Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]([CH3:11])=[C:7]([O:9][CH3:10])[CH:8]=1.[C:15]([O-:18])(=[O:17])[CH3:16].[Na+]>C(O)(=O)C.O>[C:15]([O:18][CH2:2][C:3]1[C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]([CH3:11])=[C:7]([O:9][CH3:10])[CH:8]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: COc1cc(CCl)c(OC)c(C)c1C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(COC(C)=O)c(OC)c(C)c1C
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A mixture of intermediate C (5 g, 0.023 mole) and anhydrous sodium acetate (7.1 g, 0.086 mole) in glacial acetic acid (35 ml) was refluxed for 20 hours. The reaction mixture was cooled to room temperature, diluted with 50 ml of water and extracted with dichloromethane. The organic extracts were washed with saturated sodium bicarbonate solution, dried, and concentrated to yield a dark syrup, which eventually crystallized to give 5.1 g of crude 5-acetoxymethyl-1,4-dimethoxy-2,3-dimethylbenzene (intermediate D).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([CH:11]1[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)=[O:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([CH:11]1[O:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12]1)=[O:10]
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)C1CN(Cc2ccccc2)CCO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCCC1=O)C1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.1 %

Procedure:
A suspension of N-[(1R,2R)-2-hydroxycyclohexyl]-4-(phenylmethyl)-2-morpholinecarboxamide (5.0 g, 15.7 mmol) and pyridinium chlorochromate (PCC) (4.06 g, 18.84 mmol) in CH2Cl2 (79 mL) was stirred at room temperature for 18 hours. The reaction mixture was filtered through a pad of silica gel and washed with EtOAc to get crude product (4.0 g). Purification was carried out on column chromatography (EtOAc—PE, from 2:1 to 2:0) to afford the title compound (0.7 g). LC-MS (ES) m/z=317 [M+H]+.
Reaction SMILES: [CH2:1]([O:3]/C(=C\C1C=CC(C2C=CC=C(N(C)C(NC3C=CC(C(F)(F)F)=CC=3)=O)C=2)=CC=1)/C(OCC)=O)[CH3:2].C(O/[C:41](=[CH:45]\[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([N:58]([CH3:72])[C:59]([NH:61][C:62]3[CH:67]=[CH:66][C:65]([C:68]([F:71])([F:70])[F:69])=[CH:64][CH:63]=3)=[O:60])[CH:53]=2)=[CH:48][CH:47]=1)/[C:42]([OH:44])=[O:43])C>>[CH3:2][CH2:1][O:3]/[C:45](/[C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([N:58]([CH3:72])[C:59]([NH:61][C:62]3[CH:63]=[CH:64][C:65]([C:68]([F:70])([F:69])[F:71])=[CH:66][CH:67]=3)=[O:60])[CH:53]=2)=[CH:48][CH:47]=1)=[CH:41]\[C:42]([OH:44])=[O:43]
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1)OCC
Reactant: CCO/C(=C\c1ccc(-c2cccc(N(C)C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1)C(=O)O
Product: CCO/C(=C\C(=O)O)c1ccc(-c2cccc(N(C)C(=O)Nc3ccc(C(F)(F)F)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 43e, starting with 1.5 g (3 mmol) of ethyl (Z)-2-ethoxy-3-{3′-[1-methyl-3-(4-trifluoromethylphenyl)ureido]biphenyl-4-yl}acrylate, g (%) of (Z)-2-ethoxy-3-{3′-[1-methyl-3-(4-trifluoromethylphenyl)ureido]biphenyl-4-yl}acrylic acid are obtained in the form of a tacky paste.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[N+:10]([C:13]1[C:14]([CH:23]=[O:24])=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)([O-:12])=[O:11]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:23]([C:14]2[C:13]([N+:10]([O-:12])=[O:11])=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[OH:24])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(C(O)c2cccc(F)c2)ccc2cccnc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
3-Fluorophenyl magnesium bromide (1 M solution in THF; 0.86 ml, 4.33 mmol) was added dropwise to a solution of 8-nitroquinoline-7-carbaldehyde (Intermediate 204) (0.35 g, 1.73 mmol) in dry THF (5 ml) at −78° C. and the mixture was stirred at −78° C. for 1 h. The reaction was quenched with saturated NH4Cl solution and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM as the eluent to give the title compound (0.3 g, 58%).
Reaction SMILES: COCCOC[O:7][C:8]1[CH:9]=[C:10]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:11]=[N:12][C:13]=1[C:14]([F:17])([F:16])[F:15].Cl>>[OH:7][C:8]1[CH:9]=[C:10]([C:18]2[CH:30]=[CH:29][C:21]3[N:22]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:24][C:20]=3[CH:19]=2)[CH:11]=[N:12][C:13]=1[C:14]([F:15])([F:16])[F:17]
Reactant: COCCOCOc1cc(-c2ccc3nc(NC(C)=O)sc3c2)cnc1C(F)(F)F
Agent: Cl
Product: CC(=O)Nc1nc2ccc(-c3cnc(C(F)(F)F)c(O)c3)cc2s1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A 5 mL, conical microwave vessel was charged with N-(6-(5-((2-methoxyethoxy)methoxy)-6-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.0137 g, 0.031 mmol), 1M HCl (0.093 ml, 0.093 mmol) and 1.5 mL TFE. The vessel was flushed with nitrogen, sealed, and irradiated to 100° C. using a Biotage initiator microwave for 10 minutes. The solution was concentrated in vacuo, and dried at <1.0 mm Hg for 1 h. The residue was treated with 0.5 mL EtOH, briefly sonicated, and set at room temperature for 1 h. The solids were collected using a 0.22 μm PTFE filter under positive pressure nitrogen, and washed with 0.5 mL EtOH. The precipitate was heated into 2 mL TFE, filtered through a 0.22 μm PTFE filter, and concentrated in vacuo. The solids were then dried at 60° C. and <0.5 mm Hg for 1 h to afford N-(6-(5-hydroxy-6-(trifluoromethyl)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.0068 g, 62% yield). 1H NMR (400 MHz, THF) δ ppm 2.22 (s, 3H) 7.53 (d, J=1.37 Hz, 1H) 7.68 (dd, J=8.46, 1.91 Hz, 1H) 7.77 (dd, J=8.41, 0.49 Hz, 1H) 8.18 (d, J=1.76 Hz, 1H) 8.47 (d, J=1.66 Hz, 1H) 9.68 (br. s., 1H) 11.36 (br. s., 1H). 19F NMR (377 MHz, THF) δ ppm −65.58 (s, 3 F). HPLC-MS: retention time=1.78 min (97.7%@215 nm; 97.8% @254 nm; m/z=354.0, calculated for C15H10F3N3O2S+H+=354.0).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)[CH3:24]
Reactant: Oc1ccc(Cc2cccnc2)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 19.4 %

Procedure:
A mixture of 0.70 g of the phenol compound (prepared as described in Example 9), 0.30 g of sodium hydride (content 63%) and 14 ml of N,N-dimethylformamide was stirred at 100° C. for 20 minutes, and stirred with 0.64 g of ethyl bromoacetate at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and extracted with diethyl ether. The extract was washed with water, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 0.5% V/V solution of ethanol in chloroform as eluent to give 0.166 g of the title compound having the following physical characteristics:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[CH:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C.P([O-])([O-])([O-])=O>[OH:27][CH:19]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)/[CH:18]=[CH:17]/[C@H:11]1[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[N:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2]
Reactant: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: O=C(O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reaction time: 16.5 h
Yield: 6 %

Procedure:
Rabbit liver esterase (134 units/mg, 1 mg) was added to a solution of 7-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester (15 mg, 0.39 mmol) in acetonitrile (0.2 mL) and pH 7.2 phosphate buffer (3.0 mL). After 16.5 h, acetonitrile (5 mL) was added and the reaction mixture was concentrated to dryness in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 8.7 mg (60%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:18]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:28][CH:27]=1)(=[O:25])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)(C)C)cc1
Yield: 60.7 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (5.0 g, 16 mmol) was reacted with 4-(N-tert-butylsulfamoyl)phenylboronic acid (5.4 g, 21 mmol) to afford the desired product (4.3 g, 60%) as a yellow solid: ESI MS m/z [C22H22N2O4S2+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9](N)=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-:20].[K+].O>C(O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9]([OH:20])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: NC(=O)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Temperature: 90 °C
Yield: 47.8 %

Procedure:
The reaction was split into 4, using a quarter of the reagents shown in each: to a mixture of 4-bromo-3-(trifluoromethyl)benzonitrile (4 g, 16.00 mmol), phenylboronic acid (3.90 g, 32.0 mmol) and potassium carbonate (6.63 g, 48.0 mmol) in DMF (64 ml) was added palladium tetrakistriphenylphosphine(0) (1.849 g, 1.600 mmol). Each reaction was heated in the microwave at 150° C. for 30 minutes. The combined reaction mixtures were filtered through Celite®, washed with EtOAc and the solvent removed in vacuo. The residue was partitioned between EtOAc (100 ml) and water (100 ml) and the organic phase washed with sodium bicarbonate solution (100 ml). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The brown oil was triturated with DCM and filtered to give a pale yellow solid, 2-(trifluoromethyl)-4-biphenylcarboxamide (2.47 g) which was used without further purification. To 2-(trifluoromethyl)-4-biphenylcarboxamide (2 g, 7.54 mmol) in ethanol (80 ml) was added potassium hydroxide (4.23 g, 75 mmol) and water and the mixture heated to 90° C. for 18 hrs. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM (100 ml) and 2M HCl (100 ml). The organic phase was isolated and dried (hydrophobic frit phase separator) and the solvent removed in vacuo to give the crude product. Chromatographic purification using the Biotage Horizon, reverse phase cartridge, eluting 5-100% MeCN in water to give the title compound as an off-white solid (960 mg). LCMS (ES−): C14H9F3O2 requires 266; found 265 [M−H+]
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.Cl.[NH2:26][CH2:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[N:30]1([C:28](=[O:29])[CH2:27][NH:26][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:22])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: NCC(=O)N1CCOCC1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N3CCOCC3)ccc21
Yield: 55.5 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)-amide (75 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-amino-1-morpholino-1-ethanone hydrochloride (56 mg), HBTU (127 mg), and DIEA (73 uL). LC/MS: m/z 485.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.38 (bs, 1H), 8.53 (t, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.40 (d, 1H), 4.16 (d, 2H), 3.64 (s, 3H), 3.63-3.60 (m, 2H), 3.58 (t, 2H), 3.55-3.50 (m, 2H), 3.50-3.45 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[I:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11](Cl)=[O:12])=[CH:7][CH:6]=1>C(N(CC)CC)C>[I:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([N:2]([CH3:3])[CH3:1])=[O:12])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: O=C(Cl)COc1ccc(I)cc1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)COc1ccc(I)cc1
Reaction time: 2 h

Procedure:
Dimethylamine (33% w/w in IMS, 5.85 ml) was added dropwise to a suspension of (4-iodophenoxy)acetyl chloride (9.49 g) in triethylamine (50 ml) at 0° under nitrogen. The suspension was stirred for 2 h at 0° and partitioned between ethyl acetate (300 ml) and 8% aqueous sodium bicarbonate (300 ml). The organic layer was dried and the solvent was evaporated to leave an oil which was purified by FCC eluting with diethyl ether to give the title compound as a white solid (3.96 g), m.p. 63°-65°.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[CH:30][C:31]([F:37])=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:37][C:31]1[CH:30]=[CH:29][C:28]([C:6]2[N:10]3[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]3=[N:8][CH:7]=2)=[CH:33][C:32]=1[N+:34]([O-:36])=[O:35]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
To 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (73 ml of a 0.13M solution in tetrahydrofuran, 9.44 mmol) was added 5-bromo-2-fluoronitrobenzene (4.20 g, 19 mmol) followed by tetrakis(triphenylphosphine) palladium(0) (0.62 g). The resulting mixture was heated at reflux for 4 h. The solvent was evaporated at reduced pressure and the residue chromatographed on silica gel eluting with 30% ethyl acetate in dichloromethane to afford 3-(4-fluoro-3-nitrophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 7.59 (1H, d, J 7), 7.83 (1H, dd, J 11 and 9), 8.18 (1H, m), 8.36 (1H, s), 8.53 (1H, dd, J 7 and 2), 9.36 (1H, d, J 7); m/z (ES+) 327 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=O)[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:21]([NH:28][C:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17]2)=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Reactant: NCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)NCc3ccccc3)cc2C1
Yield: 86.8 %

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-carboxyindan (400 mg, 1.44 mmol), benzylamine (0.24 ml, 2.2 mmol), triethylamine (1.4 ml, 10 mmol), propanephosphonic acid anhydride (2.1 ml), dimethylaminopyridine (a catalytic amount) and methylene chloride (12 ml), a similar procedure to a) in Production Example 218 was carried out. The product obtained was purified by silica gel chromatography (methylene chloride:methanol=95:5) to obtain N-benzyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (460 mg, 1.25 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([C:19]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:15][C:3]=1[O:4][C@@H:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][OH:7].[CH3:38][O:39][C:40](=[O:50])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[NH4+].[Cl-]>C1COCC1>[CH3:38][O:39][C:40](=[O:50])[CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][C:46]([O:7][CH2:6][C@@H:5]([O:4][C:3]2[CH:15]=[CH:16][C:17]([C:19]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)([C:20]([F:22])([F:23])[F:21])[C:24]([F:25])([F:26])[F:27])=[CH:18][C:2]=2[CH3:1])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:47][CH:48]=1
Reactant: COc1ccc(COC(c2ccc(O[C@H](CO)Cc3ccccc3)c(C)c2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OC[C@H](Cc2ccccc2)Oc2ccc(C(OCc3ccc(OC)cc3)(C(F)(F)F)C(F)(F)F)cc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To 320 mg (0.6 mmol) of (S)-2-{2-methyl-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-3-phenyl-propan-1-ol in 5 mL of THF were added 0.14 g (0.8 mmol) of 3-(4-hydroxy-phenyl)-propionic acid methyl ester and 0.2 g (0.8 mmol) of triphenylphosphine. The mixture was cooled to 0°, was treated with 0.12 mL (0.8 mmol) of DEAD and was stirred at room temperature overnight. A solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography on silica gel with EtOAc/n-heptane 1:3 to yield 330 mg (79%) of 3-[4-((S)-2-{2-methyl-4-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-3-phenyl-propoxy)-phenyl]-propionic acid methyl ester as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](O)=[O:19])[CH:8]=[CH:9]2)[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:38]([O:40][P:41]([CH2:46][O:47][NH2:48])([O:43][CH2:44][CH3:45])=[O:42])[CH3:39]>O1CCCC1>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:17][C:18](=[O:19])[NH:48][O:47][CH2:46][P:41]([O:40][CH2:38][CH3:39])([O:43][CH2:44][CH3:45])=[O:42])[CH:8]=[CH:9]2)[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c2ccc(CC(=O)O)ccc-2c(C(=O)OCC)c1N
Reactant: CCOP(=O)(CON)OCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c2ccc(CC(=O)NOCP(=O)(OCC)OCC)ccc-2c(C(=O)OCC)c1N
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 2.5 mmol of diethyl 2-amino-6-carboxymethyl-azulene-1,3-dicarboxylate in 50 ml of tetrahydrofuran is treated portionwise at 45° C. with 2.5 mmol of N,N-carbonyldiimidazole. The mixture is stirred for 30 minutes, a solution of 2.5 mmol of diethoxyphosphorylmethoxylamine (L. Maier, Phosphorus, Sulphur, and Silicon 1993, Vol. 76, 119-122) in 20 ml of tetrahydrofuran is added and the resulting mixture is heated to reflux for 3 hours. The mixture is concentrated and the residue is chromatographed on silica gel. Elution with isohexane:ethyl acetate 1:1 gives 78% of the title compound of m.p. 146-147° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10](Br)[CH:9]=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Br)cc(OCc2ccccc2)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccccc2)c1
Yield: 48.6 %

Procedure:
(3-Benzyloxy-5-bromophenyl)-acetic acid ethyl ester (0.250 g, 0.72 mmol), benzene boronic acid (0.10 g, 0.86 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.04 mmol) were suspended in a mixture of K2CO3 solution (0.72 ml, 1.44 mmol, 2M aq) and DME (2 ml). This reaction mixture was irradiated in a CEM microwave at 120° C. for 30 min. The reaction mixture was diluted with water and extracted with Et2O (×3). The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give (5-benzyloxy-biphenyl-3-yl)-acetic acid ethyl ester (0.12 g, 0.35 mmol) as a colourless gum in 48% yield. 1H NMR (CDCl3) δ 7.59-7.54 (m, 2H), 7.48-7.30 (m, 8H), 7.13-7.11 (m, 2H), 6.94-6.91 (m, 1H), 5.12 (s, 2H), 4.16 (q, 2H), 3.64 (s, 2H), 1.27 (t, 3H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Cl[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1COCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1
Yield: 95.5 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), phenylboronic acid (183 mg, 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 4-chloroanisole (0.123 mL, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 176 mg (96%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=O)[CH:16]=1.Cl.[NH2:23][OH:24].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[N:23][OH:24])[CH:16]=1
Reactant: COCOc1ccc(C2=CC(=O)CCC2)c(OCOC)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCOc1ccc(C2=CC(=NO)CCC2)c(OCOC)c1
Reaction time: 3 h
Yield: 98 %

Procedure:
3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one (200 mg), hydroxylamine hydrochloride (72 mg) and triethylamine (0.14 ml) were heated under reflux in ethanol (10 ml). After 3 hr, the cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated in vacuo to furnish the title compound as an oil (206 mg, 99%). m/z (ES+) 308 (M+H)+.