH3:8][CH:9]([N:13]([C:5](=[O:6])[CH2:4][O:3][CH2:1][CH3:2])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])[CH2:10][O:11][CH3:12]
Reactant: COCC(C)Nc1c(C)cccc1C
Reactant: CCOCC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOCC(=O)N(c1c(C)cccc1C)C(C)COC

Procedure:
With stirring, 7.3 g of ethoxyacetyl chloride in 20 ml of abs. toluene were added at room temperature to 9.6 g of N-(1'-methyl-2'-methoxyethyl)-2,6-dimethylaniline. After stirring for 3 hours at room temperature, the reaction mixture was filtered. The filtrate was freed from solvent and the residual oil was distilled in a high vacuum. Boiling point: 122°-124° C./0.04 torr.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:14])/[CH:9]=[CH:10]/[C:11](Cl)=O.[CH2:16]=[CH2:17]>OS(O)(=O)=O.[Zn].CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[O:14][C:8]([C:16]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:17]=3)=[CH:9][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C=C
Reactant: Brc1ccccc1
Reactant: O=C(Cl)/C=C/C(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CC(=O)O
Product: Brc1ccc(-c2ccc(-c3ccc(Br)cc3)o2)cc1
Reaction time: 0.08 h

Procedure:
A literature procedure as known in the art for preparation of trans-di-p-bromobenzoylethylene from bromobenzene and fumaryl chloride was employed. J. B. Conant and R. E. Lutz, J. Am. Chem. Soc. 47, 881 (1925). The ethylene compound was reduced with Zn-HOAc to prepare 1,4-di-p-bromophenyl-1,4-butanedione. E. Campaigne and W. O. Foye, J. Org. Chem. 17, 1405 (1952). The saturated 1,4-diketone (7.9 g, 0.02 mol) was suspended in 80 mL of AC2O and the mixture was heated to reflux. Concentrated H2SO4 (4-5 drops) was added and refluxing was continued for 5 min. The solution was poured into water-ice (1 L), stirred well, and filtered: crude yield 7 g (93%). Recrystallization from acetic acid gave 5.6 g (75%), mp 198°-199° C. (lit. (R. E. Lutz and W. M. Eisner, J. Am. Chem. Soc. 56, 2698 (1934)) mp 200°-201° C.).
Reaction SMILES: [Na+].[C:2]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([N:17]3[CH2:22][CH2:21][N:20](N=CSCC4CSC5N(C(=O)C5NC(=O)CC5SC=CC=5)C=4C([O-])=O)[CH2:19][CH2:18]3)=[C:11]([F:16])[CH:12]=2)[N:7]([CH:48]2[CH2:50][CH2:49]2)[CH:6]=1)([OH:4])=[O:3].C([N:59]=[C:60]=[S:61])(=O)C1C=CC=CC=1.C1C2C(=O)C(C(O)=O)=CN(C3CC3)C=2C=C(N2CCNCC2)C=1F.[Na]>C1COCC1>[NH2:59][C:60](=[S:61])[N:20]1[CH2:19][CH2:18][N:17]([C:10]2[CH:9]=[C:8]3[C:13]([C:14](=[O:15])[C:5]([C:2]([OH:4])=[O:3])=[CH:6][N:7]3[CH:48]3[CH2:49][CH2:50]3)=[CH:12][C:11]=2[F:16])[CH2:22][CH2:21]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)[O-])=C(CSC=NN3CCN(c4cc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)CSC12
Agent: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: NC(=S)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
R-[6a,7b]]-3-[[[(3-Carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-4-piperazinyl]iminomethyl]thio methyl]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid sodium salt, of the following formula ##STR332## according to this invention, is made as follows. A solution of benzoyl isothiocyanate (0.92 g) in THF (20 ml) is added to a mixture of ciprofloxacin sodium salt (2.0 g) in THF (300 ml), and the reaction is stirred for 20 hours. The reaction is concentrated to dryness and the residue is triturated with acetone. The resultant benzoylurea is added to a preheated at approximately 80° C. (176° F.) solution of 5% aqueous NaOH and the reaction is stirred for 30 minutes. The mixture is cooled to approximately 5° C. (41° F.) and acidified with 1N HCl. The solid is collected by filtration and recrystallized from DMF to yield 7-[4-(aminothioxomethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:11]
Reactant: C1CCNCC1
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2-c2cccnc2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2cccc(C(=O)N3CCCCC3)c2-c2cccnc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (21 mg, 0.0496 mmol) and piperidine (8.4 mg, 0.0988 mmol) were dissolved in methylene chloride (3 ml), then WSC-HCl (29 mg, 0.1512 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (11 mg, 0.0224 mmol, 45%).
Reaction SMILES: C(OC([CH2:21][O:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C=C)CCCCCCCCCCCCCCC.[OH2:42].[OH-].[Na+].OO.[O:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1>O1CCOCC1>[CH2:51]([O:47][CH2:37][CH:36]([CH2:21][O:22][C:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:41][OH:42])[CH2:50][CH2:49][CH2:48][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C1CCOC1
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCCCCCCCCCC
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCOCC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 66 %

Procedure:
A solution of compound 2 (5.00 g, 9.01 mmol) in 10 ml dry dioxane and BH3 -tetrahydrofuran (10 ml, 10.0 mmol) in tetrahydrofuran was stirred at room temperature for 2 hours. Water (10 ml) was added dropwise, followed by 2.5 N NaOH (20 ml) and 30% H2O2 (7.5 ml). The mixture was stirred at 50° for 2.5 hours, then was cooled and partitioned between CH2Cl2 and water. The aqueous layer was washed 3 times with CH2Cl2 and the combined extracts were dried over Na2SO4 and concentrated. Chromatography on silica gel using 10% ethyl acetatehexane afforded 3.37 g (66%) of the title compound (4) as a waxy white solid, m.p. 38°. NMR (CDCl3, (CH3)4Si); δ0.90 (t, 3H, J=6 Hz, --CH3), 1.25 (s, 26 H, --CH2 --), 1.54 (m, 2H, --OCH2CH2R), 2.16 (m, 1H, CH), 2.70 (t, 1H, J=6.5 Hz, --OH), 3.22 (d, 2H, J=6 Hz, CH2OTr), 3.41 (t, 2H, J=6 Hz, --OCH2R), 3.61 (t, 2H, J=6 Hz, CH2OR), 3.77 (t, 2H, J=6.5 Hz, CH2OH), 7.2-7.52 (m, 15H, C(C6H5)3).
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH2:31])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]([O:20][C:21](=[O:33])[NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH2:30][NH:31][C:13]([C:11]2[O:12][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][N:10]=2)=[O:15])=[C:25]([CH3:32])[N:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)c1ncc(Cc2ccccc2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1ncc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-Benzyl-oxazole-2-carboxylic acid (0.86 g, 2.8 mmol), (5-Aminomethyl-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (0.70 g, 2.8 mmol), HATU (1.4 g, 3.6 mmol) and DIPEA (2.0 mL, 11.7 mmol) in 10 mL DMF was stirred at room temperature for 16 h. The mixture was evaporated and the residue was partitioned between ethyl acetate and 1 N aq. HCl. The organic layer was dried over MgSO4 and evaporated in vacuo. The crude product was purified by preparative HPLC (Waters Sunfire Prep C18 PBD 5 um, 30×100 mm, 5 to 100% ACN and 0.1% TFA, flow 40 ml/min). LCMS (method A) RtA=1.719 min; [M+H]+=437.0
Reaction SMILES: [Si](Cl)(Cl)(C)C.[CH3:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([CH3:23])[CH-:18]3)[CH:10]=[C:11]([CH3:13])[CH:12]=1.[Li+]>C1COCC1>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[C:17]([CH3:23])[CH2:18]3)[CH:8]=[C:7]([CH3:6])[CH:12]=1
Reactant: Cc1cc(C)cc(-c2cccc3[cH-]c(C)cc23)c1
Agent: C[Si](C)(Cl)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=Cc2c(cccc2-c2cc(C)cc(C)c2)C1
Yield: 96.5 %

Procedure:
SiMe2Cl2 (1.2 g, 9.4 mmol) was dissolved in 80 mL of THF. While stirring, lithium 4-(3,5-dimethylphenyl)-2-methylindenide (4.5 g, 18.7 mmol) was added as a dry powder and the contents were allowed to stir overnight at room temperature. The solvent was removed in vacuo and the residue was taken up in pentane and filtered to remove LiCl salts. The pentane was removed in vacuo to yield a flaky white solid (4.23 g, 87%).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2-c2cc(C(N)=O)c(NC(N)=O)s2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Nc1sc(-c2ccccc2OC2CCNC2)cc1C(N)=O
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2-[(Aminocarbonyl)amino]-5-{2-[(1-tert-butyloxycarbonylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide (200 mg) was suspended in dichloromethane (30 ml) and trifluoroacetic acid (5 ml) was added. The mixture was stirred for 1 h, followed by concentration in vacuo. The product was treated with 38% aqueous ammonia and then isolated by filtration as a brown powder (98 mg).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10].[CH:18](=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].O>O1CCCC1>[CH:12]1([O:11][C:9]([O:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[CH:18]=[O:26])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccccc1O
Reactant: O=C(Cl)OC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=Cc1ccccc1OC(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
6.3 ml (45 mmol) of triethylamine and then 7.4 g (45 mmol) of cyclohexyl chloroformate are added dropwise to a solution containing 5 g (41 mmol) of salicylaldehyde in 50 ml of tetrahydrofuran at 0° C. After stirring at ambient temperature for 2 hours, the medium is treated with water and then extracted with a heptane/ethyl acetate 1/1 mixture. The organic phase is dried over magnesium sulphate, filtered and concentrated. 10.3 g of 2-(cyclohexyloxycarbonyl-oxy)benzaldehyde are obtained in the form of a yellow oil with a quantitative yield.
Reaction SMILES: [F:1][C:2]1([F:12])[C:5]([F:7])([F:6])[CH2:4][C:3]1([CH3:11])[C:8](Cl)=O.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>O1CCOCC1>[F:1][C:2]1([F:12])[C:5]([F:7])([F:6])[CH2:4][C:3]1([C:8]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH3:11]
Reactant: NNC(N)=S
Reactant: CC1(C(=O)Cl)CC(F)(F)C1(F)F
Solvent: C1COCCO1
Product: CC1(c2nnc(N)s2)CC(F)(F)C1(F)F
Temperature: 90 °C

Procedure:
A mixture of 2,2,3,3-tetrafluoro-1-methylcyclobutanecarbonyl chloride (ABCR) (2 g, 9.78 mmol) and thiosemicarbazide (Aldrich) (0.891 g, 9.78 mmol) in 10 mL of dioxane was heated at 90° C. for 12 h. The solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated NaHCO3. The organic extract was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on SiO2 (2% methanol in dichloromethane) to give the title compound. MS (ESI+) m/z 242 (M+H)+.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[C:14]([Br:16])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:19]=2)=[C:12]([Br:34])[CH:11]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].C(OCC)(=O)C>C1COCC1>[Br:16][C:14]1[CH:15]=[C:10]([OH:9])[CH:11]=[C:12]([Br:34])[C:13]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:19]=1
Reactant: COc1ccc(Oc2c(Br)cc(OC(=O)c3ccccc3)cc2Br)cc1Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(Br)cc(O)cc2Br)cc1Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a mixture of 3,5-dibromo-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]phenyl benzoate (2.14 gm, 3.75 mmol) in THF 60 mL was added 1 N NaOH 20 mL. The reaction was stirred at r.t overnight, then poured into 120 mL ethyl acetate. The aqueous layer was removed and the organic was washed 2× with aqueous NaHCO3, 1× with 1 N HCl 30 mL. The ethyl acetate was dried over Na2SO4, filtered and concentrated under reduced pressure to give 3,5-dibromo-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]phenol (1.68 gm, 93%); 1H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 7.20 (m, 2H), 7.05 (m, 4H), 6.87 (d, J=9 Hz, 1H), 6.65 (d, J=3.3 Hz, 1H), 6.46 (dd, J=9, 3 Hz, 1H), 3.84 (s, 2H), 3.71 (s, 3H); TLC conditions: Uniplate silica gel, 250 microns; hexane-ethyl acetate [3:1]; Rf=0.65.