Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[C:23](Cl)(=[O:28])/[CH:24]=[CH:25]/[CH2:26][CH3:27].[NH4+].[Cl-]>C1COCC1>[C:23]([N:8]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])(=[O:28])/[CH:24]=[CH:25]/[CH2:26][CH3:27]
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: CC/C=C/C(=O)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: -50 °C
Yield: 28.7 %

Procedure:
(S)-(+)-4-Phenyl-2-oxazolidinone (4.0 g, 24 mmol, Aldrich) was dissolved in dry THF (40 mL), and the solution was cooled to -50° C. and flushed with N2. Sodium hexamethyldisilazane (1.0M in THF, 25 mL, 25 mmol) was added slowly with stirring. The compound from step 7a (2.9 g, 24 mmol) was added slowly while maintaining the temperature at -50° C., and the mixture was stirred at this temperature for 1.5 hour. The mixture was allowed to warm to 0° C. and stirred for 1 hour. Saturated aqueous NH4Cl solution was added, the mixture was stirred for 10 minutes and the mixture was extracted with methylene chloride. The extract was dried over Na2SO4, filtered and the solvent was removed. The residue was chromatographed on silica gel, eluting with 2% methanol/methylene chloride, and the product was rechromatographed with 0.5% methanol/methylene chloride to give the title compound (1.69 g). MS m/z 246 (M+H)+, 263 (M+NH4)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:38][O:39]COC)([CH2:29][CH2:30][O:31]C1CCCCO1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([C:25]([F:28])([F:27])[F:26])[CH:12]=1)(C)(C)C.[ClH:44]>C(O)C>[ClH:44].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([C:25]([F:26])([F:27])[F:28])[CH:12]=1)([CH2:29][CH2:30][OH:31])[CH2:38][OH:39]
Reactant: CCCCCCCOc1ccc(CCC(CCOC2CCCCO2)(COCOC)NC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: CCCCCCCOc1ccc(CCC(N)(CO)CCO)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound 21-7 (1.49 g) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (3 ml) was added, and the mixture was stirred at 80° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (915 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][C@H:16]([OH:18])[CH2:15][C@H:14]2[C:19]([O:21][CH3:22])=[O:20])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].COC([C@@H]1[C@@H](O[Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])CCN1C(NC1C=CC(C#N)=C(Cl)C=1C)=O)=O>>[Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([NH:10][C:11]([N:13]2[CH2:17][C@H:16]([O:18][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:15][C@H:14]2[C:19]([O:21][CH3:22])=[O:20])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Reactant: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)Nc1ccc(C#N)c(Cl)c1C

Procedure:
The title compound was prepared from compound 56B (150 mg, 0.44 mmol) in a manner analogous to that described for compound 55B to afford a white solid (156.3 mg, 79%), mp 129-131° C. HPLC: 3.38 min (retention time) (Conditions: YMC S-5 C-18 (4.6×250 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=9.80 min (99.9%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 452 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:34]=[CH:33][CH:32]=[CH:31][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:28]=[C:27]([CH3:29])[C:21]([O:22][CH2:23][C:24](O)=[O:25])=[C:20]([CH3:30])[CH:19]=3)[O:15][C:13]=2[N:14]=1>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:34]=[CH:33][CH:32]=[CH:31][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:28]=[C:27]([CH3:29])[C:21]([O:22][CH2:23][C:24]([Cl:3])=[O:25])=[C:20]([CH3:30])[CH:19]=3)[O:15][C:13]=2[N:14]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)Cl

Procedure:
3 ml of thionyl chloride were slowly added to 336 mg of {4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetic acid. The mixture was allowed to react for 2 days. Then toluene was added and the solvents were removed in vacuo. The addition and removal of toluene was repeated to give 350 mg of the title compound as a brown oil.
Reaction SMILES: B(Br)(Br)Br.[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([O:26]C)[C:18]([Br:28])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:5]1([S:11]([CH2:14][C:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([OH:26])[C:18]([Br:28])=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
Boron tribromide (1M solution in DCM, 5.85 ml) was added dropwise to a stirred, cooled solution of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 2.3 g) in dry DCM (45 ml) at −70° C. The resultant mixture was stirred at −70° C. for 40 minutes, then allowed to warm to room temperature. It was stirred at room temperature for 2 hours then poured into sodium bicarbonate (saturated aqueous solution). The layers were separated and the aqueous layer was extracted with further DCM. The combined organic layers were washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-hydroxybenzoate (1.64 g) as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:10](Cl)[CH:11]=[CH2:12].C1(OCC=C)C=CC=CC=1>C(O)(C)C.O>[CH2:12]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH:11]=[CH2:10]
Reactant: C=CCCl
Reactant: Oc1ccccc1
Agent: C=CCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: C=CCc1ccccc1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.6 %

Procedure:
To a reaction bottle was added 8.0 moles of phenol (753 grams) dissolved in 1,200ml of isopropanol. To this was added 8.0 moles of sodium hydroxide (320 grams) dissolved in 300ml of water. The bottle was rinsed three times by adding each time 200ml of isopropanol with reaction of the sodium hydroxide and phenol occurring immediately. Allyl chloride, in an amount of 9.6 moles, was charged. The mixture was then agitated and heated. A slight nitrogen pressure of approximately 70 kPa (10 psig) was placed on the reaction bottle. The reactor was brought up to a temperature of approximately 70° C. After approximately 5 hours at 70° C, the formation of allyl phenyl ether was judged complete and the reaction bottle was allowed to come to room temperature. The reaction mixture was then washed twice with 3 liters of water to remove sodium chloride, isopropanol, and unreacted sodium phenoxide as well as other by-products. The bottle was then charged with 3 liters of toluene, mixed, and heated to a temperature of approximately 100° C. An azeotropic distillation occured and was continued for approximately 3 hours during which time the toluene was distilled off along with traces of water, isopropanol, unreacted allyl chloride, and other by-products. The remaining allyl phenyl ether was sufficiently pure to be thermally rearranged to 2-allyl phenol. The rearrangement process occurred at 200° C and continued for approximately 5 hours. After this time, the reaction was stopped and a gas chromatographic analysis of the product was made. A 2-allyl phenol yield of 90.6 percent was achieved.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[C:20](OC)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:21]1([C:20](=[O:27])[CH2:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cnccn1
Reactant: COC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(Cc1cnccn1)c1ccccc1
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To a mixture of diisopropyl-amine (1.29 g, 12.7 mmol) in anhydrous THF (10 mL) was added n-BuLi (2.5 M/L in hexane, 4.7 mL, 11.7 mmol) at −78° C., after being stirred for 30 minutes, a solution of 2-methylpyrazine (1 g, 10.6 mmol) in THF (5 mL) was added, and the mixture was stirred at −78° C. for 30 minutes, a solution of methyl benzoate (1.4 g, 10.6 mmol) in THF (5 mL) was added, and the mixture was stirred at this temperature for 3 hours. When TLC indicated that the starting material was consumed, the reaction mixture was diluted with EtOAc, and the mixture was washed with water and brine, and concentrated. The residue was purified by column chromatography (PE:EtOAc=30:1) to give Intermediate 26 (700 mg, yield 33.3%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[K+].[CH2:26]([O:28][C:29](=[O:34])[CH2:30]C([O-])=O)[CH3:27].C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4]([CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:34])=[O:6]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1ccc(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
2,3,4-trichlorobenzoic acid (4.51 g, 20.0 mmol) was dissolved in tetrahydrofuran (80 ml), carbonyldiimidazole (3.89 g, 24.0 mmol) was added thereto while cooling with ice, and then stirred at room temperature for 3 hours (solution A). Meanwhile, malonic acid monoethyl ester monopotassium salt (6.81 g, 40.0 mmol) was suspended in ethyl acetate, and while cooling with ice, triethylamine (13.9 ml, 100.0 mmol) and magnesium chloride (5.71 g, 60.0 mmol) were added thereto. After stirring at room temperature for 3 hours, the reaction solution was cooled with ice and the above-described solution A was dripped into this reaction solution over a period of 10 minutes. After then washing solution A into the reaction solution using tetrahydrofuran (10 ml), it was stirred at room temperature for 14 hours, and then the reaction solution was poured into a 10% aqueous citric acid solution (200 ml). This was then extracted with ethyl acetate (200 ml), washed with saturated saline solution (200 ml), and then dried over anhydrous sodium sulfate. After then removing the drying agent by filtration, the solvent was evaporated under a reduced pressure, and the crude product obtained was subject to silica gel chromatography, thereby obtaining 2.681 g (45%) of the title compound as a pale-red oil from an n-hexane:ethyl acetate=5:1 eluate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](O)=[N:7][C:8]=1[CH3:9])#[N:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([CH3:9])[N:7]=1
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(C#N)c(C)nc1Cl

Procedure:
200 g of 5-cyano-2-hydroxy-6-methyl-3-pyridine-carboxylic acid, ethyl ester (1 mol) are refluxed with stirring in 750 ml of phosphorous oxychloride for 5 hours. The excess of phosphorous oxychloride is removed in vacuo and the residue poured in 1 kg of ice. 2-chloro-5-cyano-6-methyl-3-pyridine-carboxylic acid, ethyl ester crystallizes and is filtered off. Yield 170 g (76%); m.p. 43°-45° C. (petrol ether).
Reaction SMILES: [C:1]([C:9]1[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:10]=1[C:11]([N:13]([CH2:25][CH:26]([OH:31])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O.Cl>CS(C)=O>[C:1]([C:9]1[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:10]=1[C:11]([N:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1)[CH2:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(O)CN(Cc1ccc(S(C)(=O)=O)cc1)C(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CCCCC(=O)CN(Cc1ccc(S(C)(=O)=O)cc1)C(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Reaction time: 1 h
Yield: 76.4 %

Procedure:
[Step 2] To a solution (25 ml) of 2-benzoyl-4-bromo-N-(2-hydroxyhexyl)-N-(4-methanesulfonylbenzyl)benzamide (2.3 g) in DMSO was added triethylamine (9 ml), and pyridine sulfur trioxide complex (5.2 g) was added at room temperature. The mixture was stirred for 1 hr. and added to water. 10% Hydrochloric acid was added to acidify the aqueous layer and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxohexyl)benzamide (1.75 g).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:20]([N:24]1[C:29](=[O:30])[C:28]([CH3:31])=[C:27](Cl)[CH:26]=[N:25]1)([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[C:20]([N:24]1[C:29](=[O:30])[C:28]([CH3:31])=[C:27]([O:15][CH2:14][C:11]2[CH:12]=[N:13][C:8]([O:7][CH2:6][C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[CH:26]=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Reactant: OCc1ccc(OCc2ccc(F)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(OCc3ccc(F)cc3)nc2)cnn(C(C)(C)C)c1=O
Temperature: 0 °C
Yield: 63.8 %

Procedure:
To a solution of 2.3 g of 6-(4-fluorobenzyloxy)-3-pyridine methanol in 20 ml of N,N-dimethylformamide was added under stirring at 0° C. 0.5 g of 55% sodium hydride (in mineral oil). After stirring for 30 minutes at room temperature, thereto was added dropwise a solution of 2.0 g of 2-t-butyl-5-chloro-4-methyl-3(2H)-pyridazinone in 5 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for additional 8 hours, poured into 50 ml of ice water and extracted twice with 50 ml of benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate and then freed of solvent by distillation under reduced pressure to give 3.8 g of a crude product. The crude product was separated and purified through thin layer chromatography (on silica gel; benzene) to obtain 2.5 g of 2-t-butyl-5-[{6-(4-fluorobenzyloxy)-3-pyridyl}-methyloxy]-4-methyl-3(2H)-pyridazinone as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[OH-].[Na+].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>CO>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2
Reactant: ClCC1CO1
Reactant: O=C1CCc2c(O)cccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2c(cccc2OCC2CO2)N1
Reaction time: 3 h

Procedure:
16.4 Grams of 5-hydroxy-3,4-dihydrocarbostyril and 3.7 g of sodium hydroxide were added into 100 ml of methanol and stirred at 40°-50° C. for 3 hours, then 150 ml of epichlorohydrin was added thereto and heated under refluxing condition for 5 hours. The reaction mixture was concentrated under a reduced pressure to dryness and the residue thus obtained was recrystallized from methanol-water (1:1) to obtain 18.5 g of 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril having the melting of 172°-173° C. as in the form of coloress amorphous crystals.
Reaction SMILES: [CH2:1]([O:7][C:8]([CH:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:9])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(CCCCCCI)OCc1ccccc1
Reactant: CCCCCCOC(=O)C1CCCN1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCOC(=O)C1CCCN1CCCCCCC(=O)OCc1ccccc1

Procedure:
A solution of 1.99 g. (0.01 mol.) of 2-[(hexyloxy)-carbonyl]pyrrolidine obtained in Example 1, 3.45 g. (0.01 mol.) of benzyl 7-iodoheptanoate and 1.21 g. (0.012 mol.) of triethylamine in 10 ml. of benzene is heated at 50° for 16 hours. The cooled reaction mixture is washed with 5% aqueous sodium bicarbonate, saturated aqueous chloride, dried, and concentrated in vacuo to give an oil, 2-[(hexyloxy)carbonyl]-1-pyrrolidineheptanoic acid benzyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]=[C:11]1[CH:21]=[O:22].FC(F)(F)S(O)(=O)=O>>[Br:1][C:2]1[C:3]2[CH2:8][CH2:9][N:10]3[C:11](=[N:12][C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:14]3)[CH:21]([OH:22])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nc(-c2ccccc2)cn1CCc1ccccc1Br
Agent: O=S(=O)(O)C(F)(F)F
Product: OC1c2cccc(Br)c2CCn2cc(-c3ccccc3)nc21

Procedure:
8-Bromo-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-4-ol is prepared from 1-[2-(2-bromophenyl)ethyl]-4-phenyl-imidazole-2-carbaldehyde (example 231C) analogously to general procedure 123B with trifluoromethanesulfonic acid instead of methanesulfonic acid.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[C:15]([CH2:27][C:28](OC)=[O:29])[N:14]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[BH4-].[Na+].O1CCCC1>O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[C:15]([CH2:27][CH2:28][OH:29])[N:14]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COC(=O)Cc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc(CCO)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 80.7 %

Procedure:
Methanol (15 ml) was added dropwise to a mixture of methyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline-2-acetate (4.0 g), sodium borohydride (1.9 g) and tetrahydrofuran (80 ml) under reflux. The mixture was stirred under reflux for 2 hours, and then poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)-6,7-dimethoxyquinazoline (3.0 g, 81%). This was recrystallized from ethyl acetate. Colorless needles, mp. 165°-166° C.
Reaction SMILES: FC1C=CC=CC=1CN1C=C(C2C3C(=NC=C(C4C=C(NS(C)(=O)=O)C=CC=4)C=3)NC=2)C=N1.I[C:35]1[C:43]2[C:38](=[N:39][CH:40]=[C:41]([C:44]3[CH:45]=[CH:46][C:47]([O:55][CH3:56])=[C:48]([S:50]([NH:53][CH3:54])(=[O:52])=[O:51])[CH:49]=3)[CH:42]=2)[N:37]([S:57]([C:60]2[CH:66]=[CH:65][C:63]([CH3:64])=[CH:62][CH:61]=2)(=[O:59])=[O:58])[CH:36]=1.[F:67][C:68]1[CH:69]=[C:70]([CH:88]=[C:89]([F:91])[CH:90]=1)[CH2:71][N:72]1[C:76]([CH3:77])=[C:75](B2OC(C)(C)C(C)(C)O2)[C:74]([CH3:87])=[N:73]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[F:67][C:68]1[CH:69]=[C:70]([CH:88]=[C:89]([F:91])[CH:90]=1)[CH2:71][N:72]1[C:76]([CH3:77])=[C:75]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41]([C:44]4[CH:45]=[CH:46][C:47]([O:55][CH3:56])=[C:48]([S:50]([NH:53][CH3:54])(=[O:52])=[O:51])[CH:49]=4)[CH:42]=3)[N:37]([S:57]([C:60]3[CH:66]=[CH:65][C:63]([CH3:64])=[CH:62][CH:61]=3)(=[O:59])=[O:58])[CH:36]=2)[C:74]([CH3:87])=[N:73]1
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Agent: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5ccccc5F)c4)c3c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)cc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Yield: 77.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example 1, 5-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (intermediate 22) (200 mg, 0.335 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (146 mg, 0.418 mmol) in sodium carbonate (100 mg, 1.0 mmol) Pd(PPh3)2Cl2 (11.7 mg, 0.011 mmol), Toluene/ethanol/water (20/10/2 ml) to afford 180 mg (77.9% yield) of the titled compound after purification by column (SiO2-eluted by 0.4 to 1.2% MeOH in CHCl3). MS: m/z=692.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[C:12]([CH2:13]Br)=[CH:11][CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:18][SH:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:22]([O:21][C:17](=[O:20])[CH2:18][S:19][CH2:13][C:12]1[C:6]2[C:5]3[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=3[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1)[CH3:23]
Reactant: CCOC(=O)CS
Reactant: Clc1ccc2c(c1)oc1cccc(CBr)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSCc1cccc2oc3cc(Cl)ccc3c12
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
To a solution of 7-chloro-1-bromomethyl-dibenzofuran (compound 1b; 7.63 g, 25.9 mmole) in 80 ml of DMF, were added ethyl thioglycolate (2.75 g, 25.94 mmole) and potassium carbonate (4 g, 29 mmole). The mixture was kept at 40-50° C. for 30 minutes. Water (500 mL) was added to give a suspension which was extracted by 2×100 mL dichloromethane, the extracts were washed by water, dried over sodium sulfate, evaporated to give 8.9 g of 2-(7-chlorodibenzofuran-1-ylmethylsulfanyl)acetic acid ethyl ester (compound Ia). This compound is pure enough for the next step without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:6]([CH3:18])[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16]C)[CH:11]=2)=[N:8][N:9]=1)(=[O:4])=[O:3].Br>C(O)(=O)C.C(O)C>[CH3:1][S:2]([C:5]1[N:6]([CH3:18])[C:7]([C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:8][N:9]=1)(=[O:4])=[O:3]
Reactant: COc1cc(-c2nnc(S(C)(=O)=O)n2C)ccn1
Agent: Br
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(-c2cc[nH]c(=O)c2)nnc1S(C)(=O)=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 111.4 %

Procedure:
The title compound of example 26.1 (6.4 g, 23.9 mmol) was dissolved in acetic acid (190 mL) and 20-30% hydrogen bromide in ethanol (190 mL) was added to the reaction. It was allowed to stir at 80° C. for 3.5 hours. The reaction was concentrated once, diluted with ethanol and concentrated again. Ethanol was added once more and the mixture was sonicated until a precipitate formed. The solid was filtered and dried under vacuum to afford the title compound (6.77 g, 85%) as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:15]O>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:15])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of quinoline-6-carboxylic acid (1.00 g, 5.77 mmol) in MeOH (10 mL) was added hydrogen chloride (2.00 mL, 8.00 mmol) (4.0M in 1,4-dioxane). The reaction was stirred 18 h at rt, LCMS shows <10% conversion. Additional hydrogen chloride (2.00 mL, 8.00 mmol) was added and the reaction heated to 50° C. in an oil bath 36 h. The reaction was cooled to rt and concentrated in vacuo. The solid was dissolved in DCM and extracted with sat. aqueous NaHCO3 (2×50 mL). The organic layer was dried (MgSO4), and concentrated to give the product which was used without further purification in the next step.