Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([NH:14][NH2:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CN(C)/[CH:20]=[N:21]/[C:22](=O)[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]>C(O)(=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:22]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=5[F:30])=[N:21][CH:20]=[N:15]4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CN(C)/C=N/C(=O)c1ccc(F)cc1F
Reactant: NNc1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: CC(=O)O
Product: Fc1ccc(-c2ncnn2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)c(F)c1
Temperature: 90 °C
Yield: 65 %

Procedure:
A suspension of (8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-hydrazine (312 mg, 1 mmol) and N-[1-dimethylamino-meth-(E)-ylidene]-2,4-difluoro-benzamide (232 mg, 1.1 mmol) in acetic acid (6 mL) was heated at 90° C. for 3 h, allowed to cool down to RT and filtered. The precipitate was washed with diethyl ether and dried to afford the title compound as a beige solid (300 mg, 65%). LCMS (Method B): RT=4.51 min, [M+H]+=461 and 463. 1H NMR (DMSO-d6): 8.50 (1 H, s), 7.82 (1 H, td, J=8.4, 6.4 Hz), 7.57 (1 H, ddd, J=10.4, 9.4, 2.5 Hz), 7.39-7.30 (2 H, m), 7.23 (1 H, d, J=2.0 Hz), 7.13 (1 H, dd, J=8.6, 2.0 Hz), 4.33 (2 H, t, J=5.0 Hz), 3.34 (2 H, t, J=5.0 Hz).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([N+:18]([O-])=O)=[N:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:3]1>C(O)C.O.Cl.[Fe]>[NH2:18][C:15]1[S:14][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)=[N:17][N:16]=1
Reactant: CCOC(=O)C(C)C1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)C1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Temperature: 85 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of ethyl 2-(1-hydroxy-4-methyl-6-(5-nitro-1,3,4-thiadiazol-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate (500 mg, 1.15 mmol, 1.00 equiv, 90%) in ethanol/H2O (15/5 mL). This was followed by the addition of Fe (280 mg, 5.00 mmol, 4.00 equiv). Then added 2 drops of HCl. The resulting solution was stirred for 2 h at 85° C. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. This resulted in 0.8 g (90%) of ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[O:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][N:7]=1.[C:17]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].N1C=CC=CC=1C(O)=O>O1CCOCC1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[O:5][C:6]1[N:7]=[CH:8][C:9]([CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1ccc(Oc2ccc(I)cn2)cc1F
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Oc2ccc(F)c(F)c2)nc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 166.9 %

Procedure:
To a suspension of 2-(3,4-difluorophenoxy)-5-iodopyridine (22 g, 41.0 mmol), diethyl malonate (6.56 g, 41.0 mmol) and Cs2CO3 (13.34 g, 41.0 mmol) in 1,4-dioxane (200 mL) was added picolinic acid (5.04 g, 41.0 mmol) and copper(I) iodide (7.80 g, 41.0 mmol). The reaction mixture was stirred at 80° C. for 10 hr. and then concentrated under reduced pressure. The residue was extracted with CH2Cl2, and then the organic layer was separated and concentrated under reduced pressure to provide diethyl 2-(6-(3,4-difluorophenoxy)pyridin-3-yl)malonate (25 g, 85%).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=O)=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)(Cl)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>C(Cl)Cl>[CH2:23]([N:25]([CH2:26][CH3:27])[C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:2](=[O:1])[C:3]3[C:8]([O:9][C:10]=2[CH:11]=1)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:18])[CH3:24]
Reactant: CCNCC
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3oc2c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
A sample of compound 5a, (13.4 g, 55.6 mmol) was suspended in 220 mL CH2Cl2 and 24.4 mL (330 mmol) of thionyl chloride was added. The mixture was refluxed over 6 h, adding approximately 10 mL of additional thionyl chloride per hour until the reaction became homogeneous. At that time, the thionyl chloride and solvent were removed under vacuum and the remaining residue was diluted with an additional 220 mL CH2Cl2. To the suspension was added 100 mL ice cold 1.5 N NaOH, 100 mL CH2Cl2, and 17 mL (166 mmol) diethyl amine. After stirring for 15 min at room temperature, the phases were separated, and the organic phase was washed with HCl and brine, dried over magnesium sulfate, filtered and concentrated to yield Compound 6a (14.7 g, 49.8 mmol). MS m/z (MH+) 296.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[N:17]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:20][CH2:19]2)[N:16]=[C:15]([C:35]([F:38])([F:37])[F:36])[CH:14]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:11]([C:13]3[N:17]([CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:20][CH2:19]4)[N:16]=[C:15]([C:35]([F:36])([F:38])[F:37])[CH:14]=3)=[N:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(N)c(NC(=O)c2cc(C(F)(F)F)nn2C2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(-c3cc(C(F)(F)F)nn3C3CCN(CCN(C)C(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Acetic acid (1.591 mL) was added to compound 106 (86 mg, 0.159 mmol) and the solution was allowed to stir for 2 h at 90° C. The reaction was cooled and neutralized with a solution of saturated Na2CO3 and extract with AcOEt. After the usual work-up crude 106 was obtained as a light yellow solid. LRMS (ESI): calc. 522.7; found 523.4 (MH)+.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O>C(OCC)C>[C:11]1([CH:10]([OH:17])[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: OC(c1ccccc1)C(Cc1ccccc1)c1ccccc1

Procedure:
Four liters of an ethyl ether solution containing 500 g of benzyl magnesium chloride were added slowly to a mixture of 1.5 Kg benzoyl chloride and 1 l of ethyl ether while cooling the whole mass. Thereafter, the whole mass was incorporated with 1 l of 30% sulphuric acid, agitated, incorporated with an alkali for neutralizing the sulphuric acid, washed with water and then distilled to remove therefrom 183 g of a distillate (phenyl-o-tolylketone) boiling in the range of 164°-169° C. at 9 mm Hg and then obtain 200 g of a distillate (1,2,3-triphenylpropanol) boiling in the range of 224°-235° C. at 8 mm Hg. This propanol (180 g) was incorporated with 150 cc of toluene and 35 g of potassium sulphite to form a mixture which was heated under reflux and, after distillation-off of the toluene, obtain 153 g of 1,2,3-triphenylpropene-1 as the distillate boiling in the range of 185°-188° C. at 0.03 mm Hg. The thus obtained distillate (128 g) was incorporated with 14 g of a rhodium-activated carbon catalyst (rhodium content: 5 wt.%) and 500 cc of n-hexane in a 2-liter autoclave where the resulting mixture was heated to 65° C. for 20 minutes and then at 95° C. for one hour under a hydrogen pressure of 100 Kg/cm2, and further heated to 200° C. for 5 hours under a hydrogen pressure of 200 Kg/cm2 to distil off the n-hexane and then obtain 124 g of a distillate boiling in the range of 140°-146° C. at 0.025 mm Hg and having a refractive index (nD25) of 1.4959. It was found from the NMR spectrum of this distillate that at least 95% of hydrogenation of the aromatic nuclei and aliphatic unsaturated bonds in the distillate had been effected. The distillate was 1,2,3-tricyclohexylpropane having a kinetic viscosity of 7.69 cSt (98.9° C.) and a traction coefficient of 0.075. The distillate or conventional traction fluid obtained herein had a comparatively high viscosity but it was very unsatisfactory in traction coefficient as compared with the traction fluids (II) of this invention (traction coefficient: 0.092~0.094 as indicated in Examples 3-5). Further, it is very uneconomical that the synthesis of such a conventional traction fluid will require a Grignard's reaction using benzyl magnesium chloride and benzoyl chloride.
Reaction SMILES: [O:1]=[C:2]([C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=[C:10]([F:17])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[BH4-].[Na+].[CH2:20]([OH:22])[CH3:21]>>[C:20]([O:1][CH:2]([C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=[C:10]([F:17])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:22])[CH3:21]
Reactant: CCO
Reactant: CCOC(=O)C(=O)c1cc(F)cc2ccoc12
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)C(OC(C)=O)c1cc(F)cc2ccoc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 0.894 gm (3.78 mMol) ethyl 2-oxo-2-(5-fluorobenzofur-7-yl)acetate and 0.143 gm (3.78 mMol) sodium borohydride in 5 mL ethanol was stirred at room temperature for 1 hour. The reaction was quenched by the dropwise addition of water and was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, and the organic phase concentrated under reduced pressure. The residual oil was subjected to flash silica gel chromatography, eluting with chloroform containing 2% methanol. Fractions containing ethyl 2-hydroxy-2-(5-fluorobenzofur-7-yl)acetate were combined and concentrated under reduced pressure. This residue was dissolved in 2.5 mL of pyridine and 2.5 mL acetic anhydride and was stirred at room temperature for 1 hour. The reaction mixture was then diluted with 25 volumes of ethyl acetate, washed with water, and concentrated under reduced pressure to provide 0.675 gm (64%) of the desired compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([C:16]([OH:18])=O)[CH2:13][CH2:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20]([NH2:23])[CH:21]=[CH2:22]>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([C:16]([NH:23][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:13][CH2:12][C:11]=3[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C1CCc2cc(C3CCCCC3)ccc2O1
Reactant: C=CCN
Product: C=CCNC(=O)C1CCc2cc(C3CCCCC3)ccc2O1

Procedure:
5 Also was prepared, as white crystals, mp: 93°-94° C., by the procedure described in the last paragraph of Example 2, from the ethyl ester of 6-cyclohexyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (Witiak et al. (1975)) and 2-propenamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:3]=1[F:25].[I:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30].IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[F:25][C:3]1[CH:4]=[C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:7][C:2]=1[NH:1][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=1[I:26]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1F
Reactant: O=C(Cl)c1ccccc1I
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3I)c(F)c2)c2ccc3ccccc3c2N1
Yield: 37.3 %

Procedure:
By using 5-(4-amino-3-fluorophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.09 mmol) synthesized in the same manner as that of Example 1, (3), and 2-iodobenzoyl chloride (0.134 mmol), the title compound (19 mg, yield 38%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.ClC[CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:42][CH2:43][N:38]3[CH2:37][CH2:41][CH2:40][CH2:39]3)=[C:22]([CH3:27])[CH:21]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)c2cccc3c2CCCC3)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)c(C)c2)c2cccc3c2CCCC3)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(3-methyl-4-hydroxy-phenyl)-5,6,7,8-tetrahydro-naphth-1-yl-methane (330 mg, 0.001 mol), anhydrous. K2CO3 (2.0 gm, 0.14 mol), 1-(2-chloroethyl)piperidine hydrochloride (400 mg, 0.002 mol) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent to give the title compound of formula I. Yield 210 mg. (7.19%).
Reaction SMILES: O=C1CC(CN[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=4)=[CH:17][N:18]=3)[N:15]=2)CCN1C(OC(C)(C)C)=O.[C:37](O)([C:39](F)(F)F)=[O:38]>C(Cl)Cl>[NH2:14][CH2:13][CH:12]1[CH2:11][CH2:10][N:15]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:28])[F:29])[CH:20]=4)=[CH:17][N:18]=3)[N:15]=2)[C:37](=[O:38])[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1=O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(c2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of compound tert-butyl 2-oxo-4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)methyl)piperidine-1-carboxylate (114 mg, 0.23 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 30 min and condensed. The residue was purified by prep-HPLC to give 4-(aminomethyl)-1-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)piperidin-2-one as white solid.
Reaction SMILES: [C:1]1([CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:12][Mg]Br.Cl>C(OCC)C>[C:1]1([CH2:6][CH2:7][CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(=O)CCCC1=CCCC1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CC(C)(O)CCCC1=CCCC1
Temperature: 25 °C
Yield: 11 %

Procedure:
5-(Cyclopent-1-enyl)-2-pentanone (5.95 g; 39 mmol) in ethyl ether (6 ml) was added dropwise to a 3M solution of methylmagnesium bromide in the same solvent (17 ml; 51 mmol) during 15 minutes. After 2 hours at reflux, the mixture was cooled down to room temperature, poured into ice (20 g), acidified with 5N HCl (20 ml) and extracted with MTBE (60 ml). The aqueous phase was separated and extracted again with MTBE (2×100 ml). The combined organic phases were washed with saturated NaHCO3 (80 ml), H2O (80 ml), brine (80 ml), dried over MgSO4 and concentrated in vacuo. Bulb-to-bulb distillation (80° C./0.06 torr) yielded quantitatively 5.84 g of 5-(cyclopent-1-enyl)-2-methylpentan-2-ol containing 11% of 5-cyclopentylidene-2-methylpentan-2-ol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]3[NH:26][N:25]=[C:24]4[C:27]5[C:32]([C:33](=[O:34])[C:23]=34)=[C:31]([NH:35][C:36](=[O:44])[NH:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:30]=[CH:29][CH:28]=5)[CH2:18][CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[N:11]1([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]3[NH:26][N:25]=[C:24]4[C:27]5[C:32]([C:33](=[O:34])[C:23]=34)=[C:31]([NH:35][C:36](=[O:44])[NH:37][N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[CH:30]=[CH:29][CH:28]=5)[CH2:18][CH2:17]2)=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H]2CC[C@H](c3[nH]nc4c3C(=O)c3c(NC(=O)NN5CCOCC5)cccc3-4)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc2c1C(=O)c1c-2n[nH]c1[C@H]1CC[C@H](C(=O)N2CCNCC2)CC1)NN1CCOCC1

Procedure:
Prepared in a similar fashion as described for exampleCXXVI, step 7, using 3-(trans-4-(4-(t-butoxycarbonyl)piperazinocarbonyl)cyclohexyl)-5-(morpholinocarbamoylamino)indeno[1,2-c]pyrazol-4-one as the starting material. mp 247-248° C. (TFA salt); ESI-MS (M+H) calc'd for C26H34N7O4: 508.2672, found: 508.2670.
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>>[OH:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:30]2[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCO)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2NCCO)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 152 using 5-bromo-6-((2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 159.1) and (6-methylpyridin-3-yl)boronic acid. LC-MS (Condition 6) tR=0.87 min, m/z=433.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:9]1[S:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([C:9]1[S:13][C:12]([CH:14]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(C=O)s1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(C=CC(=O)OCC)s1

Procedure:
A solution of 75.4 g. 5-octyl-2-thiophenecarboxaldehyde and 117.6 g. ethyl (triphenylphosphoranylidene)acetate in 400 ml. tetrahydrofuran is refluxed for 20 hours. The solution is concentrated, the semi-solid residue is slurried with ether and filtered. Concentration followed by distillation of the resultant oil yields ethyl 5-octylthiophene-2-acrylate as an oil.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][NH:6][C:5](=O)[C:4]=1[F:10])[CH3:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[C:4]([F:10])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: CCc1nc[nH]c(=O)c1F
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1ncnc(Cl)c1F
Yield: 66 %

Procedure:
A mixture of the product of part (i) (6.4 g, 45 mmol) and phosphoryl chloride (30 ml) was heated under reflux for 3 hours. The excess phosphoryl chloride was removed by distillation under reduced pressure and the residue was poured into ice-water. The resulting mixture was extracted with methylene chloride (3×50 ml) and the combined organic extracts were washed with water and dried over magnesium sulphate. The solvent was removed under removed pressure and the resulting oil was distilled under reduced pressure to provide the title compound (4.81 g, 66%), b.p. 74° C. at 22 mm Hg, which was characterised by 1H-NMR spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)[CH:10]=[CH:11][CH:12]=1)([O-])=O>C(O)C.CN(C)C=O.[C].[Pd]>[NH:17]1[C:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[NH2:1])=[N:14][N:15]=[N:16]1
Reactant: O=[N+]([O-])c1ccccc1Oc1cccc(-c2nnn[nH]2)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccccc1Oc1cccc(-c2nnn[nH]2)c1
Yield: 96.9 %

Procedure:
In a mixture of 18 ml of ethanol and 9 ml of N,N-dimethylformamide was dissolved 1.5 g of 5-[3-(2-nitrophenoxy)phenyl]-1H-tetrazole and catalytic hydrogenation was carried out in the presence of 0.3 g of palladium-carbon at atmospheric temperature and pressure. After this reaction, the catalyst was filtered off and the filtrate was concentrated to give 1.3 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=3)[CH:9]=2)[CH:4]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc2cc(Br)ccc2c1
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2)c1

Procedure:
The title compound was prepared by reacting 6-methoxy-2-bromonaphthalene (3.09 g, 13.0 mmol) with 3-methoxyphenylboronic acid (2.18 g, 14.3 mmol according to method A to yield 1.18 g (34%) of a white solid: mp 80° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 3.92(3H, s), 6.90 (1H, dd, J=2.17 Hz, J=7.76 Hz), 7.14-7.18 (2H, m), 7.22-7.24 (1H, m), 7.28 (1H, d, J=7.45 Hz), 7.36-7.39, (1H, m), 7.70 (1H, dd, J=1.86 Hz, J=8.70 Hz), 7.77-7.80 (2H, m), 7.96 (1H, d, J=1.24 Hz); MS (ESI) m/z 265 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([O:13]CC)=[O:12])[CH2:9][N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Na+].[Cl-]>C1COCC1.O>[C:19]([O:18][C:16]([N:8]1[CH2:7][C@@H:6]([C:4]([OH:5])=[O:3])[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](C(=O)O)C1

Procedure:
Compound 1b (1 g, 3.17 mmol) was dissolved in of THF (8 ml), and 80 mL of water was added. The reaction mixture was immersed in an ice-water bath and cooled to 0 C. To this reaction mixture, 96 ml of 0.25 N NaOH was added in small portions with stirring until the consumption of the starting diester was detected by thin-layer chromatography. The reaction was stirred at the same temperature for about 30 min to 1 h, and the reaction mixture was acidified with 1 N HCl at 0° C., saturated with NaCl, extracted with ethyl acetate four times (each 100 ml), and dried with sodium sulfate. The organic phase is evaporated to dryness and dried in vacuo. Yield: 0.68 g (82.7%), ESI-MS: m/z=258 [M−H]−
Reaction SMILES: C1(CN(C2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)CCC2C=CC(O)=CC=2)CC1.Cl.ClCCN1CCCCCC1.[N:46]1([CH2:53][CH2:54][O:55][C:56]2[CH:61]=[CH:60][C:59]([CH2:62][CH2:63][N:64]([CH2:85][CH:86]3[CH2:88][CH2:87]3)[C:65]3[CH:70]=[C:69]([O:71]C)[CH:68]=[CH:67][C:66]=3[CH:73]3[CH2:82][CH2:81][C:80]4[C:75](=[CH:76][CH:77]=[C:78]([O:83]C)[CH:79]=4)[CH2:74]3)=[CH:58][CH:57]=2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>>[N:46]1([CH2:53][CH2:54][O:55][C:56]2[CH:61]=[CH:60][C:59]([CH2:62][CH2:63][N:64]([CH2:85][CH:86]3[CH2:87][CH2:88]3)[C:65]3[CH:70]=[C:69]([OH:71])[CH:68]=[CH:67][C:66]=3[CH:73]3[CH2:82][CH2:81][C:80]4[CH:79]=[C:78]([OH:83])[CH:77]=[CH:76][C:75]=4[CH2:74]3)=[CH:58][CH:57]=2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(OCCN3CCCCCC3)cc1)CC1CC1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(CCc1ccc(O)cc1)CC1CC1)C2
Agent: Cl
Agent: ClCCN1CCCCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1N(CCc1ccc(OCCN3CCCCCC3)cc1)CC1CC1)C2
Yield: 50.4 %

Procedure:
Synthesized from 4-{2-{cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, {2-[4-(2-azepan-1-ylethoxy)phenyl]ethyl}cyclopropylmethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (392 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (188 mg).