Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1I.N1C=CC=CC=1C(O)=O.C(=O)(O)[O-].[K+]>CN(C)C=O.Cl.C(OCC)(=O)C.[Cu]I>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: Clc1ccccc1I
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c2c(c(=O)n1-c1ccccc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Yield: 4.7 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 1.24 g, 6 mmol), 1-chloro-2-iodobenzene (666 μL, 5.4 mmol), copper(I) iodide (57 mg, 0.3 mmol), picolinic acid (150 mg, 1.2 mmol), and potassium bicarbonate (840 mg, 8.4 mmol) in N,N-dimethylformamide (20 mL) was irradiated in a microwave oven at 200° C. for 160 min. The reaction mixture was diluted with 0.1 M HCl (200 mL) and then extracted with ethyl acetate (200 mL). The organic layer was washed with 0.1 M HCl, 0.25 M NaOH, and brine, then dried (magnesium sulfate), filtered, evaporated and purified using an ISCO CombiFlash® Sg100c chromatography system, eluting with 5-100% ethyl acetate/dichloromethane to give a tan semi-solid which was taken up in ethyl acetate and washed with 0.1 M HCR. The solvent was evaporated and the residue was recrystallized from ethyl acetate. The mother liquor was evaporated and the residue recrystallized from ethyl acetate. The crystals were combined to give (4S,7R)-2-(2-chloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (80 mg, 5%) as a white solid. APCI-MS (M+H) 317.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[C:30]([C:26]1[CH:25]=[C:24]([CH2:23][CH:15]([NH:14][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:13])[C:16]([N:18]2[CH2:22][CH2:21][S:20][CH2:19]2)=[O:17])[CH:29]=[CH:28][CH:27]=1)#[N:31]
Reactant: N#Cc1cccc(CC(N)C(=O)N2CCSC2)c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: N#Cc1cccc(CC(NC(=O)c2cc3cc(Cl)ccc3[nH]2)C(=O)N2CCSC2)c1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3-(3cyano-phenyl)-1-thiazolidin-3-yl-propan-1-one.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH:17]=[CH:18][C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20]>CN(C=O)C>[CH3:24][O:23][N:21]([CH3:22])[C:19]([CH:18]1[CH2:4][CH:17]1[C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[F:9])=[O:20]
Reactant: CON(C)C(=O)C=Cc1cc(F)ccc1F
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(2,5-difluoro-phenyl)-N-methoxy-N-methyl-acrylamide (21 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (18 g) as an oil.
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[C:11](=[O:13])[CH3:12].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl>C1COCC1>[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:3][C:4]3[C:5]([C:11](=[O:13])[CH:12]=2)=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1c(O)cccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc([N+](=O)[O-])cc2)oc2cccc(O)c12
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (52.5 mmol, 4 equivalents) is added in one portion to a well-stirred solution of 2′,6′-dihydroxyacetophenone (13.1 mmol) in dry THF (40 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of 4-nitrobenzoyl chloride (14.46 mmol) in THF (40 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (400 g) and concentrated HCl (16 ml) and extracted with dichloromethane (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (100 ml) and sulfuric acid (0.5 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 4′-nitro-5-hydroxyflavone. 1H NMR (250 MHz, CDCl3): δ=6.75–8.5 (m, 7H), 12.3 (s, 10H); EI-MS (70 eV) m/e (rel. abund.)=283.
Reaction SMILES: [C:1]1([C:7]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:16](=[O:32])[CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24]CC4C=CC=CC=4)[CH2:14]3)[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])([OH:33])[CH:9]([OH:42])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:43]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:16](=[O:32])[CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[OH:24])[CH2:14]3)[C:10]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])([OH:33])[CH:9]([OH:42])[CH2:8]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3OCc3ccccc3)CC21
Solvent: CCO
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3O)CC21
Temperature: 60 °C

Procedure:
A mixture of 1.5 g of (3aRS, 4RS, 5RS, 7aRS )-7,7-diphenyl-4-(2-methoxyphenyl )-2-[(2-benzyloxyphenyl)acetyl]perhydroisoindole-4,5-diol and 50 cm3 of ethanol is heated at 60° C. while stirring; 0.5 g of 20% strength palladium hydroxide-on-charcoal is added and the reaction mixture is then hydrogenated at a temperature of 60° C. and under atmospheric pressure, while stirring. After a reaction time of 45 minutes, the theoretical volume of hydrogen was absorbed; the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 20 cm3 of isopropyl ether. 0.8 g of (3aRS, 4RS, 5RS, 7aRS ) -7,7-diphenyl-4- (2-methoxyphenyl )-2-[(2-hydroxyphenyl)acetyl] perhydroisoindole-4,5-diol which melts at 188°-190° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:20][NH:21][O:22][CH3:23]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:17])[N:21]([O:22][CH3:23])[CH3:20])=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: CNOC
Reactant: Cc1ccc(CCOc2ccc(N=C=O)cc2)cc1
Solvent: c1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc(C)cc2)cc1
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
Into a solution of 5.5 g of 4-(4-methylphenethyloxy)phenyl isocyanate in 100 ml of benzene, a solution of 2 g of N,O-dimethylhydroxylamine in 50 ml of benzene is added dropwise at 20° to 30° C. After the addition is finished, the reaction mixture is continuously stirred at the same temperature for an additional 30 minutes. Thereafter, the solvent is removed under reduced pressure, and the residue is recrystallized from ethanol to obtain 7.4 g of N'-[4-(4-methylphenethyloxy)phenyl]-N-methoxy-N-methylurea as white needles, M.P. 82°-83° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][N:31](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:30]#[N:31])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: COCCn1c(C)nc2cc(Br)cc(OCc3ccccc3)c21
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: [C-]#N
Product: COCCn1c(C)nc2cc(C#N)cc(OCc3ccccc3)c21
Temperature: 90 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A mixture of 7-(benzyloxy)-5-bromo-1-(2-methoxyethyl)-2-methyl-1H-benzimidazole (1.00 g, 2.66 mmol, Step 3), zinc cyanide (376 mg, 3.20 mmol), and tetrakis(triphenylphosphine)palladium (154 mg, 0.13 mmol) in N,N-dimethylformamide (15 mL) was stirred at 90° C. for 3 hours under nitrogen gas. After cooling to room temperature, the mixture was poured onto saturated potassium carbonate aqueous solution (100 mL), and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residual solid was washed with ethyl acetate/diisopropyl ether (1:2) to afford the title compound as a white solid (648 mg, 76%).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3cnccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)sc2cnccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.3 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylthieno[2,3-c]pyridin-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (151 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (80.2 mg, 56%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.[CH3:26][CH:27]1[CH2:32][NH:31][CH2:30][CH2:29][NH:28]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:31]1[CH2:30][CH2:29][NH:28][CH:27]([CH3:26])[CH2:32]1)=[O:13])=[CH:5]2
Reactant: CC1CNCCN1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1CN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A mixture of 5-chloroindole-2-carboxylic acid (0.196 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.288 g) in dichloromethane (10 mL) was treated with 2-Methyl-piperazine (0.15 g) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (50 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give the title compound (0.229 g). 1H NMR (400 MHz, CDCl3): δ 10.99 (br s, 1H), 7.55 (d, J=1.76 Hz, 1H), 7.33 (d, J=8.80 Hz, 1H), 7.14 (dd, J=1.96, 6.65 Hz, 1H), 6.63 (br s, 1H), 4.55 (br s, 2H), 3.23-2.61 (m, 5H), 1.76 (br s, 1H), 1.08 (d, J=5.87 Hz, 1H). MS (electrospray): exact mass calculated for C14H16ClN3O, 277.10; m/z found, 278.1 [M+H]+.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N+:4]=1[O-:10].[NH2:11][CH2:12][CH2:13][CH2:14][OH:15].C([O-])(O)=O.[Na+]>C(O)(CC)(C)C.C(Cl)Cl>[OH:15][CH2:14][CH2:13][CH2:12][NH:11][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N+:4]=1[O-:10]
Reactant: NCCCO
Reactant: Cc1cc[n+]([O-])c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(C)(C)O
Product: Cc1cc[n+]([O-])c(NCCCO)c1
Yield: 76.1 %

Procedure:
A mixture of 2-chloro-4-methylpyridine-N-oxide hydrochloride (7.16 g, 39 mmole), 3-aminopropanol (6.01 g, 80 mmole), and NaHCO3 (16.8 g, 200 mmole) in tert-amyl alcohol (50 mL) was heated at reflux for 19 hr. The reaction mixture was diluted with CH2Cl2 (200 mL) and filtered, and the filtrate was concentrated on the rotavap. Recrystallization from CH2Cl2/Et2O gave the title compound (5.41 g, 75%) as a yellow solid: TLC (15% MeOH/CH2Cl2) Rf 0.44; 1H NMR (400, CDCl3) δ7.92 (d, J=6.7, 1 H), 7.28 (br t, 1 H), 6.43 (s, 1 H), 6.33 (dd, J=6.6, 2.1 Hz, 1 H), 3.73 (t, J=5.7 Hz, 2 H), 3.47 (q, H=6.3 Hz, 2 H), 2.29 (s, 3 H), 1.82-1.88 (m, 2 H); MS (ES) m/e 183 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.N1C=CC=CC=1.[CH:19]([N:22]([CH:35]([CH3:37])[CH3:36])[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=1[O:33][CH3:34])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[N:32]([C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][N:22]([CH:19]([CH3:21])[CH3:20])[CH:35]([CH3:37])[CH3:36])=[C:27]([O:33][CH3:34])[CH:28]=1)[C:9]2=[O:10]
Reactant: COc1cc(N)ccc1OCCN(C(C)C)C(C)C
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1cc(N2C(=O)c3ccc(Br)cc3C2=O)ccc1OCCN(C(C)C)C(C)C
Temperature: 85 °C
Yield: 64.2 %

Procedure:
4-Bromophthalic anhydride [Apin] (2.27 g, 10 mmol) was dissolved in 1,2-dichloromethane (8 ml), and pyridine (10 mmol, 0.81 ml) was added, followed by 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine [Patent WO-9901127] (2.44 g, 10 mmol) and a catalytic amount of 4-dimethylaminopyridine [Aldrich]. The mixture was heated for 16 h at 85° C. The mixture was evaporated in vacuo and applied to a Biotage Flash40M cartridge, (eluting with dichloromethane-methanol-aqueous ammonia) to give the 5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dione 3.05 g, 68%, as the trifluoroacetate salt;
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1>>[N:1]1([C:11]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C1CCCC(=O)C1
Product: O=C1C=C(N2CCCc3ccccc32)CCC1
Yield: 15.6 %

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (5 g) and 1,3-cyclohexanedione (4.21 g) was heated at ca. 150° for 5 h. The cooled reaction mixture was purified by FCC eluting with ethyl acetate to give the title compound (1.33 g) as an oil, t.l.c. (ethyl acetate) Rf 0.34.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:16]O>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cccc(F)c1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(F)c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-bromo-3-fluorobenzoic acid (300 mg, 1.37 mmol) in methanol (10 mL) at rt, was added SOCl2 (0.11 mL, 1.51 mmol) and the mixture was stirred at rt for 18 h. The solvent was distilled off under reduced pressure. The crude was basified by adding saturated aqueous NaHCO3 solution and the aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The obtained crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH:16]=O)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO.C([N:23](CC)CC)C.[N+](C1C=C2C(=O)OC(=O)C2=CC=1)([O-])=O>C(#N)C.O>[CH2:1]([O:8][C:9]1[C:10]([C:16]#[N:23])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C=O)n1
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Agent: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: O
Solvent: CC#N
Product: Cc1ccc(OCc2ccccc2)c(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
3-Benzyloxy-6-methyl-pyridine-2-carbaldehyde (100 mg) was dissolved in acetonitrile (5 ml) to prepare a solution. Hydroxylamine hydrochloride (72 mg) and triethylamine (0.25 ml) were added to the solution, and the mixture was stirred at room temperature for one hr. 4-Nitrophthalic anhydride was added to the reaction solution, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using ethyl acetate-hexane to give 3-benzyloxy-6-methylpyridine-2-carbonitrile (53 mg, yield 54%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+].Cl>C(O)C.O>[CH2:27]([O:26][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[C:14]2[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1CCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
The above 5-benzyloxy-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (0.2 g, 0.44 mmol, 1.0 equiv) was dissolved in 5 mL of ethanol. A solution of lithium hydroxide hydrate (0.2 g) in 5 mL of water was added and the resulting solution was stirred for 16 h at ambient temperature. The pH was adjusted to <1 with concentrated HCl and the product was quickly extracted with 2×15 mL of ethyl acetate. The organic layers were combined, dried over Na2SO4, decanted and concentrated to provide 5-benzyloxy-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid (186 mg) as a beige glass.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4].[CH2:20](O)[CH2:21][OH:22].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(=O)OCC.O>[CH3:18][C:17]1([C:15]2[O:16][C:12]([CH2:11][N:8]3[CH:9]=[CH:10][C:6]([N+:3]([O-:5])=[O:4])=[N:7]3)=[CH:13][CH:14]=2)[O:22][CH2:21][CH2:20][O:19]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Cn3ccc([N+](=O)[O-])n3)o2)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus under inert atmosphere (N2), a solution of 1-[5-(3-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-ethanone (1.760 g, 7.48 mmol), ethylene glycol (4.18 mL, 74.98 mmol) and TsOH (14 mg, 0.08 mmol) in toluene (74.8 mL) was heated to reflux for 4 h. The reaction mixture was allowed to cool to rt. Water (125 mL) and EA (25 mL) were added and the aq. phase was extracted with EA (2×50 mL). The combined org. extracts were washed with sat. aq. NaHCO3, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as a yellow oil. TLC: rf (60:40 hept-EA)=022. LC-MS-conditions 02: tR=0.92 min; [M+H]+=280.04. 1H NMR (400 MHz, CDCl3) δ 1.71 (s, 3H), 3.95-4.02 (m, 2H), 4.02-4.09 (m, 2H), 5.36 (s, 2H), 6.33 (d, J=3.3 Hz, 1H), 6.41 (d, J=3.0 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2]([C:1]([OH:14])=[O:13])=[CH:3][C:4]=1[O:5][CH3:6])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Solvent: c1ccncc1
Product: COc1cc(C(=O)O)cc(OC)c1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
In a 100 ml flask, under a nitrogen atmosphere, 1.50 g (7.57 mmoles) of syringic acid is dissolved in 15 ml of dry pyridine. 0.86 ml (9.08 mmoles) of acetic anhydride is added dropwise and the mixture is agitated at ambient temperature for 18 hours. The pyridine is evaporated off under reduced pressure, the residue is taken up in 25 ml of dichloromethane and washed with 10 ml of a molar solution of HCl then with 2×10 ml of water. The organic phase is dried over sodium sulphate, filtered and evaporated under vacuum. 1.72 g (95%) of a beige powder is obtained. Melting point: 181-183° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[Si:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42])[S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Si:43]([O:50][CH2:51][CH2:52][CH2:53][CH2:54]I)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>O.O1CCCC1>[Si:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[F:42])([CH2:54][CH2:53][CH2:52][CH2:51][O:50][Si:43]([C:46]([CH3:47])([CH3:49])[CH3:48])([CH3:44])[CH3:45])[S:25]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCC(CCCCO[Si](C)(C)C(C)(C)C)(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.358 ml, 0.562 mmol) was added to a tetrahydrofuran (4 ml) solution of the 2-[5-(t-butyldimethylsilyloxy)-1-[(4-chlorophenyl)sulfonyl]pentyl]-1,4-difluorobenzene (250 mg, 0.511 mmol) obtained in Example 15. The temperature of the resulting mixture was raised to room temperature. After cooling to −78° C., 4-(t-butyldimethylsilyloxy)-1-iodobutane (0.146 ml, 0.562 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and then concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (6% ethyl acetate-hexane), whereby the title compound (167 mg, 48%) was obtained as a colorless solid.