Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH:21]1[C:33]2[NH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:30]1[C:31]2[N:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=5)=[N:11][N:12]=4)=[CH:4][CH:3]=3)[C:33]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(-c2nnc(-c3ccc(I)cc3)o2)c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nnc(-c3ccc(-n4c5ccccc5c5ccccc54)cc3)o2)c1
Reaction time: 4 h

Procedure:
To a solution of 2-(4-iodophenyl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (3.0 g, 7.93 mmol), carbazole (1.5 g, 8.97 mmol), Cu (2.0 g, 31.47 mmol) in DMF (20.0 ml) was added potassium carbonate (4.0 g, 28.94 mmol) under nitrogen and stirring. Heating was started. The reaction was carried out at 150° C. for 4 h. After cooling, the reaction mixture was filtrated. The solid residues were carefully washed with THF. THF was evaporated from the combined filtration solution, Water (200.0 ml) was added, the yellow solid product was obtained by filtration. The crude product was purified by silica gel column chromatography using dichloromethane/ethyl acetate (9.5:0.5) as eluent. After evaporating solvent, the white solid was recrystallized from acetone/water and finally dried under vacuum. Pure product was obtained as white solid in 3.2 g (96.7%) yield. 1H NMR (400 MHz, CDCl3, δ): 8.38 (m, 2H), 8.16 (d, J=8.0 Hz, 2 Hz), 7.81-7.72 (m, 4H), 7.52-7.43 (m, 5H), 7.33 (m, 2H), 7.12 (m, 1H). 13C NMR (100 MHz, CDCl3, δ): 164.72, 164.02, 159.99, 140.90, 140.21, 130.28, 128.58, 127.21, 126.21, 124.88, 123.76, 122.40, 120.57, 120.48, 119.33, 118.29, 111.61, 109.68, 94.23, 55.55. [M]+ calcd for C27H19N3O2, 417.2. found 417.1.
Reaction SMILES: [Mg].C(COCCOCCOC)CCC.II.BrCCBr.[CH:21]1([CH3:31])[CH2:26][CH2:25][CH:24]([CH:27]([CH3:29])[CH3:28])[CH:23](Cl)[CH2:22]1.[C:32](=[O:34])=[O:33]>>[CH:21]1([CH3:31])[CH2:26][CH2:25][CH:24]([CH:27]([CH3:29])[CH3:28])[CH:23]([C:32]([OH:34])=[O:33])[CH2:22]1
Reactant: CC1CCC(C(C)C)C(Cl)C1
Reactant: O=C=O
Agent: CCCCCOCCOCCOC
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Product: CC1CCC(C(C)C)C(C(=O)O)C1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Magnesium (37 g, 50 mesh), butyl diglyme (600 g), and iodine (0.1 g) were added under nitrogen to a 1-liter flask equipped with agitation, addition funnel, off-set adaptor for thermometer, gas addition tube, and condenser. The mixture was stirred for 30 min. at 90° C., and then 1,2,-dibromo ethane (2 cc) was slowly added. p-Menth-3-yl chloride (200 g) was then added at a rate of 50 g/hr (0.32 mole/hr). After approximately ½ of the p-menth-3-yl chloride was added, carbon dioxide was concurrently added by bubbling the carbon dioxide into the mixture at a rate of 15.91 g/hr (0.36 mole/hr), and at a temperature of 90° C. Addition of the carbon dioxide was continued at a temperature of 90° C. until 30 min. after all of the p-menth-3-yl chloride was added. After carbonation was complete, the resultant mixture was hydrolyzed with aqueous hydrochloric acid (1:1 hydrochloric acid/water), and the resultant oil layer was neutralized with trisodium phosphate. VPC analysis showed a yield of 93.18% by weight of p-menthane-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([CH3:16])[C:13](O)=[O:14])[N:4]=1.[CH3:17][S:18]([NH2:21])(=[O:20])=[O:19].N12CCCN=C1CCCCC2>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([CH3:16])[C:13]([NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[O:14])[N:4]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cc(OC)nc(OC(C)C(=O)O)n1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(OC(C)C(=O)NS(C)(=O)=O)n1
Yield: 58.6 %

Procedure:
To a solution of 1,1-carbonyldiimidazole (1.70 g, 0.0105 mol) in dry tetrahydrofuran (130 ml), 2-(4,6-dimethoxypyrimidin-2-yl)oxypropionic acid (2.28 g, 0.01 mol), prepared as described in Example 1(b) above, in tetrahydrofuran (30 ml) was added dropwise at room temperature (~20° C.). The solution was refluxed for 1/2 hour and allowed to cool. Methanesulphonamide (0.95 g, 0.01 mol) was added in one solid portion and the mixture stirred for 15 minutes before 1,8-diazabicyclo[5.4.0]undec-7-ene (1.52 g, 0.01 mol) in tetrahydrofuran (30 ml) was added dropwise at room temperature (~20° C.). After a short duration the tetrahydrofuran was removed and the residue acidified with IM hydrochloric acid solution. The product was extracted with chloroform, backwashed with water and dried. The solvent was removed and the product purified on silica gel eluting with 3% by volume methanol/chloroform to yield the title compound as a solid (1.79 g).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([CH2:11][CH2:12][CH2:13][OH:14])[O:7][C:6]1=[O:22])[CH3:4].CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:24][C:2]([CH3:23])([CH3:1])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@:8]([CH2:11][CH2:12][C:13]([OH:27])=[O:14])([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[O:7][C:6]1=[O:22])[CH3:4]
Reactant: CC(C)=O
Reactant: C[C@H](N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[C@H](N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of (R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (150 mg, 0.45 mmol) in acetone (10 mL) was added Jones reagent (2.5 mol/L, 0.5 mL) at 0° C., and the mixture was stirred at rt for 1 h. The reaction mixture was concentrated, and the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give 3-((R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid (50 mg, 32%).
Reaction SMILES: [CH:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[CH:1]([CH:4]1[N:9]([C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)C1NCCn2c1nc1ccc(S(C)(=O)=O)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1c1nccc(C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
To a solution of 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (15 mg, 0.05 mmol) in DMSO (3 mL) was added 2-chloro-4-(trifluoromethyl)pyrimidine (19 mg, 0.10 mmol) and DIEA (20 mg, 0.15 mmol) under N2. The mixture was stirred at 100° C. for 2 h. Water (10 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and then purified by preparative TLC to afford 1-isopropyl-7-(methylsulfonyl)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (5.10 mg, 23% yield) as a white solid. LC-MS m/z 440.2 (MH+). 1H NMR (CDCl3 400 MHz): δ 8.58 (d, J=4.8 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.90-7.81 (m, 2H), 6.89 (d, J=4.8 Hz, 1H), 6.12 (d, J=8.0 Hz, 1H), 5.39 (dd, J=4.0 and 14.0 Hz, 1H), 4.34-4.30 (m, 1H), 4.23-4.16 (m, 1H), 3.83-3.75 (m, 1H), 3.09 (s, 3H), 2.55-2.49 (m, 1H), 1.33 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[SH3+].[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:17][O:16]1>CC(O)(C)C.CS(C)=O>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:17][CH2:1][O:16]1
Reactant: CC(C)(C)[O-]
Reactant: Brc1cnccc1C1CO1
Agent: [K+]
Agent: [SH3+]
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Product: Brc1cnccc1C1CCO1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
potassium tert-butoxide (561 mg, 5 mmol) was added to a solution of sulfonium salt (1100 mg, 5 mmol) in t-BuOH (20 mL) at room temperature. After 15 min, a solution of 3-Bromo-4-oxiranyl-pyridine (200 mg, obtained above) in DMSO (10 mL) was added dropwise at 50° C. The resulting mixture was stirred at 50° C. for 15 h. The reaction mixture was quenched with brine, and the resulting mixture was extracted with ethyl acetate twice. The combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column and afforded the title compound (96 mg). ESI-MS m/z: 216.1 [M+1]+, Retention time 1.01 min; 1HNMR (CDCl3, 400.342 MHz) δ ppm 2.50-2.59 (m, 1H), 3.31-3.39 (m, 1H), 4.65-4.70 (m, 1H), 4.87-4.92 (m, 1H), 5.91 (t, J=8 Hz, 1H), 7.95 (d, J=8 Hz, 1H), 8.68 (d, J=8 Hz, 1H), 8.73 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:17][CH:18](O)[CH:19]=[CH2:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:17]([CH:8]1[C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:18]=[CH:19][CH3:20]
Reactant: CCC1(CC)CC(=O)c2cc(OC)ccc21
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(OC)ccc2C1(CC)CC
Yield: 15 %

Procedure:
A solution of 22.0 g of 6-methoxy-3,3-diethyl-1-indanone, 20.8 ml of 3-buten-2-ol and 220 mg of p-toluenesulfonic acid in 220 ml of 2,2-dimethoxypropane was boiled under reflux for 87 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 6:1). In addition to 15.7 g of educt, there were obtained 4.1 g (15%) of (RS)-2-(2-buten-1-yl)-6-methoxy-3,3-diethyl-1-indanone as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#N.[CH3:13]I.[H-].[Na+].C[N:18]([CH3:21])C=O>>[F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([CH3:13])([CH3:5])[C:21]#[N:18]
Reactant: CN(C)C=O
Reactant: CI
Reactant: COc1cccc(CC#N)c1F
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(C(C)(C)C#N)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.5 %

Procedure:
4 g (24.22 mmol) of 2-fluoro-3-methoxybenzyl cyanide is dissolved in 38 ml of N,N-dimethylformamide and mixed with 6.87 g (48.35 mmol) of methyl iodide. At 0° C., 2.11 g (48.35 mmol) of sodium hydride (55%) is added in portions within 45 minutes. After 20 hours of stirring at room temperature, the batch is poured into ice water and extracted three times with 200 ml each of diethyl ether. The organic phases are washed with water and brine and dried. After the desiccant is filtered off and after the solvent is spun off, the residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 4.66 g (99.5%) of the desired compound is isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].[Li]CCCC.[CH3:31][C:32]1[N:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:33]=1[CH:34]=[O:35]>C1COCC1>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:34]([C:33]3[C:32]([CH3:31])=[N:39][C:38]([CH3:40])=[CH:37][CH:36]=3)[OH:35])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(C=O)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (1.85 g, 4.3 mmol, Intermediate 5: step d) was added THF (45 mL) at room temperature which resulted in a colorless homogeneous solution. The solution was cooled to −70° C. and then n-BuLi (2.5 M in hexanes, 1.75 mL, 4.38 mmol) was added dropwise. After 2 minutes, 2,6-dimethylnicotinaldehyde (755 mg, 5.50 mmol, in 2 mL THF) was introduced and the color of the mixture changed from a reddish-brown to green. The reaction mixture was allowed to warm to −20° C. over 40 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (3×50 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (10% acetone-hexane increasing to 30% acetone) afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)[C:4]([O:28][CH3:29])=[CH:3][C:2]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reactant: OB(O)c1cccc(F)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccc(F)c2)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 120 °C
Yield: 64.6 %

Procedure:
A vial was charged with 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE HHHHH; 80.29 mg, 0.178 mmol), (3-fluorophenyl)boronic acid (49.8 mg, 0.356 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.828 mg, 4.45 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (6.74 mg, 8.90 μmol), and potassium phosphate (113 mg, 0.534 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (809 μl) and water (81 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc (3×). The aq. layer was acidified with 0.5N aq. HCl, then extracted with EtOAc (2×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-7.5% MeOH/DCM) to give 1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (58.84 mg, 0.115 mmol, 64.7% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=14.50 (br. s., 1H), 8.79 (s, 1H), 8.71 (d, J=5.8 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.14 (d, J=5.4 Hz, 1H), 7.94-7.88 (m, 1H), 7.85-7.78 (m, 1H), 7.64-7.53 (m, 3H), 7.42-7.27 (m, 3H), 3.72 (s, 3H). m/z (ESI) 511.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][C:18]([CH3:22])=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:23]([O-])=O)[CH:3]=1.O.NN>[Ni].CO.C1COCC1>[NH2:23][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][C:18]([CH3:22])=[CH:17]2)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C)cnc23)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cc(C)cnc23)c(N)c1
Yield: 21.8 %

Procedure:
In a similar fashion using route 6 general procedure 14, 4-methyl-N-(3-methylquinolin-8-yl)-2-nitrobenzenesulfonamide (Intermediate 157) (100 mg, 0.28 mmol), Raney nickel (20 mg, 20% wt), hydrazine hydrate (42 mg, 0.84 mmol) and MeOH/THF (4:1, 5 ml) gave the title compound (20 mg, 22%) after purification by column chromatography with n-hexane/EtOAc (1:0-4:1) gradient elution.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[CH2:26](O)[CH3:27].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]([O:24][CH2:26][CH3:27])=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Reaction time: 3 h

Procedure:
52.4 g (0.15 mol) of 1-benzyl-3-(5-carboxy-2-furyl)indazole, potassium salt, were initially charged in 1250 ml of toluene, and after addition of 200 ml of abs. ethanol and 50 ml of conc. sulfuric acid the mixture was stirred under reflux on a water separator. After 3 hours, the mixture was concentrated using a rotary evaporator, the oil that remained was taken up in water/ethyl acetate and the aqueous phase was separated off. The organic phase was washed with water and 7.5% strength NaHCO3 solution, dried with sodium sulfate and concentrated. The residue was recrystallized from isopropanol. This gave 37.8 g (73%) of the title compound. m.p.: 98-99° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[O:17][CH3:18].[N+:19]([O-])([OH:21])=[O:20]>ClCCl.C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([N+:19]([O-:21])=[O:20])[C:7]=1[O:17][CH3:18]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc(OCCCCl)c(OC)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCCCCl)c(OC)c1[N+](=O)[O-]
Yield: 82 %

Procedure:
WO 02/36587 describes a process for preparing a 5-alkoxy-4-halogenoalkoxy-2-nitrobenzoic acid compound from a 3-alkoxy-4-hydroxybenzoic acid compound. For example, ethyl vanillate (i.e., ethyl 4-hydroxy-3-methoxybenzoate) is reacted with 3-bromo-1-chloropropane in an aqueous potassium carbonate solution in the presence of N-butyl-ammonium bromide to produce ethyl 4-(3-chloropropoxy)-3-methoxybenzoate, and the ethyl 4-(3-chloropropoxy)-3-methoxybenzoate is reacted with 70% nitric acid in a mixture of dichloromethane and acetic acid, to give ethyl 4-chloropropoxy-3-methoxy-2-nitrobenzoate in 82% yield (based on the amount of ethyl vanillate).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)[CH3:14].N1CCCC1>CO.O>[CH2:13]([N:15]1[CH2:16][CH:17]=[C:18]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:19][CH2:20]1)[CH3:14]
Reactant: CCN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: CO
Solvent: O
Solvent: C1CCNC1
Product: CCN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 77.6 %

Procedure:
A solution of 5-nitro-1H-indole (0.67 g, 4.13 mmol), 1-ethylpiperidin-4-one (1.094 mL, 8.26 mmol) and pyrrolidine (1.025 mL, 12.40 mmol) in dry methanol (10 mL) was refluxed for 48 h. The reaction was brought to room temperature, diluted with water and product was extracted into CH2Cl2 (2×50 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated, crude was stirred with isopropanol: hexanes, (15 mL, 1:7) and the yellow precipitate was filtered and dried to obtain 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (0.87 g, 78%). 1H NMR (DMSO-d6) δ 11.87 (s, 1H), 8.69 (d, 1H, J=2.1 Hz), 8.01 (dd, 1H, J=2.4, 9.0 Hz), 7.65 (s, 1H), 7.55 (d, 1H, J=9.0 Hz), 6.18 (s, 1H), 3.16-3.12 (m, 2H), 2.64 (t, 2H, J=5.1 Hz), 2.54-2.42 (m, 4H, merged with DMSO-peak), 1.70 (t, 3H, J=7.2 Hz); ESI-MS (m/z, %): 272 (MH+, 100).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1n[nH]c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2n[nH]c3ccccc23)cc1
Temperature: 100 °C
Yield: 5.4 %

Procedure:
A mixture of 3-bromo-1H-indazole (0.20 g, 1.0 mmol), 4-methoxyphenylboronic acid (0.228 g, 1.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.228 g, 0.1 mmol) in ethylene glycol dimethyl ether (5 mL) and 2.0 M sodium carbonate solution (6 mL) under nitrogen was heated at 100° C. for 18 hours. It was quenched by water and extracted with chloroform. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide the title compound (0.012 g, 5% yield): 1H NMR (CDCl3) δ 10.4 (br s, 1H), 8.01 (d, 1H), 7.92 (d, 2H), 7.46 (m, 2H), 7.22 (m, 1H), 7.06 (d, 2H), 3.89 (s, 3H); EI-MS (m/z) 224 [M]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23]#N)=[CH:11][N:10]=1)=[O:8])[CH3:2].[OH-:28].[Na+].Cl.C[OH:32]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23]([OH:32])=[O:28])=[CH:11][N:10]=1)=[O:8])[CH3:2]
Reactant: [OH-]
Reactant: CO
Reactant: CCOc1cccc(C(=O)c2ncc(C#N)c3cc(OC)c(OC)cc23)c1
Agent: Cl
Agent: [Na+]
Product: CCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To the suspension of 1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carbonitrile (from example 82) (2.0 g, 5.52 mmol) in methanol (120 mL) was added 25% of aqueous sodium hydroxide solution (30 mL, 190 mmol). The mixture was stirred at 100° C. for 12 h more. After cooling to room temperature, the reaction was adjusted to pH=2 with 2 N HCl solution. The product was extracted with chloroform (2×200 mL). The combined organic layers were washed with water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give solid. Recrystallization from ethanol and ether to afford 1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid yellow solid. LC/MS m/e calcd for C21H19NO6 (MH+) 382,
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1ccc(F)cc1
Product: C[C@@H](CCl)COc1ccc(F)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [Br:1][C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[C:4]=2[C:5](O)=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:19]>>[Br:1][C:2]1[C:3]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[C:4]=2[C:5]([Cl:19])=[N:6][CH:7]=1
Reactant: Oc1ncc(Br)c2sc3ccc(Cl)cc3c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2sc3c(Br)cnc(Cl)c3c2c1

Procedure:
A suspension of 4-bromo-8-chloro[1]benzothieno[3,2-c]pyridine-1-ol in POCl3 (1 M) was placed in a microwave reactor at 240° C. (normal absorption) for 10 min. The reaction mixture was carefully extracted with EtOAc/NaHCO3, dried over Na2SO4, filtered and evaporated to provide the title compound.