Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.CO[N:7]=[C:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][C:9]1=[O:20]>[Pd].C(OCC)(=O)C>[NH2:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][C:9]1=[O:20]
Reactant: CON=c1c(=O)[nH]c2ccccc2[nH]c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC1C(=O)Nc2ccccc2NC1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Wet 10% Pd/C (37.5 g) with glacial acetic acid (HOAc, 3.75 L). Add 1,5-dihydro-benzo[b][1,4]diazepine-2,3,4-trione 3-(O-methyl-oxime) (150 g, 0.684 mol), and subject the resulting mixture to catalytic hydrogenation under 50 psi H2 at ambient temperature for ˜18 hours until complete by HPLC. Remove the catalyst by filtration over glass fiber paper/Hyflo and rinse with HOAc (2 L). Concentrate the filtrate in vacuo to obtain the crude product as an amber waxy solid. Treat the solid with ethyl acetate (EtOAc, 3 L) and heat to 70° C. with stirring for 1 hour. Allow the slurry to cool to ambient temperature, then force cool to 0° C. Isolate the product by filtration and dry to afford 109.9 g (84%) of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 10.48 (bs, 2H), 7.18 (m, 4H), 3.75 (s, 1H), ˜3.5 (bs, 2H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 164.5, 129.2, 125.1, 122.2, 55.8, 55.7; IR (KBr) 3375, 3306, 3282, 3047, 2750, 1697, 1670, 1559, 1500, 1433, 1411, 1337, 1307, 1258, 1183 cm−1; V (EtOH) λmax 217 nm (ε 33772), 285 nm (ε 3210); HRMS (ES+) exact mass calc'd for C9H9N3O2 192.0773, Found 192.0768.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:8]=1[N:14]([C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[CH:9][C:8]=1[N:14]([C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@@H](C)N(C(=O)C(F)(F)F)c1cc(F)ccc1C(=O)OC(C)(C)C
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: COC[C@@H](C)N(C(=O)C(F)(F)F)c1cc(N2CCN(C)CC2)ccc1C(=O)OC(C)(C)C
Yield: 84.1 %

Procedure:
A solution of 4-fluoro-2-[((R)-2-methoxy-1-methyl-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid tert-butyl ester (2 g, 5.28 mmol) and N-methylpiperazine (5.86 mL, 52.8 mmol) in tetrahydrofuran (20 mL) was stirred at 60° C. for 7 days. The solution was then evaporated, NaHCO3 satured solution was added and the mixture extracted with dichloromethane (3 times). The organic layer was washed with water, brine, dried over sodium sulfate filtered and evaporated to obtain a crude, which was purified by column chromatography on silica gel (dichloromethane-methanol 93:7). The title compound (2.04 g, 84%) was obtained as yellowish solid.
Reaction SMILES: [Al+3].[Cl-:2].[Cl-].[Cl-].Cl.C[O:7][C:8]1[C:17]([O:18]C)=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([NH:20][CH3:21])[CH2:13]2>C1(C)C=CC=CC=1>[ClH:2].[OH:7][C:8]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH:12]([NH:20][CH3:21])[CH2:13]2
Reactant: [Cl-]
Reactant: CNC1CCc2c(ccc(OC)c2OC)C1
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: CNC1CCc2c(ccc(O)c2O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
41.4 g of dry AlCl3 (310.4 moles), 230 ml of toluene and 20.0 g of 5,6-dimethoxy-2-methylaminotetralin HCl (77.6 moles) are placed into a 4-necked round-bottomed flask, with stirring, under a slight stream of dry nitrogen. Temperature is brought to 80° C. to obtain a stirrable brown mixture, left at 80° C. for 4 hours, then cooled to room temperature and poured into ice-water (about 1000 ml total). The aqueous phase is separated and evaporated under vacuum (T about 80° C.). The whitish solid is triturated at room temperature in 750 ml of absolute ethanol, then dried at 60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[C:30]#[N:31])[CH2:5][N:6]1[C:11](=[O:12])[CH2:10][N:9]([CH2:13][C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=3)[CH2:8][CH:7]1[C:24]([OH:26])=[O:25].[N:32]1C=NC=N[CH:33]=1.CC(O)=O>CCO>[NH2:31][C:30]1[C:29]2[C:2](=[CH:3][C:4]([CH2:5][N:6]3[C:11](=[O:12])[CH2:10][N:9]([CH2:13][C:14]4[NH:15][C:16]5[C:21]([CH:22]=4)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=5)[CH2:8][CH:7]3[C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)[N:1]=[CH:33][N:32]=1
Reactant: c1ncncn1
Reactant: N#Cc1ccc(CN2C(=O)CN(Cc3cc4cc(Cl)ccc4[nH]3)CC2C(=O)O)cc1N
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ncnc2cc(CN3C(=O)CN(Cc4cc5cc(Cl)ccc5[nH]4)CC3C(=O)O)ccc12
Temperature: 25 °C
Yield: 9.3 %

Procedure:
A solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-(5-chloro-1H-indol-2-ylmethyl)-6-oxo-piperazine-2-carboxylic acid (200 mg, 0.30 mmol), 1,3,5-triazine (244 mg, 3.00 mmol), and glacial HOAc (180 mg, 3.00 mmol) in absolute EtOH (20 mL) is maintained at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and the solid is collected on a Buchner funnel and washed with EtOH followed by diethyl ether. Oven-drying in vacuo provided 13 mg (76%) of the title compound as an off-white solid. 1H NMR (300 MHz, d6-DMSO) δ2.63 (m, 1H), 3.06 (d, J=16.4 Hz, 1H), 3.24-3.42 (m, 4H), 3.68 (ABq, ΔAB=34.5 Hz, JAB=14.1 Hz, 2H), 3.96 (m, 1H), 4.63 (ABq, ΔAB=400 Hz, JAB=15.8 Hz, 2H), 6.27 (s, 1H), 6.99 (dd, J=8.6, 2.0 Hz, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.40 (s, 1H), 7.46 (s, 1H), 7.69 (br s, 2H), 8.10 (d, J=8.5 Hz, 1H), 8.32 (s, 1H), 11.20 (s, 1H) ppm; MS (ion spray): m/z 465 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11](=[O:28])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C([N-]C(C)C)(C)C.[Li+].Cl[C:38]([O:40][C:41]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=1)=[O:39]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:11](=[O:28])[N:10]2[C:38]([O:40][C:41]2[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=2)=[O:39])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CN2C(=O)NC(c3ccc(F)c(F)c3)c3ccccc32)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)N(C(=O)Oc3ccc([N+](=O)[O-])cc3)C(c3ccc(F)c(F)c3)c3ccccc32)cc1

Procedure:
The title compound was prepared by treating 10 (0.292 g, 0.767 mmol) with lithium diisopropylamide (2.0 M THF solution, 1.1 equivalents) in THF at −78° C. for 20 minutes followed by the rapid addition of 4-nitrophenyl chloroformate (1.5 equivalents) in THF. The 1H NMR was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=O)[CH2:15][C:16](=[O:18])[CH3:17])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=[S:29])[CH2:15][C:16](=[O:18])[CH3:17])=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=O)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-4-methanesulfonyl-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as brown solid. MS (ESI): m/z=308.4 [M+H]+.
Reaction SMILES: C(O[C:4](=[O:25])[C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[C:18]=1[CH3:24])=[CH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([CH3:16])[CH3:15])[CH:9]=1)C>O>[Br:23][C:19]1[C:18]([CH3:24])=[C:17]([C:5]2[C:4](=[O:25])[C:13]3[C:8](=[CH:9][C:10]([N:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=CNc1cccc(N(C)C)c1)c1cccc(Br)c1C
Solvent: O
Product: Cc1c(Br)cccc1-c1c[nH]c2cc(N(C)C)ccc2c1=O
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To 2-(3-Bromo-2-methyl-phenyl)-3-(3-dimethylamino-phenylamino)-acrylic acid ethyl ester (100 mg, 0.248 mmol) was added 4 g polyphosphoric acid. This stirred at 140° C. for 10 minutes. 50 ml water was added and the mixture was stirred. The resulting precipitate was filtered and washed with water. The filtrate was extracted with 10%methanol/dichloromethane solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was combined with the precipitate and purified by flash chromatography (gradient elution 2 to 5% methanol/dichloromethane) to yield 3-(3-Bromo-2-methyl-phenyl)-7-dimethylamino-1H-quinolin-4-one (22 mg, 0.062 mmol). MS (ESI) 357.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:28][N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:41]2[CH2:42][CH2:43][N:38]([C:30]3[N:29]([CH3:28])[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=3)[CH2:39][CH2:40]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 1-methyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[Cl:14][CH:15]([Cl:19])[C:16](O)=O>Cl.O>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:16]([CH:15]([Cl:19])[Cl:14])=[N:1][C:2]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: O=C(O)C(Cl)Cl
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cc2[nH]c(C(Cl)Cl)nc2cc1Cl
Reaction time: 0.08 h
Yield: 26.9 %

Procedure:
To 11.8 g of 2-amino-4-chloro-5-sulfamyl aniline in 50 ml of 4 N hydrochloric acid was added 20.5 g of dichloroacetic acid and the suspension refluxed for 6 hours. Concentration in vacuo provided a dark viscous oil which was suspended in 150 ml of water and crystallized through vigorous scratching. The dark brown solid was then dissolved in methanol, the solution brought to a boil, and charcoal added. After boiling for five minutes, the suspension was filtered through filter paper, cooled and then filtered through Celite. Concentration in vacuo gave a viscous oil which upon setting at ambient temperature for 48 hours crystallized. Tritration with acetonitrile provided 4.5 g of beige crystals, m.p. 225°-227°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:21]([O:25][C:26]([N:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:29]3[N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH:32]=[CH:31][CH:30]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Product: COc1cc(Nc2cncc(-c3cccn3C(=O)OC(C)(C)C)n2)cc(OC)c1OC
Yield: 4.1 %

Procedure:
Using Method C with 100 mg (0.34 mmol) 2a and 86 mg (0.41 mmol) 1-tert-butoxycarbonyl-2-pyrrolyl boronic acid, 6 mg pure title compound were obtained. The filtrate was submitted to purification by preparative HPLC (eluent:AcOEt) and a fraction of 52 mg of a product containing 25% (LC-MS) of the desired compound was obtained. A second purification using a semi-preparative Supelco discovery C18 column (250×10 mm) (eluent: acetonitrile:H2O 9:1) led to 6 mg (4.1%) of pure title compound. Reaction time: 18 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 1.25 (s, 9H, t-Bu), 3.60 (s, 3H, CH3O(4′)), 3.72 (s, 6H, CH3O(3′+5′)), 6.33 (t, 1H, Hpyr 4′, J=3.30), 6.58-6.60 (m, 1H, Hpyr 3′ or 5′), 7.16 (s, 2H, Harom(2+6)), 7.42-7.44 (m, 1H, Hpyr 5′ or 3′), 8.04 (s, 1H, HP5), 8.12 (s, 1H, HP3), 9.53 (s, 1H, NHamine); MS, (C22H16N4O5), m/z: 427 [M++1, 100].
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)=[O:6].[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:5]1([C:4]2[CH:16]=[CH:17][C:18]([N:20]([CH3:22])[CH3:21])=[CH:19][C:3]=2[N:2]([CH3:1])[CH3:23])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:11])[O:6]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)c(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c(N(C)C)c1

Procedure:
A mixture of crude 2-(2,4-bis(dimethylamino)benzoyl)benzoic acid (7 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (1.64 g.) and acetic anhydride was warmed (at 25°-35° C.) during two to three hours, then poured into dilute hydrochloric acid (10%). The resulting mixture was basified and filtered with a filter aid. The filter cake was extracted with hot toluene. Dilution of the toluene extract with hexane afforded 3,3-bis(2,4-bis(dimethylamino)phenyl)phthalide (I: X=Y2 =Y4 =(CH3)2N, Z4 =Z5 =Z6 =Z7 =H) (m.p. 186°-188° C.).
Reaction SMILES: [CH2:1]([C:3](O)([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[C:4]#[CH:5])[CH3:2].C[O:14][C:15]([CH3:17])=[CH2:16]>>[CH2:1]([C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:4][CH:5]=[CH:16][C:15](=[O:14])[CH3:17])[CH3:2]
Reactant: C=C(C)OC
Reactant: C#CC(O)(CC)CCC=C(C)C
Product: CCC(=CC=CC(C)=O)CCC=C(C)C

Procedure:
The acid catalysed reaction of 3-ethyl-7-methyl-oct-1-yn-6-en-3-ol with isopropenyl methyl ether and subsequent base-catalysed isomerisation of the resulting β-ketoallene (G. Saucy, R. Marbet, Helv. 50, 1158, 1967) gave a good yield of 6-ethyl-10-methyl-undeca-3,5,9-trien-2-one which was cyclised with 85% phosphoric acid in a known manner [H. Rouve, M. Stoll, Helv. 30, 2216 (1947)]. The resulting product contained 90% 11-methyl-α-ionone and 11-methyl-γ-ionone (two isomers) in the ratio of 7:3. In a manner analogous to the epoxidation of α-ionone (Example 4), from 13.4 g (0.065 mol) of 11-methyl-α-ionone there were obtained 13.9 g of crude 11-methyl-α-ionone epoxide of which 13.4 g (~0.06 mol) were dissolved together with 6.1 g (0.03 mol) of aluminium isopropylate in 30 ml of isopropanol. By following the procedure described in Example 1 there were obtained 13.7 g of a crude product. From this crude product there were obtained by distillation over a 5 cm Widmer column 2.10 g (17%) of olfactorily good product of boiling point 73°-75° C./0.05 mmHg and which contained above 85% 17 and the corresponding 7-oxa-bicyclooctane 17a. A sample purified by means of preparative GC showed the following spectral data:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:52][S:53]([CH3:56])(=[O:54])=[O:55])[CH:39]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)ccc4F)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 49.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step-i of example-4) (200 mg, 0.368 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 17) (120 mg, 0.368 mmol) using sodium carbonate (117 mg, 1.1049 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.018 mmol) in DME/water (15/2 ml) to afford 121 mg (49.5% yield) after purification by column chromatography (Silica gel 230/400) using 50% ethyl acetate in hexane as eluent. MS: m/z=664.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]([C:15]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=4[C:17]#[N:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.[NH2:30][OH:31]>CCO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:29]=[CH:28][C:11]3[N:12]([C:24]([CH3:25])([CH3:26])[CH3:27])[C:13]([C:15]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=4[C:17]([NH:30][OH:31])=[NH:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1
Reactant: NO
Reactant: CC(C)(C)n1c(-c2cc(F)ccc2C#N)nc2cc(-c3cnc(N)nc3)ccc21
Solvent: CCO
Product: CC(C)(C)n1c(-c2cc(F)ccc2C(=N)NO)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 75 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a suspension of 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-fluoro-benzonitrile (500 mg, 1.29 mmol) in EtOH (8 mL) is added hydroxylamine 50% aqueous solution (1.71 mL, 25.88 mmol) at room temperature. The solution is stirred at 75° C. for 18 hours. The reaction mixture is cooled to room temperature and the ethanol removed in vacuo. Water (30 mL) is added to the reaction mixture and the resultant precipitate is filtered and washed with 10% EtOAc/heptane (10 mL) to afford 2-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-fluoro-N-hydroxy-benzamidine (485 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:27]4[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][OH:35])[CH2:31][CH2:32]4)=[C:23]([C:24]#[N:25])[CH:26]=3)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)c(Cl)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCO)CC3)c(C#N)c2)cnn1-c1ccc(F)c(Cl)c1

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-chloro-4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid is (3.5 g) and 5-amino-2-[4-(2-hydroxyethyl)-piperazin-1-yl]benzonitrile (3.7 g), the title compound (1.0 g) was obtained, melting point: 191° C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:27])[C:21]([O:24][CH2:25][CH3:26])([CH3:23])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:45])[C@@H:15]2[CH2:28][CH2:29][C@H:30]2[O:35][C:34](=[O:36])[CH2:33][C@H:32]([O:37][Si](C(C)(C)C)(C)C)[CH2:31]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:27])[C:21]([O:24][CH2:25][CH3:26])([CH3:22])[CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:45])[C@@H:15]2[CH2:28][CH2:29][C@H:30]2[O:35][C:34](=[O:36])[CH2:33][C@H:32]([OH:37])[CH2:31]2)=[CH:10]1
Reactant: CCOC(C)(C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(C)(C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using the whole of the fraction (414 mg) containing (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-(2-ethoxy-2-methylpropionyloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 151, above] and 6.2 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 25 mg of the titlecompound as colorless needle-like crystals, melting at 132° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([NH2:13])[CH3:12])[C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:36]=[CH:35][C:28]3[N:29]=[C:30](S(C)=O)[O:31][C:27]=3[CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17]>C1COCC1>[CH3:14][NH:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:36]=[CH:35][C:28]3[N:29]=[C:30]([NH:13][CH:11]([C:10]4[C:5]5[O:4][CH2:3][CH2:2][O:1][C:6]=5[CH:7]=[CH:8][CH:9]=4)[CH3:12])[O:31][C:27]=3[CH:26]=2)[CH:21]=[CH:20][N:19]=1)=[O:17]
Reactant: CC(N)c1cccc2c1OCCO2
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc3nc(NC(C)c4cccc5c4OCCO5)oc3c2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-ethylamine (3 eq) in THF was added 4-(2-methanesulfinyl-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (1 eq). This was stirred at room temperature for 8 hours, concentrated and the residue was purified by preparatory reverse phase HPLC. MH+=447.1.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:27]([F:29])[F:28])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Li+]>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[C:8]2[O:26][CH:27]([F:29])[F:28]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC(F)F)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorobenzyl)-4-difluoromethoxy-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.10 g), methanol (6.0 mL), water (0.6 mL) and saturated aqueous lithium hydroxide solution (0.3 mL) was stirred at room temperature for 17 hours. The methanol was removed under reduced pressure and the pH of the residue adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration and washed with water. Purification of the solid by preparative reverse-phase HPLC using a gradient over 37 minutes of acetonitrile in water (20% to 95% of organic modifier) gave title compound as a cream solid, 0.020 g.