Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:7][CH2:6]2
Reactant: Cc1ccncc1I
Reactant: COc1ccc2c(c1)CCNC2=O
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCN(c1cnccc1C)C2=O
Yield: 53.1 %

Procedure:
Using analogous reaction conditions as described in Example 1, 6-methoxy-3,4-dihydro-2H-isoquinolin-1-one (I-11d: 0.400 g, 2.2471 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.492 g, 2.2471 mmol), 1,4-dioxane (40 mL), copper iodide (0.042 g, 0.2247 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.095 g, 0.6741 mmol) and potassium phosphate (1.190 g, 5.6177 mmol) to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane) afforded 0.320 g of the product (53% yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][NH2:12])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(CCCN)OCC
Solvent: c1ccncc1
Product: CCOP(=O)(CCCNC(C)=O)OCC
Reaction time: 4 h
Yield: 96 %

Procedure:
97 g. of 3-aminopropanephosphonic acid diethyl ester is dissolved in 400 ml. of dry pyridine and 55 g. of acetic anhydride is added with stirring. The mixture is then boiled for 4 hours with refluxing and freed of the low-boiling components by evaporation in a light vacuum. Gaschromatographically pure N-acetyl-3-aminopropanephosphonic acid diethyl ester is obtained in a 96% yield by shortcut distillation in vacuo. It is a pale yellow, highly viscous oil with a boiling point of 166° to 160° C (0.4 Torr).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([OH:59])[CH2:43][N:44](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:38][C:37]=1[NH:60][S:61]([CH3:64])(=[O:63])=[O:62])C1C=CC=CC=1>>[OH:59][CH:42]([C:39]1[CH:40]=[CH:41][C:36]([OH:35])=[C:37]([NH:60][S:61]([CH3:64])(=[O:63])=[O:62])[CH:38]=1)[CH2:43][NH:44][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 7) according to the procedure of Example 255 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35–1.60 (m, 2 H), 1.90–2.10 (m, 2 H), 2.06 (s, 3 H), 2.50–3.00 (m, 5 H), 3.16 (s, 3 H), 3.55–3.70 (m, 2 H), 4.65–4.80 (m, 1 H), 6.00 (brs, 1 H), 6.70–7.25 (m, 7 H), 7.58 (d, J=9.0 Hz, 2 H), 7.68 (d, J=9.0 Hz, 2 H), 10.39 (s, 1 H); MS (ES) m/z: 618.1 (MH+); HRMS Calcd. for C28H36N5O7S2 (MH+): 618.2056. Found: 618.2036.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:26]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)(=[O:28])[CH3:27].C(NC(C1C(C2C=CC=CC=2C(S(C2C=CC(C(=O)C)=CC=2)(=O)=O)N)=CC=CC=1)=O)CC1C=CC=CC=1>>[CH2:1]([NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][S:35]([C:32]2[CH:31]=[CH:30][C:29]([C:26](=[O:28])[CH3:27])=[CH:34][CH:33]=2)(=[O:37])=[O:36])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccc1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)c1ccc(S(=O)(=O)C(N)c2ccccc2-c2ccccc2C(=O)NCCc2ccccc2)cc1
Product: CC(=O)c1ccc(S(=O)(=O)NCc2ccccc2-c2ccccc2C(=O)NCCc2ccccc2)cc1

Procedure:
From 0.61 mmol of 2′-aminomethylbiphenyl-2carboxylic acid phenethylamide (precursor 5a) and 4-acetylphenylsulfonyl chloride, according to the general working procedure 258 mg of 2′-(4-acetylphenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid phenethylamide were obtained;
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C@H:22]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@@H:23]3[OH:24])[O:16][C@H:15]([O:33][CH2:34][CH2:35][NH:36][C:37](=[O:66])[CH2:38][CH2:39][C@H:40]([NH:44][C:45](=[O:65])[CH2:46][CH2:47][CH2:48][C:49](=[O:64])[NH:50][CH2:51][CH2:52][O:53][C@@H:54]3[O:62][C@@H:61]([CH3:63])[C@@H:59]([OH:60])[C@@H:57]([OH:58])[C@@H:55]3[OH:56])[C:41]([OH:43])=[O:42])[C@H:14]2[OH:67])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[B-](F)(F)(F)F.CN(C(O[N:81]1[C:86](=[O:87])[CH2:85][CH2:84][C:82]1=[O:83])=[N+](C)C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(C#N)(C)=O>CN(C=O)C>[C@H:1]1([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C@H:22]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@@H:23]3[OH:24])[O:16][C@H:15]([O:33][CH2:34][CH2:35][NH:36][C:37](=[O:66])[CH2:38][CH2:39][C@H:40]([NH:44][C:45](=[O:65])[CH2:46][CH2:47][CH2:48][C:49](=[O:64])[NH:50][CH2:51][CH2:52][O:53][C@@H:54]3[O:62][C@@H:61]([CH3:63])[C@@H:59]([OH:60])[C@@H:57]([OH:58])[C@@H:55]3[OH:56])[C:41]([O:43][N:81]3[C:86](=[O:87])[CH2:85][CH2:84][C:82]3=[O:83])=[O:42])[C@H:14]2[OH:67])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCC(=O)N[C@@H](CCC(=O)NCCO[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H]2O)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: CC(=O)C#N
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCC(=O)N[C@@H](CCC(=O)NCCO[C@H]2O[C@H](CO[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)[C@@H]2O)C(=O)ON2C(=O)CCC2=O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-5-[(2-{[α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl]oxy}ethyl)amino]-5-oxo-2-[5-oxo-5-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)pentanamido]pentanoic acid (366 mg, 0.373 mmol) in DMF (2 mL) at 0° C. was added TSTU (115 mg, 0.381 mmol) and DIPEA (0.1 mL, 0.573 mmol). After stirring at 0° C. for 1 hour, the reaction was quenched with TFA (60 μL, 0.784 mmol). The reaction mixture was transferred dropwise, via autopipette, to a tube containing AcCN (45 mL). The resulting white suspension was centrifuged (3000 rpm, 15 minutes, at 4° C.) to generate a clear supernatant and a white pellet. The supernatant was discarded and the white pellet was washed with AcCN (1 mL) and dried to yield title compound UPLC Method B: calculated for C42H68N4O28 1076.40, observed m/e: 1077.28 [M+1]; Rt=0.90 min.
Reaction SMILES: [CH3:1][Li].[OH:3][C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:10]3[CH2:11][CH:12]=[C:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[OH:3][C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:10]3[CH2:11][C@@H:12]([CH3:1])[C@@H:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Reaction time: 0.5 h

Procedure:
To a stirred slurry of cuprous iodide (950 mg.) in dry ether (75 ml.) under dry nitrogen at 0° was added a solution of methyl-lithium in ether (c 1.6M; 6 ml.) until the initially formed yellow precipitate just redissolved to give a clear solution. To the stirred solution at 0° was added a solution of 3α-hydroxy-5α-pregn-16-ene-11,20-dione (600 mg.) in dry tetrahydrofuran (50 ml.). During the addition a bright yellow precipitate formed. The mixture was stirred at 0° for 30 minutes, and then poured into cold, saturated ammonium chloride solution (200 ml.). More ether (200 ml.) was added, and the organic layer was separated, washed with saturated ammonium chloride solution (200 ml.) and with water (200 ml.) dried over sodium sulphate and purified by preparative t.l.c. in ethyl acetate to give a product which was further purified by preparative t.l.c. in ethyl acetate/chloroform, 1/l to give a white solid (380 mg.) which was recrystallised from ether/petrol to give title compound (248 mg.) as colourless plates, m.p. 138°-140°, [α]D + 99°, (c 0.95).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[CH2:10][CH2:9][NH:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([CH:26]([C:30](N)=[O:31])[C:27](N)=[O:28])=[C:21]([CH3:33])[CH:20]=1>C1(C)C(C)=CC=CC=1.ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH3:33])[C:22]([CH:26]2[C:30](=[O:31])[N:7]3[CH2:6][CH2:5][N:4]([O:3][CH3:2])[CH2:10][CH2:9][N:8]3[C:27]2=[O:28])=[C:23]([CH3:25])[CH:24]=1
Reactant: CON1CCNNCC1
Reactant: Cc1cc(Cl)cc(C)c1C(C(N)=O)C(N)=O
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CON1CCN2C(=O)C(c3c(C)cc(Cl)cc3C)C(=O)N2CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A degassed suspension of 5-methoxy-[1,2,5]triazepane hydrochloride salt (100 mg, 0.49 mmol) and triethylamine (0.33 ml, 207 mg, 2.05 mmol) in xylene (2.5 ml) was stirred under argon at 60° C. for 30 minutes in a microwave vial. After further addition of 2-(4-chloro-2,6-dimethyl-phenyl)-malonamide (120 mg, 0.50 mmol), the vial was capped and irradiated twice with microwaves at 180° C. for 10 minutes. The solid deposit on the vial wall was dissolved in dichloromethane, the solvent evaporated, the oily residue dissolved in 5N aqueous sodium hydroxide, the aqueous layer extracted with ethyl acetate (3×) and the combined organic layers discarded. The aqueous alkaline phase was acidified with cooling to pH 2-3 by addition of a 4N HCl solution and the product thoroughly extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Yield: 10 mg of 8-(4-chloro-2,6-dimethyl-phenyl)-3-methoxy-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.2) as a beige solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH3:13])([CH3:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].O>C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[N:5]([C:6]([CH3:12])([CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: CCOC(=O)C(C)(C)NCCCCl
Reactant: O=C=Nc1ccccc1F
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C)(C)N(CCCCl)C(=O)Nc1ccccc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A solution of ethyl 2-(3-chloropropylamino)isobutyrate (7.5 g) prepared according to Example 3-(1) in toluene (45 mL) was cooled to 0° C. To the solution was added 2-fluoropheyl isocyanate (5 g), and the mixture was stirred overnight at 0° C. to room temperature. Water was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 10.9 g of crude ethyl 2-[3-(2-fluorophenyl)-1-(3-chloropropyl)ureido]isobutyrate.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]([CH3:23])[O:11][C@H:6]1[O:7][CH2:8][CH:9]=C)(=[O:3])[CH3:2].C[N+]1([O-])CC[O:28]CC1>CC(C)=O.O.O=[Os](=O)(=O)=O.C(O)(C)(C)C>[C:1]([O:4][C@H:5]1[C@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]([CH3:23])[O:11][C@H:6]1[O:7][CH2:8][CH:9]=[O:28])(=[O:3])[CH3:2]
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCC=O)O[C@@H](C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
To a solution of prop-2-en-1-yl 2,3,4-tri-O-acetyl-α-L-fucopyranoside (1.34 g, 4.06 mmol) in acetone (30 mL) and water (7.5 mL) was added 4-methylmorpholine 4-oxide (950 mg, 8.11 mmol) followed by the addition of 2.5% OsO4 in tert-butanol (2.04 mL, 0.162 mmol). The mixture was allowed to stir at rt for 16 hr. To the resulting mixture was then added a solution of NaIO4 (1.74 g, 8.11 mmol) in water (15 mL). After stirring for additional 4 hr, the precipitate was filtered and washed with acetone (50 mL). The volume of the filtrate was reduced to approximately ⅓ of the initial volume and then diluted with sat. NaHCO3 (100 mL). The mixture was extracted with EtOAc (3×50 mL). The organic phases were combined and washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (Teledyne Isco: 120 g), eluting with 0-80% EtOAc in hexanes to give the title compound (660 mg, 49%). 1H NMR (CDCl3) δ 9.72 (1H, s), 5.44 (1H, dd, J=10.9 and 3.3 Hz), 5.35 (1H, dd, J=3.4 and 1.8 Hz), 5.19 (1H, dd, J=10.9 and 3.8 Hz), 5.13 (1H, d, J=3.8 Hz), 4.26 (3H, m), 2.19 (3H, s), 2.15 (3H, s), 2.02 (3H, s), 1.17 (3H, d, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][C:22]=2[CH2:33][C:34]([O:36]C)=[O:35])=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][C:22]=2[CH2:33][C:34]([OH:36])=[O:35])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1cc(-c2ccccc2)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(-c3ccccc3)cc2CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 102.8 %

Procedure:
To a mixture of methyl 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-phenylphenyl]acetate (0.65 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (2.8 mL) and the mixture was stirred at 50° C. for 1.5 hrs. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (0.65 g, 92%) of 2-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-5-phenylphenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 102-103° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:12][C:4]1[N:3]=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2cc(C(F)(F)F)cc(Cl)n2)CC1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
Dissolve 2,6-dichloro-4-(trifluoromethyl)pyridine (215 mg, 1 mmol) and DIEA (129 mg, 1 mmol) in DMF (2 mL), add 1-methyl piperazine (100 mg, 1 mmol). Stir the reaction at 120° C. overnight. Cool to room temperature; concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, MeOH:DCM=1:10) affords the product (253 mg, 91%). MS: (M+1): 280.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:8][NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH2:34][OH:35])=[N:17][N:18]3[CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=3[O:32][CH3:33])=[CH:14][CH:13]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39].Cl>O1CCCC1.CN(C)C=O>[CH:3]1([CH2:8][NH:9][C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH2:34][O:35][C:38](=[O:39])[N:37]([CH3:41])[CH3:36])=[N:17][N:18]3[CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=3[O:32][CH3:33])=[CH:14][CH:13]=2)=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc(Cn2nc(CO)c3ccc(C(=O)NCC4CCCC4)cc32)c(OC)c1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2nc(COC(=O)N(C)C)c3ccc(C(=O)NCC4CCCC4)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23 %

Procedure:
To a suspension of 60% sodium hydride dispersion (13 mg) (petroleum ether washed) in tetrahydrofuran (1 ml) at 0° was added a solution of methyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-hydroxymethylindazol-1-ylmethyl]-3-methoxybenzoate (151 mg) in 7:1 dimethylformamide:tetrahydrofuran (8 ml). After stirring for 45 minutes, dimethylcarbamoyl chloride (0.033 ml) was added. The reaction was stirred for 15 minutes and was allowed to warm to room temperature. After 3 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried (MgSO4). Evaporation and flash chromatography over 15 g silica gel, eluting with 2:8 ethyl acetate:methylene chloride (50 ml) and 4:6 ethyl acetate:methylene chloride, afforded methyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-(dimehylcarbamoyloxymethyl)indazol-1-ylmethyl]-3-methoxybenzoate as a colorless solid (40 mg, 23%); mass spectrum (chemical ionization) 523 (M+H). NOTE: Still further Examples of compounds of the invention are provided by the benzoic acid starting materials for formula I (M=CO2H) described in connection with Examples 6, 8 and 9.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:24][CH2:23]2)=[C:12]([NH:14][C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:16])[CH:13]=1)=[O:7].C(N(C(C)C)CC)(C)C.[CH3:44][C:45]([CH3:51])([CH2:49][CH3:50])[C:46](Cl)=[O:47]>C(Cl)Cl>[CH3:44][C:45]([CH3:51])([CH2:49][CH3:50])[C:46]([N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:26][CH2:27]2)=[C:12]([NH:14][C:15]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[O:16])[CH:13]=1)=[O:7])=[O:47]
Reactant: CNCCNC(=O)c1ccc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2ccco2)c1
Reactant: CCC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)(C)C(=O)N(C)CCNC(=O)c1ccc(N2CCN(c3ccccc3C)CC2)c(NC(=O)c2ccco2)c1
Temperature: 12.5 °C
Reaction time: 4 h

Procedure:
Furan-2-carboxylic acid [5-{2-[(2,2-dimethyl-butyryl)-methyl-amino]-ethylcarbamoyl}-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide (compound no. 133) was prepared as follows: To a solution of furan-2-carboxylic acid [5-(2-methylamino-ethylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide (0.04 g, 0.086 mmol) and diisopropylethylamine (0.5 mL) in CH2Cl2 (2.0 mL), 2,2-dimethyl butyryl chloride (0.173 mmol) was added at 0° C., and the reaction was stirred at 0-25° C. for 4 h. Reaction was diluted with CH2Cl2 and washed with a solution of saturated NaHCO3. Organic layer was concentrated and dissolved in ACN and purified on preparative HPLC using water/MeOH (0.1% TFA) as eluent to give the product (0.01 g, 21% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH3:23][N:24]([CH:26](OC)OC)[CH3:25]>CN(C=O)C>[CH3:23][N:24]([CH3:26])[CH:25]=[CH:1][C:2]1[C:7]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1c(C(=O)c2cccc3ccccc23)cccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1c(C(=O)c2cccc3ccccc23)cccc1[N+](=O)[O-]

Procedure:
Following a procedure similar to that described in Preparation 2A above, 57 g (0.195 mole) of 2-methyl-3-(1-naphthylcarbonyl)nitrobenzene and 103 ml (0.784 mole) of DMF dimethyl acetal in 300 ml of DMF was heated under reflux for seventeen hours and then taken to dryness to give 2-(2-dimethylaminoethenyl)-3-(1-naphthylcarbonyl)nitrobenzene as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12](Cl)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:20]#[N:21].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C1(C)C=CC=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[CH:8][C:7]=1[C:20]#[N:21]
Reactant: CN1CCNCC1
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(c2cc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c3cc2[N+](=O)[O-])CC1

Procedure:
A stirred mixture of 4-(3-chloro-4-fluoroanilino)-7-chloro-6-nitro-3-quinolinecarbonitrile (1.88 g, 5.0 mmol), N-methylpiperazine (5 ml, 45 mmol), and 10 ml of toluene was refluxed for 45 m, evaporated to remove volatile matter, and stirred in water with potassium carbonate (2.75 g). The resulting solid was filtered, washed with water, and dried to give 2.26 g. An acetone solution was passed onto a pad of silica gel; elution with 50:2:1 acetone-MeOH-TEA and evaporation gave a red solid, mp 240-246°; ms 441.2 (M+H)+, 221.2 (M+2H)+2.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([SH:11])[CH:7]=[CH:8]2)=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH:13]=1>C(O)C>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22][S:11][C:6]2[CH:7]=[CH:8][C:9]3[C:4](=[CH:3][CH:2]=[CH:1][CH:10]=3)[CH:5]=2)[CH:13]=1
Reactant: C=CC(=O)CCc1cccnc1
Reactant: Sc1ccc2ccccc2c1
Solvent: CCO
Product: O=C(CCSc1ccc2ccccc2c1)CCc1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Thionaphthol was added to a solution of 1-(3-pyridyl)-4-penten-3-one (0.200 g) in ethanol (30 ml) followed by stirring overnight at room temperature. The ethanol was removed under reduced pressure and the residue purified by column chromatography over silica eluting with dichloromethane:ethyl acetate (2:1) to give the sub-title compound as a white solid (0.142 g).