Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2](=[O:1])[NH:3][CH:4]=2)=[O:8])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccc(=O)[nH]c2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a solution of 6-hydroxynicotinic acid (4.87 g, 35 mmol) in DMF (100 mL) at room temperature, was added potassium tert-butoxide (3.93 g, 35 mmol). The reaction mixture was stirred at 60° C. for 1 h. 4-Methoxybenzylchloride (8.30 g, 53 mmol) was added and the reaction mixture was stirred at 60° C. for 4 h. The DMF was evaporated under vacuum, the residue was dissolved in ether (200 mL) and washed with water (3×100 mL). The organic phase was dried with Na2SO4 and evaporated to give 4.41 g of 6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 4-methoxybenzyl ester.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC=C)(=O)C>C(OC(C)C)(C)C>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCC(O)CC1)c1ccccc1
Solvent: CC(C)OC(C)C
Solvent: C=COC(C)=O
Product: O=C(O[C@H]1CC[C@@H](O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxycyclohexyl benzoate (81.5 g) and Lipase QLG (40 g) in diisopropyl ether (800 mL) was added vinyl acetate (120 mL) at room temperature. After being stirred at room temperature for 2 hr, Lipase QLG was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (37.5 g, 46%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:24][CH2:25][CH3:26])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:6](=[O:8])[CH:7]=1.C([O-])(=O)C.[Na+].[Br:32]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:32][C:7]1[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:4]([CH2:24][CH2:25][CH3:26])=[N:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (8.44 g) and sodium acetate (2.22 g) in acetic acid (100 mL) was added bromine (1.39 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.68 g, 64%) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:28])/[C:5](=[N:25]/[O:26][CH3:27])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH3:27][O:26]/[N:25]=[C:5](\[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)/[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)/C(=N/OC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CO/N=C(/C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 50 °C
Yield: 84.4 %

Procedure:
(Z)-alpha-(methoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid ethyl ester (0.2 g) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 3N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 50° C. for 30 minutes. After the solvents were removed in vacuo, the concentrate was diluted with water (10 mL), acidified with 1N hydrochloric acid (3 mL) and extracted with dichloromethane (2×10 mL). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The resulting solid was crystallized from dichloromethane-hexane to provide 0.157 g of (Z)-alpha-(methoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid as its hernihydrate, mp 118°-120° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][CH2:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:12][CH:13]=2)[O:8]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:33]1COCC1>>[C:20]1([S:17]([C:11]2[CH:10]=[C:9]3[C:14]([CH2:15][CH2:16][C@H:7]([CH2:6][N:5]([CH3:33])[CH2:4][CH2:3][OH:2])[O:8]3)=[CH:13][CH:12]=2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1CCOC1
Reactant: COC(=O)CNC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(CCO)C[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Reaction time: 1 h

Procedure:
(R)-[(7-benzenesulfonyl-chroman-2-ylmethyl)-amino]-acetic acid methyl ester (40 mg, 1 mmol) was dissolved in 2 mL dry THF under Ar atmosphere. LAH (0.25 mL of 1M solution in THF) was added dropwise, and the reaction mixture was stirred for one hour. The reaction was quenched by addition of aqueous sodium sulfate solution. The mixture was extracted with methylene chloride and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. The residue was recrystallized from diethyl ether and 1 M HCl in EtOH to give 32.2 mg of (R)-2-[(7-Benzenesulfonyl-chroman-2-ylmethyl)-methyl-amino]-ethanol as a hydrochloride, MS (M+H)=362.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2nc(C3CCNCC3)oc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
560 mg tert-butyl 4-(4,5-diphenyloxazol-2-yl)-piperidine-1-carboxylate are placed in 2 ml dichloromethane, then 1.1 ml trifluoroacetic acid are added. The reaction mixture is stirred for 15 hours at ambient temperature, then evaporated to dryness. The residue is combined with toluene and evaporated to dryness again. The residue is mixed with diethyl ether and the precipitated solid is suction filtered and dried. 510 mg (V-10) are obtained. Analytical HPLC-MS (method B): RT=1.38 min.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:12]([C:14]([CH3:16])=[O:15])=[CH2:13]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH2:13][CH2:12][C:14](=[O:15])[CH3:16])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: C=CC(C)=O
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Product: CC(=O)CCOCc1ccc([N+](=O)[O-])cc1

Procedure:
Treat 4-nitrobenzyl alcohol with methyl vinyl ketone in a manner similar to Preparation 2 to obtain the title compound.
Reaction SMILES: [Cl-].[NH4+:2].CC1C=CC(S([O:13][C@@H:14]2[CH2:18]O[C@@H:16]3[C@@H:19](Br)[CH2:20][O:21][C@H:15]23)(=O)=O)=CC=1.N.CO>O.CC(O)C.[Zn]>[NH2:2][CH2:18][C@@H:14]([C@@H:15]1[CH:16]=[CH:19][CH2:20][O:21]1)[OH:13]
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Agent: N
Agent: [Cl-]
Agent: [Zn]
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: NC[C@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A solution of ammonium chloride (560 mg, 10.5 mmol) in water (7 mL) was added to a solution of bromotosylate (46) (2.86 g, 7.88 mmol) in propan-2-ol (14 mL) under argon. Zinc dust (560 mg, 8.67 mmol) was then added in portions over 4 minutes then the suspension stirred for 16 hours before filtering through celite in vacuo. The filter cake was washed with diethyl ether (60 mL). Hydrochloric acid (1M, 60 mL) was added to the filtrate then the organic phase separated. The aqueous layer was extracted with diethyl ether (60 mL) then the combined organic phase was washed with brine (60 mL), then dried (MgSO4), filtered and reduced in vacuo. The residue was dissolved in ammonium hydroxide (18 mL) and a solution of ammonia in propan-2-ol (12 mL, 2.0M, 24 mmol) then divided into three equal portions and heated in sealed tubes at 75° C. for 16 hours. The mixtures were combined using methanol then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (S)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO.O.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>[C:3]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
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: O
Solvent: Cc1ccccc1
Solvent: CO
Product: c1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
In 10 ml of toluene was added 600 mg (1.11 mmoles) of (4-bromophenyl)perfluorohexyl sulfone, and 20 mg (0.17 mmoles) of Pd(PPh3)4. To this clear colorless solution was added 170 mg (1.12 mmoles) of 4-methoxyphenylboronic acid in 2 ml of methanol, 240 mg (2.26 mmoles) of Na2CO3 in 1 ml of water. The mixture was stirred under nitrogen at 80° C. overnight. Isolation in accordance with the procedure of Example 9 gave after flash chromatography (silica gel, 50% CHCl3 /hexane) 343 mg of the biphenyl (0.60 mmoles, 54.6%). Elemental analyses: Found: C: 40.29; H: 2.03; calculated for C19H11F13O3S: C: 40.30; H: 1.96 Mp: 101.5°-103° C. SHG: not active. 1H nmr (CD2Cl2): 8.05 (d, J=8.6 Hz, 2H), 7.87 (d, J=8.6Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 3.87 (s 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15](OCC)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[OH:21].[BH4-].[Li+].O>C(OCC)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:21])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In diethyl ether (20 ml) was dissolved ethyl N-tert-butoxycarbonyl-4-piperidineacetate (1.18 g) followed by addition of methanol (0.19 ml). Then, lithium borohydride (123 mg) was added under ice-cooling. The mixture was stirred at room temperature for 15 hours, after which time water was added under ice-cooling. The mixture was diluted with ethyl acetate, washed with aqueous NaCl solution, dried over MgSO4, and concentrated to provide the title compound as colorless oil (0.96 g). 1H-NMR (CDCl3) δ: 1.0-1.4(4H,m), 1.45(9H,s), 1.5-1.8(4H,m), 2.69(2H,t,J=13.3Hz), 3.6-3.8(2H,brm), 4.0-4.2(2H,brm).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C(N(CC)CC)C.[Cl-].C([O:27][C:28](=O)[C:29](O)=[O:30])C>O1CCCC1>[N+:8]([C:6]1[CH:7]=[C:2]2[C:3](=[CH:4][CH:5]=1)[N:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[C:28](=[O:27])[C:29](=[O:30])[NH:1]2)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1NCCC(=O)O
Reactant: CCOC(=O)C(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
At a bath temperature of +4° C., under argon and with exclusion of moisture, 211 mg (0.9 mmol) of 3-(2-amino-4-nitrophenylamino)propionic acid is combined with 200 mg (2 mmol) of triethylamine in 20 ml of dry tetrahydrofuran. A solution of 270 mg (2 mmol) of oxalic acid ethyl ester chloride and 5 ml of dry tetrahydrofuran is added dropwise to the batch, and the latter is stirred for 2 hours at room temperature. Furthermore, 0.05 ml of triethylamine and 0.05 ml of oxalic acid ethyl ester chloride are added to the mixture and the latter stirred for one hour at room temperature. The batch is filtered and the filtrate concentrated and distributed in water and ethyl acetate. The organic phase is concentrated. The residue is taken up in 15 ml of ethanol and 15 ml of 1N hydrochloric acid and refluxed for 2 hours at a bath temperature of 110° C. The batch is concentrated, taken up in a small amount of water, and suctioned off, yielding 120 mg of 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)propionic acid, mp: 148-156° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:12][N:13]([CH2:18][C:19](O)=[O:20])[CH2:14][C:15](O)=[O:16].CS(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([B:9]2[O:11][C:19](=[O:20])[CH2:18][N:13]([CH3:12])[CH2:14][C:15](=[O:16])[O:10]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CN(CC(=O)O)CC(=O)O
Reactant: OB(O)c1cc(Br)cnc1F
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CN1CC(=O)OB(c2cc(Br)cnc2F)OC(=O)C1
Yield: 82 %

Procedure:
5-Bromo-2-fluoropyridin-3-ylboronic acid (14.87 g, 67.7 mmol) (Frontier Scientific) and 2,2′-(methylazanediyl)diacetic acid (10.95 g, 74.4 mmol) (Aldrich) were dissolved in toluene (242 mL) and DMSO (97 mL) and the resulting mixture was heated at reflux under a Dean Stark trap for 2 h. After water (>2.5 mL) was collected in the trap, the reaction mixture was concentrated in vacuo to remove toluene, and water was slowly added to the resulting solution until the desired product precipitated as a white solid. This solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven to give the title compound (82% yield) as a fluffy white solid. m/z (ESI, +ve ion) 330.8/332.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1OCCC.[Cl-].[Al+3].[Cl-].[Cl-].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:16]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCOc1ccccc1Br
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
69.7 g (324.2 mmol) of 1-bromo-2-propoxybenzene was added dropwise to a dichloromethane (350 ml) solution containing 51.8 g (388.6 mmol) of aluminum chloride and 45.6 g (324.3 mmol) of benzoyl chloride which was cooled to 0° C. After addition, the resulting solution was stirred for 2 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (40) as 67.3 g (210.7 mmol, yield of 65%) of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:3]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:4][C:5]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1NCc1ccc(O)cc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(-c2cccs2)nc1NCc1ccc(O)cc1

Procedure:
A mixture of 4-[(3-amino-6-bromo-pyrazin-2-ylamino)-methyl]-phenol (25 mg, 0.085 mmol), 2-thiopheneboronic acid (13 mg, 0.10 mmol), Pd(PPh3)2Cl2 (2 mg, 0.0028 mmol), and NaHCO3 (21 mg, 0.25 mmol) in DME (0.5 mL) and water (0.15 mL) was put in a microwave reaction tube and reacted in a microwave reactor at 110° C. for 7 minutes. The reaction mixture was partitioned in ethyl acetate and water, and the organic layer was evaporated. The residue was purified on a C-18 reversed phase preparative HPLC eluting with Methanol/Acetonitrile containing 0.1% trifluoroacetic acid to 4-[(3-amino-6-thiophen-2-yl-pyrazin-2-ylamino)-methyl]-phenol trifluoroacetic add salt as a white solid (12 mg).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[C:6]([O:21][CH:22]([CH3:24])[CH3:23])[CH:5]=1.CCO.O.[OH-].[Na+]>C1COCC1>[CH:22]([O:21][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=1)[C:3]([OH:25])=[O:2])([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(OC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a solution of 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid methyl ester (prepared as in Example 6 Step A) (6.50 g, 17.8 mmol) in THF (120 mL) was added EtOH (80 mL) and water (40 mL) at room temperature. Sodium hydroxide solution (1.0 M, 36.0 mL) was added slowly with some external cooling, if needed. The mixture was stirred at room temperature overnight. On the second day organic solvents were removed by evaporation. The residue was partitioned between ether and water. After the ether layer was discarded, the aqueous layer was acidified with HCl (6.0 M, ˜6.0 mL) to pH<2, and extracted with EtOAc three times. Combined EtOAc layers were washed with brine, dried with anhydrous MgSO4, filtered, and concentrated to give 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid (6.40 g, 100%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 9.91 (s, 1H), 7.93 (d, J=9 Hz, 2H), 7.23 (m, 1H), 7.14 (d, J=9 Hz, 2H), 7.10 (m, 1H), 6.85 (m, 1H), 4.57-4.65 (m, 1H), 3.01 (s, 3H), 1.37 (d, J=6 Hz, 6H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12]C=3NC=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O-])([O-])=O.[K+].[K+].CI.[CH3:26][N:27]([CH:29]=O)[CH3:28]>>[CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][C:28]=3[N:27]([CH3:26])[CH:29]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc2[nH]cc(C3CCCCC3)c2s1
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CI
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)cn2C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution (0.5 M) of 6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in DMF was treated with K2CO3 (2 eq.) and MeI (4 eq.). The reaction mixture was stirred at RT for 2 days. After dilution with AcOEt it was washed with water, brine and dried. Evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (1:4 AcOEt/petroleum ether) affording methyl 6-cyclohexyl-4-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate that was dissolved in DCE. POCl3 (1.4 eq.) was poured in a flask and cooled at 0° C. under nitrogen atmosphere. DMF (1.2 eq.) was added and the resulting oil was stirred at RT for 6 h, and then cooled again to 0° C. To this cool oil was added the previously prepared solution (0.02 M) in DCE. After stirring for 12 h, the reaction mixture was treated with aqueous Na2CO3 (30% solution) and extracted with AcOEt. The combined organic phase was washed with brine, dried. Evaporation of the solvent under reduced pressure gave a crude that was dissolved in dry MeOH. The resulting solution (0.1 M) was treated with K2CO3 (1 eq.) and TosMIC (1 eq.). The reaction mixture was heated to reflux for 12 h, then cooled and diluted with water. The aqueous phase was extracted with AcOEt. The combined organic phase was washed with water and brine and dried. After concentration under vacuum, the resulting crude was dissolved in MeOH. The resulting solution (0.1 M) was treated with aqueous NaOH (2 N solution, 4 eq.). The reaction mixture was heated to 80° C. for 1 h. After cooling down, the reaction was acidified at pH 2 with aqueous HCl (3 M) affording a precipitate that was filtered, dissolved in the minimum amount of DMSO and purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 5 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; linear from 95% A to 5% A in 10 min) to afford the title compound (3%) as a solid.
Reaction SMILES: ClC1C(Cl)=CC=CC=1C=O.Cl[C:12]1[N:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[Cl:25])=[CH:16][CH:17]=1.[C:26]([NH:29][NH2:30])(=O)[CH3:27]>C(O)CCC>[CH3:27][C:26]1[N:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[Cl:25])[CH:16]=[CH:17][C:12]2=[N:30][N:29]=1
Reactant: CC(=O)NN
Reactant: Clc1ccc(-c2cccc(Cl)c2Cl)nn1
Agent: O=Cc1cccc(Cl)c1Cl
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cccc(Cl)c3Cl)nn12

Procedure:
As described in Example 35, 2,3-dichlorobenzaldehyde is converted to 3-chloro-6-(2,3-dichlorophenyl)pyridazine. A mixture of this compound and acetic acid hydrazide in n-butanol is refluxed for 24 hours to give the product of the example.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:26]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C:25]=3[S:24][C:10]=2[N:11]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12](=[O:15])[CH2:13][N:14]=1.ClC1C=C(C=CC=1)C(OO)=[O:43].C(OC(C)C)(C)C.CCC(C)C>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:26]3[CH2:27][CH2:28][NH:29][CH2:30][C:25]=3[S:24][C:10]=2[N:11]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12](=[O:15])[CH:13]([OH:43])[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3c2C(c2ccccc2Cl)=NCC(=O)N3CCc2ccccc2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CCC(C)C
Product: O=C1C(O)N=C(c2ccccc2Cl)c2c(sc3c2CCNC3)N1CCc1ccccc1
Reaction time: 24 h

Procedure:
t-butyl 5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4′,3′:4.5]thieno[2,3-e]-1,4-diazepine-8-carboxylate (22 g, 41 mmol) is dissolved a 23° C. in 1,2-chloro ethane (320 ml). Meta-chloroperoxybenzoic acid at 85% (21.6 g, 0.1 mol) is added. Agitation is carried out for 24 hours at 23° C. then a solution of 5N sodium hydroxide (400 ml) is added. After decanting, the organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated with a rotary evaporator. After purification by chromatography on a silica column (eluent: ethyl acetate-heptane: 50-50 to 80-20), the fractions containing only the product ae evaporated. The solid obtained is agitated in a mixture of solvents: isopropyl ether-isopentane (20-80). After filtration on frit and washing with isopentane, the desired product is obtained in the form of a white powder (5.9 g, 26%).