Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:28])([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:35]=[CH:34][S:33][C:32]=1[C:36]1[O:41]C(C)(C)[O:39][C:38](=O)[CH:37]=1>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:28][C:38](=[O:39])[CH2:37][C:36]([C:32]1[S:33][CH:34]=[CH:35][C:31]=1[Cl:30])=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2sccc2Cl)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1NC(=O)CC(=O)c1sccc1Cl
Yield: 54.1 %

Procedure:
Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamic acid tert.-butyl ester (Example G30) (216 mg, 0.55 mmol) and 6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2) (142 mg, 0.58 mmol) according to the general procedure K. Obtained as a beige solid (172 mg).
Reaction SMILES: [CH3:1][N:2]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)(=[O:33])=[O:32])[C:3]1[CH:4]=[C:5]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)[CH2:15][N:16]=1)=[CH:8]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][N:2]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)(=[O:33])=[O:32])[C:3]1[CH:4]=[C:5]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)COc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1cc(OCC(=O)O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of ethyl ({7-[methyl(pyridin-2-ylsulfonyl)amino]-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-5-yl}oxy)acetate (275 mg) in tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (0.70 mL), and the mixture was stirred overnight at room temperature. The organic solvent was evaporated under reduced pressure, and the residue was neutralized with 1N hydrochloric acid. The mixture was extracted with a mixed solvent of tetrahydrofuran-ethyl acetate, and the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (137 mg, yield 53%) as colorless crystals. melting point 132-134° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)[C:5]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[N:9]=[C:8]([CH2:16][CH3:17])[C:6]=2[N:7]=1.[NH:26]1[CH2:34][CH2:33][CH:29]([C:30]([OH:32])=[O:31])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O.CS(C)=O>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:5]2[C:4]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=3)=[N:3][C:2]([N:26]3[CH2:34][CH2:33][CH:29]([C:30]([OH:32])=[O:31])[CH2:28][CH2:27]3)=[N:7][C:6]=2[C:8]([CH2:16][CH3:17])=[N:9]1)[CH3:15]
Reactant: CCOCCn1nc(CC)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Reactant: O=C(O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: CCOCCn1nc(CC)c2nc(N3CCC(C(=O)O)CC3)nc(Nc3cc(C)ccn3)c21
Temperature: 112.5 °C
Reaction time: 1 h

Procedure:
Alternatively, a mixture of N-[5-chloro-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-methylpyridin-2-ylamine from step 5 can be combined with isonipecotic acid (between 1 to 10 equivalents) and a base and heated between 100-125° C. in a solvent until the reaction is complete. Suitable bases include cesium carbonate, sodium carbonate and potassium carbonate. Suitable solvents include DMSO and N,N-dimethylformamide. Upon cooling, water can be added and the basic solution extracted (between 1 to 3 times) with an organic solvent such as ethyl acetate. The remaining basic layer is acidified to pH 5 with HCl. The mixture is stirred for approximately 1 hour. The solid is filtered off, washed with water, and dried in vaccuo to provide the title compound.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[OH:14].[I:15]Cl>O.Cl>[ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[C:6]([I:15])[C:5]=1[OH:14]
Reactant: ClI
Reactant: CC(C)(C)c1ccc(O)c(CN)c1
Agent: Cl
Solvent: O
Product: CC(C)(C)c1cc(I)c(O)c(CN)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 81.1 %

Procedure:
To a solution of 2-aminomethyl-4-(1,1-dimethylethyl)phenol hydrochloride (215 g., 1.0 mole) in water (1.6 l.) is added a solution of iodine monochloride (165 g., 1.0 mole) in 3N hydrochloric acid (800 ml.). The resulting reaction mixture is stirred at 20° C. for 3 hours and then cooled to -20° C. whereupon solid is deposited. The deposited solid is collected and crystallized from ethanol 12N-hydrochloric acid (1:1) to give the desired 2-aminomethyl-4-(1,1-dimethylethyl)-6-iodophenol hydrochloride (277 g.), m.p. 200°-201° C. (dec.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[CH3:22]/[C:23](/[CH:31]=[O:32])=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H][H]>C(O)(C)C>[CH3:22]/[C:23](/[CH2:31][OH:32])=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C/C(C=O)=C/c1ccccc1
Reactant: [H][H]
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Product: C/C(=C\c1ccccc1)CO
Yield: 84.9 %

Procedure:
Into a stainless steel autoclave equipped with a glass inner tube, Cu(NO3)(PPh3)2 (11.7 mg, 0.018 mmol) and triphenylphosphine (28.3 mg, 0.108 mmol) were introduced. The inside of the autoclave was then replaced with nitrogen. To the autoclave, an isopropyl alcohol solution of sodium hydroxide (0.03 M) (6.0 mL, 0.18 mmol), and α-methyl cinnamic aldehyde (0.50 mL, 3.6 mmol) were added, and stirring was performed at a hydrogen pressure of 5 MPa at 50° C. for 16 hours. The hydrogen was released with great care, and the conversion was analyzed by GC (>99%). The contents were concentrated, and then purified by silica gel chromatography. Thus, 453 mg of the α-methyl cinnamic alcohol was obtained (yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5]O.C1(C)C=CC=CC=1.N1C=CC=CC=1.P(Br)(Br)[Br:29]>CCOCC>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][Br:29]
Reactant: COc1ccc(CO)c(OC)c1OC
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1ccc(CBr)c(OC)c1OC
Temperature: 4 °C
Reaction time: 0.75 h

Procedure:
2.04 g (10 mmol) of 2,3,4-trimethoxybenzyl alcohol in 30 ml of abs. toluene are treated with 0.258 ml (0.32 equivalents) of pyridine, and the solution is cooled down to approximately 4° C. using ice-water. 0.951 ml of phosphorus tribromide in 5 ml of abs. toluene is added dropwise, at this temperature and over the period of 30 min, to this solution, which is left to stir at this temperature for a further 45 min. The reaction mixture is diluted with ether and the whole is poured onto ice-water, with this mixture then being stirred for 5 min. After the phases have been separated, the organic phase is washed, in succession, with water, saline, sat. sodium bicarbonate solution and once again with saline (all being cold). After the organic phase has been dried over sodium sulfate, it is concentrated, and residual solvents are removed from the residue under high vacuum for 1 h. The resulting title compound is subjected, without purification, to further processing. 1H-NMR (200 MHz; CDCl3)=7.05/d (1H); 6.65/d (1H); 4.55/s (2H); 4.07, 3.88 and 3.85/each s (each 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:32]([O:34]C)=O)=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:36].CO>C1COCC1>[C:32]([C:16]1[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[N:17]=1)(=[O:34])[NH2:36]
Reactant: COC(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)nc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (1015 mg, 2.0 mmol) in THF (15 mL) at room temperature under argon was added 7M ammonia in methanol (4.3 mL, 30 mmol). The reaction mixture was stirred at room temperature overnight. The solvents were removed in vacuo. The crude product 1.0 g (100%) was used directly to next step. MS (ESI) 437 (M+H-tBu).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13].CCN(C(C)C)C(C)C.[O:23](S(C(F)(F)F)(=O)=O)[S:24]([C:27]([F:30])([F:29])[F:28])(=O)=[O:25]>ClCCl>[F:28][C:27]([F:30])([F:29])[S:24]([O:13][C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:25])=[O:23]
Reactant: COc1cccc2c(O)cccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c(OS(=O)(=O)C(F)(F)F)cccc12
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
To a solution of 5-methoxynaphthalen-1-ol (above Step-1 intermediate) (19 g, 0.11 mol) in anhydrous dichloromethane (250 mL) at 0° C. was added, DIPEA (23 mL, 0.16 mol) and the mixture was stirred for 15 min. To this, Tf2O (21.7 mL, 0.13 mol) was added slowly at 0° C. and the reaction mixture was stirred for 1.5 h and then quenched slowly with water (100 mL). The aqueous layer was extracted with CH2Cl2 (4×100 mL) and the combined organic layer was washed with water (100 mL), brine (100 mL), dried and filtered. The solvent was then evaporated and the crude product was purified by column chromatography (5% EtOAc:Hexanes) to furnish the desired compound (28.5 g, 85%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1Cl

Procedure:
A solution of 2,3-dichloro-4,5-difluorobenzoic acid (9.3 g) and dimethylformamide (0.013 ml) in thionyl chloride (40 ml) was refluxed for 2.5 hours, and then concentrated. The resulting residue was purified by distillation in nitrogen atmosphere to give the title compound (8.7 g) as pale yellow oil, bp 123°-126° C./40 mmHg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=3)[NH:11][C:10]2=[O:29])[CH:2]=1.S(=O)(=O)(O)O>[C].[Pd].[I-].[K+].CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][N:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:19]([F:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:21])([F:23])[F:22])[CH:16]=3)[NH:11][C:10]2=[O:29])[CH:2]=1
Reactant: O=C1Nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2CN1N=Cc1cccnc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2CN1NCc1cccnc1
Temperature: 45 °C
Yield: 95 %

Procedure:
In a 200-ml autoclave were placed 8.40 g (20 mmol) of 3,4-dihydro-3-(3-pyridylmethylideneamino)-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone, 0.21 g (0.05 mmol) of 5% palladium-carbon (containing 50% water), 1.68 mg (0.01 mmol) of potassium iodide, 0.4 g (98%, 4 mmol) of concentrated sulfuric acid and 50 ml of dimethylformamide. They were heated to 45° C. with stirring and the reaction was carried out at a hydrogen pressure of 2 kg/cm2 until the hydrogen absorption rate decreased. After the reaction mixture was cooled to room temperature, the catalyst was removed by filtration. The filtrate was poured into 100 ml of water and the crystals precipitated were collected by filtration. The crystals were recrystallized from toluene to obtain 8.02 g of the desired compound.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:18])=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:21]([C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][NH:29][CH2:30]2)=[CH:25][CH:24]=1)#[N:22].CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>C(Cl)Cl>[ClH:18].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][C:23]([C:21]#[N:22])=[CH:24][CH:25]=4)[CH2:30]3)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)CNCC2
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CN(C(=O)c1ccc(OCCCN3CCCCC3)cc1)CC2
Reaction time: 16 h
Yield: 15.5 %

Procedure:
A solution of 4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3) (0.14 g) in DCM (10 ml) was added to 7-cyano-1,2,3,4-tetrahydroisoquinoline (WO98/50364) (0.08 g) and diethylaminomethyl polystyrene (0.6 g, 3.2 mmol/g). The mixture was stirred for 16 h then loaded directly onto a silica column and eluted with 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM. The isolated free base was dissolved in DCM (5 ml) and treated with 4N HCl/dioxane solution (1 ml) with stirring for 10 min. The mixture was concentrated and the residue co-evaporated with toluene (3×10 ml) then crystallised from ethanol/diethyl ether, and dried at 80° C. under high vacuum for 16 h to yield the title compound (E18) as a beige solid (0.03 g). MS electrospray (+ion) 404 (MH+). 1H NMR δ (DMSO-d6): 9.91 (1H, s), 7.85 (1H, m), 7.65 (1H, d, J=7.9 Hz), 7.42 (3H, m), 7.02 (2H, d, J=8.6), 4.73 (2H, s), 4.11 (2H, t, J=5.9 Hz), 3.68 (2H, m), 3.44 (2H, m), 3.17 (2H, m), 2.93 (4H, m), 2.20 (2H, m), 1.91-1.41 (6H, m).
Reaction SMILES: [Li][CH2:2]CCC.[OH:6][C:7]1[CH:8]=[C:9]([CH:27]=O)[C:10]2[CH2:11][CH:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:13]3[CH2:19][CH2:18][CH2:17][CH:14]3[C:15]=2[CH:16]=1.C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([CH:12]2[CH2:11][C:10]3[C:15](=[CH:16][C:7]([OH:6])=[CH:8][C:9]=3[CH:27]=[CH2:2])[CH:14]3[CH2:17][CH2:18][CH2:19][CH:13]23)=[CH:21][CH:22]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21

Procedure:
Combine BuLi (0.1 ml, 1.6M, 0.16 mmol), methyltriphenylphosphonium bromide (0.063 g, 0.175 mmol) and tetrahydrofuran (1.0 ml) and stir 15 minutes. Add 8-Hydroxy-4-(4-hydroxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-6-carbaldehyde (0.012 g, 0.04 mmol) in tetrahydrofuran (1.0 ml) and stir 30 minutes. Take into ethyl acetate and wash with ammonium chloride solution solution, then brine. Dry over anhydrous sodium sulfate and concentrate to a residue which yields after separation on silica gel with 33% EtOAC/hexanes, the titled compound (0.006 g, 50%). 1H NMR (CD3OD) 7.15 (d, J=8.4, Hz, 2H), 7.04 (dd, J=11 and 6 Hz, 1H), 6.75 (m, 3H), 3.4 (m, 1H), 3.0 (m, 1H), 2.85 (m, 2H), 2.55(m, 1H) 2.2 (m, 1H), 1.6-1.2. MS m/z 305 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=2)(O)[CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[CH:4][C:3]=1[CH3:25].S([O-])(O)(=O)=O.[K+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=2)=[CH:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(O)(Cc2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=Cc2nnnn2C)c2ccc(F)c(C)c2)ccc1F
Temperature: 195 °C
Yield: 95 %

Procedure:
A mixture of 1,1-bis(4-fluoro-3-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (3.58 g, 10.9 mmoles) and potassium hydrogen sulfate (530 mg) was heated at 195° C. for 1.5 hours. The mixture was cooled to 70° C. and chloroform (50 ml) was added. The insoluble material was removed by filtration and the filtrate evaporated. The residue was crystallized from EtOAc-Hexane to afford 3.38 g (100%) of the title compound; m.p.=138°-139° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[N:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27]>COCCOC.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:24]([C:20]1[CH:19]=[C:18]([C:9]2[N:10]=[C:11]([C:13]([OH:15])=[O:14])[S:12][C:8]=2[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=2)[CH:23]=[CH:22][CH:21]=1)#[N:25]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1nc(-c2cccc(C#N)c2)c(Br)s1
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: N#Cc1cccc(-c2nc(C(=O)O)sc2-c2cccc(C#N)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At room temperature, 3.0 ml of an aqueous 2M sodium carbonate solution and 41.1 mg (0.036 mmol) of tetrakis(triphenylphosphine)palladium are added to 400 mg (1.19 mmol) of the compound from Example 35A and 261 mg (1.78 mmol) of (3-cyanophenyl)boronic acid in 15 ml of DME, and the mixture is subsequently stirred at 80° C. overnight. The crude product is filtered through a short kieselguhr column and the filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography (mobile phase: dichloromethane). 104 mg (26% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:23]([O:25]C)=[O:24])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:23]([OH:25])=[O:24])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCNCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCNCC3)nc2c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
Solutions of methyl 2-phenyl-3-(piperazin-1-yl)quinoxaline-6-carboxylate (160 mg, 0.42 mmol, 1.00 equiv.) in THF/MeOH (1:1) (20 mL) and sodium hydroxide (91.9 mg, 2.30 mmol, 5.00 equiv) in water (1.5 mL) were placed in a 50-mL round bottom flask, stirred for 3 hrs at 30° C. in an oil bath, and then concentrated under vacuum. The residue was dissolved in 4 mL of DMSO and purified via silica gel column (DCM/MeOH (5:1)) yielding 42 mg (29%) of 2-phenyl-3-(piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:10]1[O:11][C:12]([CH3:17])=[C:13]([OH:16])[C:14]=1[OH:15])(OCC)=O>CN(C)C=O.C1(C)C=CC=CC=1>[OH:15][C:14]1[C:13](=[O:16])[CH:12]([CH3:17])[O:11][C:10]=1[CH3:5]
Reactant: CCOC(=O)c1oc(C)c(O)c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC1=C(O)C(=O)C(C)O1
Reaction time: 20 h
Yield: 64.8 %

Procedure:
In a 1 L three-necked flask fitted with a mechanical stirrer and a gas inlet tube is placed a suspension of 34 g of sodium ethoxide in a mixture of 100 ml of dimethylformamide and 300 ml of toluene. To the stirred suspension is added at room temperature, under nitrogen, 93 g of 2-carbethoxy-5-methyl-3,4-dihydroxy-furan. Gaseous methyl bromide is bubbled through the stirred reaction mixture at 30°-40° C. till the pH of the reaction mixture reaches 6.5-7.0. The solvents are removed under vacuum and the residue is dissolved in a solution of 80 g of sodium hydroxide in 350 ml of water. The reaction mixture is kept at room temperature under nitrogen for 20 hours, acidified with hydrochloric acid and continuously extracted with ether. The ether extract is dried and the solvent removed under vacuum, the residue is recrystallized from ether, yielding 41.5 g (65%) of 4-hydroxy-2,5-dimethyl-3-oxo-2H-furan, m.p. 81.5°-83.1° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].[C:16]1([C:22]2[N:23]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=3)[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH-].[Na+]>C(OCC)(=O)C.O1CCCC1.CO.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:38][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][N:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:30]=[C:22]3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:37][CH:36]=2)[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: OCc1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)CCc1ccc(OCc2ccc(Cn3c(-c4ccccc4)cc4ccccc43)cc2)cc1F
Temperature: 0 °C
Yield: 78.6 %

Procedure:
To a mixture of ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate (0.29 g, 1.34 mmol), {4-[(2-phenyl-1H-indol-1-yl)methyl]phenyl}methanol (0.38 g, 1.22 mmol), tributylphosphine (0.46 mL, 1.83 mmol) and tetrahydrofuran (7.6 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.46 g, 1.83 mmol) with stirring at 0° C., and the mixture was stirred at room temperature for 18 hr. Diethyl ether was added to the reaction mixture. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give a colorless oil. Then, a mixture of the obtained oil, 1 N aqueous sodium hydroxide solution (2.5 mL), methanol (5.0 mL) and tetrahydrofuran (10.0 mL) was stirred at room temperature for 14 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 1 N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) to give the title compound (0.46 g, yield 79%) as colorless crystals. MS (APCI−): 478 (M−H), 1H NMR (CDCl3) δ: 2.64 (2H, t, J=7.8 Hz), 2.91 (2H, t, J=7.8 Hz), 4.96 (2H, s), 5.38 (2H, s), 6.61-6.70 (3H, m), 7.01-7.20 (6H, m), 7.32 (2H, d, J=8.1 Hz), 7.34-7.47 (5H, m), 7.67 (1H, m).