Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.[F:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][C:34]=1/[C:35](/[NH:38]O)=[N:36]/[H])[NH:31][CH:30]=[C:29]2[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(OCC)(=O)C.C(Cl)CCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:36]=[C:35]([C:34]3[CH:33]=[C:32]4[C:28]([C:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:30][NH:31]4)=[CH:27][C:26]=3[F:25])[N:38]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: [H]/N=C(\NO)c1cc2[nH]cc(CCC(=O)OCC)c2cc1F
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1c[nH]c2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c(F)cc12
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (132 mg) in tetrahydrofuran (THF) (12 mL) was added EDC (235 mg) and HOBt (188 mg) and the mixture was stirred at RT for half an hour. Ethyl 3-{5-fluoro-6-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D155) (180 mg) was then added and the resulting mixture was stirred for another 1 hour. Finally, TBAF (642 mg) was added to the solution and the reaction vessel was sealed and heated in Biotage Initiator using initial high at 120° C. for 2 hours. After cooling the reaction, the solution was diluted with ethyl acetate (80 mL) and washed with water (2×60 mL). The organic layer was then concentrated under vacuo and the residue was chromatographed on silica gel eluting with EA and PA to give the designed product ethyl 3-[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D156) (200 mg). MS (ES): C24H23ClFN3O4 requires 471.1. found 472.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1.[NH3:20]>C(O)CO.O>[NH2:20][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC
Reactant: N
Solvent: O
Solvent: OCCO
Product: CCCOc1ccc(-c2ccc(N)nn2)cc1OC
Yield: 81.7 %

Procedure:
10 g (35.9 mmol) of 3-chloro-6-(3-methoxy-4-propoxyphenyl)pyridazine are heated in 50 ml of ethylene glycol which has been saturated with ammonia at 0° C. in an autoclave at 220° C. for 6 hours. After cooling, the reaction mixture is diluted with 500 ml of water, and the precipitate which forms is filtered off with suction. The crude product is dried and then purified by column chromatography on silica gel with chloroform as eluent. 7.6 g (81.7%) of the title compound of m.p. 147° C. are obtained.
Reaction SMILES: CO[C:3](=[O:21])[C:4]([OH:20])=[CH:5][C:6](=[O:19])[N:7]([O:17][CH3:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:30][N:31](C)[C:32](C1CN(C)C(=O)C=1O)=O>>[CH3:18][O:17][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:6]([C:5]1[CH2:30][N:31]([CH3:32])[C:3](=[O:21])[C:4]=1[OH:20])=[O:19]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(OC)cc1)OC
Agent: C=O
Agent: CN
Product: COc1ccc(CN(OC)C(=O)C2=C(O)C(=O)N(C)C2)cc1
Yield: 58 %

Procedure:
2-Hydroxy-3-[methoxy-(4-methoxybenzyl)-carbamoyl]-acrylic acid methyl ester (Compound 55-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (58% yield); mp 135–137° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.09 (3H, s, NCH3), 3.71 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.14 (2H, s, NCH2), 4.82 (2H, s, NCH2), 6.88 (2H, m, aromatics), 7.27 (2H, m, aromatics). Anal. calcd for C15H18N2O5: C, 58.81; H, 5.92; N, 9.14. Found: C, 58.62; H, 5.88; N, 9.12.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][C:6]([O:17][CH2:18][CH3:19])=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH3:16])C.CCOC(C)=O.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:18]([O:17][C:6]1[CH:5]=[C:4]([OH:20])[C:13]2[C:8](=[C:9]([CH3:16])[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]=1)[CH3:19]
Reactant: CCOC(=O)CC(=Nc1cccc(OC)c1C)OCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOc1cc(O)c2ccc(OC)c(C)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
3-Ethoxy-3-(3-methoxy-2-methyl-phenylimino)-propionic acid ethyl ester (1.56 g, 5.57 mmol) was dissolved in diphenyl ether then placed in a 300° C. sand bath. The internal temperature was kept between 240-250° C. for 15 minutes then the reaction was cooled to room temperature. The crude material was directly loaded onto a silica gel column (0→60% EtOAc/hexane) to afford 2-ethoxy-7-methoxy-8-methyl-quinolin-4-ol (882 mg, 68%). LCMS found 234.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:26]([CH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)([CH3:28])[CH3:27].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][CH2:33][CH:29]1[CH:26]([CH3:28])[CH3:27])=[O:5])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(C)C1CCCN1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2C(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-isopropylpyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.71 minutes; C24H26Cl2N4O2 (473.40); mass spectrum: (M−H)−=472/474/476 (chlorine isotope).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:12].[C:21]1([CH3:29])[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1.ClCCl>O1CCCC1.[Cl-].[Na+].O>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([NH:17][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:29])=[CH:22][CH:23]=2)=[NH:28])[CH:18]=[CH:19][CH:20]=1)[CH3:12]
Reactant: Cc1ccc(C#N)cc1
Reactant: CCOc1cccc(N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOc1cccc(NC(=N)c2ccc(C)cc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide in 5.0 mL of tetrahydrofuran at ambient temperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and the resulting solution was stirred for 20 min. To this reaction mixture was slowly added a solution of 0.47 g (4.0 mmol) of p-tolunitrile in 2.0 mL of tetrahydrofuran. The resulting mixture was stirred at ambient temperature for 5 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as yellow solid which was used without further purification. LC/MS 255.2 (M+1).
Reaction SMILES: [C:1]([C:4]1([CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CN(P(N(C)C)(N(C)C)=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:48]1([CH2:54][CH:55]=[O:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[Cl-].[NH4+]>C1COCC1.CCOCC>[C:48]1([CH2:54][CH:55]([OH:56])[CH2:2][C:1]([C:4]2([CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[O:3])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=CCc1ccccc1
Reactant: CC(=O)C1(CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(C(=O)CC(O)Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-acetyl-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (4.6 g, 12 mmol) in THF (120 mL) at −70° C. was added HMPA (20.7 mL, 120 mmol) and 1M LHMDS in THF (12 mL, 12 mmol). After 1 h, phenylacetaldehyde (5.7 g, 48 mmol) was added in THF (80 mL) over 10 min and the reaction was stirred for 1 h. The mixture was then poured into ether and aq. ammonium chloride solution and extracted three times with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (10 to 30% ethyl acetate in hexanes) to afford recovered starting material (2.15 g) and the title product (2.2 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:23][C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][N:26]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:25]1
Reactant: CC1(C)CCCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC1(C)CCCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 3,3-dimethylpiperidine (1.2 equiv) to give 164 (12.1 mg, M+1 409.1)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-])=O)[CH:4]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O.[H][H]>C(OC)(=O)C.[Pt]=S>[NH2:13][C:5]1[CH:4]=[C:3]([S:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(SC)cc1[N+](=O)[O-]
Agent: S=[Pt]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: COC(C)=O
Product: COC(=O)c1ccc(SC)cc1N

Procedure:
A mixture of methyl 4-(methylthio)-2-nitrobenzoate (11.3 g. 49.7 mmol) and 5% platinum sulfide on carbon catalyst (0.7 g) in methyl acetate (40 mL) was hydrogenated at 750 Psi and 75° C. until hydrogen uptake ceased. The mixture was filtered through Celite®, and the filtrate solvent was rotary evaporated, leaving methyl 2-amino-4-(methylthio)benzoate as a slightly tan crystalline solid (8.7 g) melting at 57°-59° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([N:18]([CH2:23][C:24](O)=[O:25])[CH2:19][C:20](O)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:20](=[O:21])[CH2:19][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:23][C:24]2=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccccc1
Product: O=C1CN(Cc2ccccc2)CC(=O)N1CCCc1ccccc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
3-Phenyl-1-propylamine (3.63 g) and N-benzyliminodiacetic acid (6.0 g) was mixed and heated to 200° C. under a nitrogen atmosphere. The mixture was stirred at this temperature for 1 h, cooled and purified by column chromatography (SiO2, 40°-60° C. petroleum ether/chloroform) to give the title material as a pale orange liquid (5.53 g, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[C:17]([NH2:22])[C:16]=1[NH2:23].C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)=[C:17]([NH2:22])[C:16]=1[NH2:23]
Reactant: Nc1c(Br)ccc(Br)c1N
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OC)cc(-c2ccc(Br)c(N)c2N)c1
Temperature: 105 °C
Reaction time: 3 h
Yield: 37.9 %

Procedure:
A mixture of 3,5-dimethoxyphenylboronic acid (15.1 g, 82.7 mmol, 1.1 equiv) (Step 1.8) in EtOH (50 mL) was added dropwise to a mixture of 3,6-dibromo-benzene-1,2-diamine (20 g, 75.2 mmol) (Step 1.6), PdCl2(dppf) (6.1 g, 7.5 mmol, 0.1 equiv), Na2CO3 (2 M solution in H2O, 150 mL, 300.8 mmol, 4 equiv) in toluene (300 mL) at 105° C., under an argon atmosphere. The reaction mixture was stirred at 105° C. for 3 h, allowed to cool to rt, diluted with EtOAc and H2O and extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM) followed by trituration in EtOH to afford 9.2 g of the title compound as a white solid: ES-MS: 323.0/325.0 [M+H]+; tR=4.43 min (System 1); Rf=0.15 (DCM).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-])=O)=[CH:7][C:6]=2[N:5]([C:19](=[O:30])/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[CH2:4]1.CO.O.CC(O)=O>C1COCC1.[Fe]>[NH2:16][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:3]([CH2:2][Cl:1])[CH2:4][N:5]([C:19](=[O:30])/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[C:6]=2[CH:7]=1
Reactant: COc1cccc(/C=C/C(=O)N2CC(CCl)c3c2cc([N+](=O)[O-])c2ccccc32)c1
Agent: [Fe]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cccc(/C=C/C(=O)N2CC(CCl)c3c2cc(N)c2ccccc32)c1
Yield: 53.8 %

Procedure:
To a hot solution of 14l (110 mg, 0.26 mmol) in THF (10 mL) was added in sequential fashion MeOH (5 mL), H2O (2 mL), AcOH (0.2 mL) and Fe powder (0.5 mL). The mixture was heated at reflux for 1 h, then basified with CaO (1 g), filtered, concentrated to a small volume under reduced pressure below 30° C. and diluted with water. The resulting precipitate was chromatographed on silica gel, eluting with CH2Cl2 /EtOAc (9:1), to give a solid which was recrystallised from CH2Cl2 /petroleum ether to give 15l (55 mg, 54%) mp >200° C. 1H NMR [(CD3)2SO] δ 8.06 (d, J=8.5 Hz, 1 H, H-6), 7.83 (bs, 1 H, H-4), 7.72 (d, J=8.3 Hz, 1 H, H-9), 7.63 (d, J=15.4 Hz, 1 H, PhC=CH), 7.44 (t, J=7.4 Hz, 1 H, H-8), 7.40-7.34 (m, 3 H, PhH), 7.26 (t, partially obscured, J=7.9 Hz, 1 , H-7), 7.22 (d, J=15.4 Hz, 1 h, PhCH=CH), 7.04-6.97 (m, 1 H, PhH), 5.95 (br s, 2 H, NH2), 4.53-4.38 (m, 2 H, H-2), 4.19-4.08 (m, 1 H, H-1), 3.95 (dd, J=11.0, 2.9 Hz, 1 H, CHHCl), 3.83 (s, 3 H, OCH3), 3.76 (dd, J=10.9, 8.1 Hz, 1 H, CHHCl). Anal. Calculated for C23H21ClN2O2 : C, 70.3; H, 5.4; N, 7.1; Cl, 9.0. Found: C, 70.4; H, 5.6; N, 6.9; Cl, 9.1%.
Reaction SMILES: C([NH:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]2[C:8]([C:9]([CH3:21])([CH3:20])[C:10](=[O:19])[NH:11][C:12]2=[O:18])=[CH:7][CH:6]=1)(=O)C.OS(O)(=O)=O>>[NH2:4][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]2[C:8]([C:9]([CH3:21])([CH3:20])[C:10](=[O:19])[NH:11][C:12]2=[O:18])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Agent: O=S(=O)(O)O
Product: CC1(C)C(=O)NC(=O)c2c1ccc(N)c2[N+](=O)[O-]
Temperature: 70 °C
Yield: 99 %

Procedure:
The above amide was converted to 7-acetamido-4,4-dimethyl-8-nitro-2H,4H-isoquinoline-1,3-dione as described in U.S. Pat. No. 4176184 (1979). 7-Acetamido-4,4-dimethyl-8-nitro-2H,4H-isoquinoline-1,3-dione (4.0 g, 13.7 mmol) was added to 90% H2SO4 and heated at 70° C. for 8 h. The cooled mixture was poured onto ice. The precipitate was collected, dissolved in ethyl acetate, washed with water, dried and evaporated to give 7-amino-4,4-dimethyl-8-nitro-2H,4H-isoquinoline-1,3-dione (3.38 g, 99%), mp 259-263° C.; MS (CI) 250 (MH+).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH2:15]([NH:17][C:18]([C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=O)=[O:19])[CH3:16].N1CCCCC1>ClCCl>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[C:18]([NH:17][CH2:15][CH3:16])=[O:19])(=[O:4])=[O:3]
Reactant: CCNC(=O)C(=O)c1ccc[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCNC(=O)C(=C1C(=O)Nc2ccc(S(N)(=O)=O)cc21)c1ccc[nH]1

Procedure:
Alternatively, a mixture of 5-aminosulfonylindolin-2-one (0.22 g, 1.0 mmol), 2-(ethylamino)carbonylcarbonylpyrrole (0.33 g, 2.0 mmol) and piperidine (0.2 mL, 2.0 mmol) was irradiated in a microwave at 160° C. for 5 minutes. The reaction mixture was dissolved in dichloromethane (25 mL). The resulting mixture was washed with 0.2 N HCl (25 mL) and saturated sodium bicarbonate (25 mL), dried (magnesium sulfate) and concentrated. Chromatography on SiO2 (10 g) using hexane/ethyl acetate afforded 5-aminosulfonyl-3-[(pyrrol-2-yl)(ethylaminocarbonyl)methylene]indolin-2-one; (45 mg), 1H NMR (400 MHz, DMSO-d6) δ 1.16 (t, 3H), 3.36 (q, 2H), 6.40 (s, 1H), 6.64 (s, 1H), 7.02 (d, 1H), 7.20 (brs, 2H), 7.42 (s, 1H), 7.64 (d, 1H), 7.75 (s, 1H), 8.85 (t, 1H), 11.40 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH:33]([CH3:37])[C:34](=O)[CH3:35]>C(#N)C>[CH3:37][C:33]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=4)[C:14]4=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]4[CH:12]=3)=[O:10])[CH:5]=[CH:4][N:3]2[C:34]=1[CH3:35]
Reactant: Nc1cc(NC(=O)c2cc3cc(C(F)(F)F)cnc3n2Cc2cccc(F)c2)ccn1
Reactant: CC(=O)C(C)Br
Solvent: CC#N
Product: Cc1nc2cc(NC(=O)c3cc4cc(C(F)(F)F)cnc4n3Cc3cccc(F)c3)ccn2c1C
Yield: 33.4 %

Procedure:
Compound 16 was prepared according to a process similar to that described in step 15.3, by reacting 0.12 g (0.28 mmol) of N-[2-aminopyrid-4-yl]-5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.2, with 0.084 g (0.56 mmol) of 3-bromobutan-2-one in 5 mL of acetonitrile. 45 mg of the expected product are obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:10]=2[O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].C1COCC1.Cl>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:10]=2[O:11][C:12]([CH3:18])([CH3:19])[C:13]([OH:15])=[O:14])=[CH:26][CH:27]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OC(C)(C)C(=O)O)c1
Yield: 91 %

Procedure:
A mixed solution of ethyl 2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoate obtained in Reference Example 153 (6.65 g, 18.1 mmol) and a 8 N aqueous sodium hydroxide solution (4.5 mL) in methanol (40 mL)-THF (20 mL) was stirred at room temperature for 16 hours. The reaction solution was acidified with hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to obtain 5.59 g (yield 91%) of the title compound. Oily matter.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Br:36])(=[O:19])[CH3:18].O>C1(C)C=CC=CC=1.FC(F)(F)C(O)=O>[C:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[C@H:28]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Br:36])[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:14]1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccc(Cl)cc1/C=C/c1ccccc1Br
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)Oc1ccc(Cl)cc1[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1Br
Temperature: 25 °C

Procedure:
N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)amine (5.0 g, 21.06 mmol) was added dropwise with a syringe over 30 minutes to a suspension of (E)-2-(2-bromostyryl)-4-chlorophenyl acetate (Example 1; 7.0 g, 19.9 mmol) in toluene (25 ml) containing trifluoroacetic acid (3 drops) while stirring at room temperature. After additional stirring for one hour water (10 ml) was added. The toluene layer was separated. The aqueous layer was extracted with toluene (25 ml). The combined organic layers were dried with Na2SO4 and evaporated under vacuum to give the crude cycloadduct as a clear and colorless oil, 10.76 g (>100%) in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:10]1[CH2:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].C(CN)O.Cl>O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:16]1[NH:10][C:11](=[O:12])[NH:13][C:14]1=[O:15]
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: NCCO
Product: O=C1NC(=O)C(=Cc2ccccc2Cl)N1
Reaction time: 4.25 h

Procedure:
A mixture of o-chlorobenzaldehyde (2.50 g.) and hydantoin (1.78 g., 1 molar ratio) was treated with water (15 ml ) and heated to 70°. Monoethanolamine (1.63 g., 1.5 molar ratio) was added and the mixture was stirred magnetically at 90°-92° (bath temperature) for 4.25 hours. The mixture was cooled in an ice-bath, acidified with concentrated HCl, refrigerated overnight, filtered, washed with water and dried at 55°/10 mm. The title compound was obtained as a pinkish solid (2.63 g.), m.p. 266°-270° decomp.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH2:13][CH2:12][C@H:11]2[C:6](=[CH:7][CH2:8][C@H:9]3[C@@:17]([C:19]([OH:21])=[O:20])([CH3:18])[CH2:16][CH2:15][CH2:14][C@@:10]32[CH3:22])[CH:5]=1)[CH3:3].CO.C(O)C.C(O)=CC>[Pd].C1C=CC=CC=1.C(O)(=O)C>[CH3:3][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C@@:10]3([CH3:22])[CH2:14][CH2:15][CH2:16][C@:17]([C:19]([OH:21])=[O:20])([CH3:18])[C@@H:9]3[CH2:8][CH2:7][C:6]=2[CH:5]=1)[CH3:1]
Reactant: CC(C)C1=CC2=CC[C@@H]3[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1
Agent: [Pd]
Agent: CC=CO
Solvent: c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)c1ccc2c(c1)CC[C@H]1[C@](C)(C(=O)O)CCC[C@]21C
Reaction time: 8 h

Procedure:
said abietic acid at 200–300° C. for 1–5 hours with the catalyst of 0.1–5% (wt) of 5%–10% palladium/carbon, or incubating directly at 220–380° C. After incubation and cooling down, adding 0.5 to 10-fold (volume) solvent, said solvent can be any one of methanol, ethanol, propenol, acetyester acetic acid, benzene and methbenzene, keeping refluxed for 1–3 hours, filtering when it is warm, cooling down, allowing it to stand for overnight and be crystallized. Dehydroabietic acid is obtained after filtering.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1>>[CH3:7][C:6]1[N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]2)[N:4]=[CH:3][C:2]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(I)cnn1[C@H]1CC[C@H](O)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1[C@H]1CC[C@H](O)CC1
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-(4-iodo-5-methyl-1H-pyrazol-1-yl)cyclohexanol (150.0 mg, 0.4900 mmol) in THF (9 mL, 100 mmol) was added 2 M isopropylmagnesium chloride in THF (0.73 mL, 1.5 mmol) at rt, and the mixture was stirred for 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.32 mL, 2.0 mmol) was added, and the mixture stirred at rt for 2 h. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil.