Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].O.[Br:4][C:5]1[C:6]([CH3:23])=[CH:7][C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:14]=1)[C:10]([O:12]C)=[O:11]>O1CCCC1>[Br:4][C:5]1[C:6]([CH3:23])=[CH:7][C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([CH:14]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc(Br)c(C)cc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)c(C(=O)O)cc1Br
Temperature: 40 °C

Procedure:
Lithium hydroxide (0.29 g, 12.08 mmol) and water (4 ml) were added to a solution of methyl 5-bromo-4-methyl-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 8; 1.35 g, 4.03 mmol) in tetrahydrofuran (20 ml). The reaction was heated at 40° C. for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water (20 ml) and ethyl acetate (30 ml). The aqueous layer was acidified to pH2 using 2N HCl. The organic layer was separated, dried (MgSO4) and the solvent removed in vacuo to yield the title compound as a white solid. 1.26 g.
Reaction SMILES: [C:1]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20]>C(O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([CH2:10][C:11](=[O:13])[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])[CH3:9])([CH3:5])([CH3:6])[CH3:7]
Reactant: NCCOCCO
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: CCO
Product: CN(CC(=O)NCCOCCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BOC-sarcosine (900 mg, 4.76 mmol) was dissolved in ethanol (10 ml). 2-(2-Aminoethoxy)ethanol (0.477 ml, 4.76 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) (1.79 g, 5.71 mmol) were added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane-methanol) to give {[2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-methyl}-methyl-carbamic acid tert-butyl ester. This was used in the next reaction without complete purification.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][O:51][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][OH:51])[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)CCO2)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of compound 47(827 mg, 0.87 mmol) in THF (4.0 mL) was added dropwise tetra-n-butylammonium fluoride (1.0 M in THF, 2.17 mL, 2.17 mmol) at 0° C. After being stirred for 2 hours at room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 48 (578 mg, 93%) as a white solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])(=O)=O)=CC=1.[CH2:28]1[O:38][C:37]2[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][C:30]=2[O:29]1>O1CCCC1>[CH2:28]1[O:38][C:37]2[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH2:12][NH:13][S:14]([C:17]3[C:18]4[CH:19]=[CH:20][N:21]=[CH:22][C:23]=4[CH:24]=[CH:25][CH:26]=3)(=[O:15])=[O:16])=[CH:31][C:30]=2[O:29]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)OCCNS(=O)(=O)c2cccc3cnccc23)cc1
Solvent: C1CCOC1
Product: O=S(=O)(NCCNCc1ccc2c(c1)OCO2)c1cccc2cnccc12
Yield: 48 %

Procedure:
To 4.06 g of the thus obtained N-(2-paratoluenesulfonyloxyethyl)-5-isoquinolinesulfonamide was added 40 ml of tetrahydrofuran containing 4.53 g of 3,4-methylenedioxybenzylamine. The resultant mixture was heated in a sealed vessel at 100° C. for 17 hours and then, the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a column for chromatography packed with 200 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using, as an eluent, a mixture of methanol and chloroform (0.5% methanol) to obtain 1.84 g of N-[2-(3,4-methylenedioxybenzylamino)ethyl]-5-isoquinolinesulfonamide (3) (yield: 48%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=O)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:13]([NH2:16])[CH2:14][CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:16][CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc2C1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNC1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7-bromo-3,4-dihydro-1H-naphthalen-2-one, prepared as described in J. Med. Chem, 1993, 36, 2279-2291, (5.2 g, 23 mmol) in 1,2 dichloroethane (30 mL), propyl amine (1.63 g, 28 mmol) was added, followed by addition of sodium triacetoxyborohydride (7.3 g, 34.5 mmol). The reaction was stirred at ambient temperature under nitrogen for 24 h, at which time it was concentrated in vacuo. The remaining solid was partitioned between 1 M sodium hydroxide and ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulfate, and filtered to yield (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (2.75 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].C([O-])([O-])=O.[Cs+].[Cs+].O>CC#N>[CH3:15][C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccccc1
Yield: 47.5 %

Procedure:
To a solution of phenol (2 g, 21.25 mmol) in CH3CN (50 mL) was added ethyl 2-bromo-2-methylpropanoate (5 g, 25.5 mmol) and Cs2CO3 (20 g, 63.75 mmol) at 25° C. The mixture was heated at reflux for 16 h then water (100 mL) added and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (2.1 g, 47.7%) as colorless oil which was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[Li+].[CH3:15][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:15])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1Cc2ccccc2C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)Cc2ccccc2C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
Indane-2-carboxylic acid methyl ester (550 mg, 3.125 mmol) was dissolved in THF (20 mL). At −78° C. LiHMDS (1M solution in THF, 3.75 mL) was added into the reaction mixture. The solution was stirred for 15 min at −78° C., warmed to 0° C. for 15 min and then −78° C. for an additional 15 min. Methyl iodide (250 μL, 4.01 mmol) was then added into the reaction mixture followed by stirring at −78° C. for 15 min, room temperature for 30 min and then quenched with saturated ammonium chloride. The solution was then diluted with diethyl ether and washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and concentrated. The crude mixture was then purified by silica gel flash column chromatography to afford 2-methyl-indan-2-carboxylic acid methyl ester (52 mg, 9%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.16 (m, 4H), 3.72 (t, 3H), 3.48 (d, 2H), 2.81 (d, 2H), 1.36 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH3:27][N:28]1[C:33]2[CH:34]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:36]=[CH:37][C:32]=2[O:31][CH2:30][C:29]1=[O:47]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[CH:37][C:32]5[O:31][CH2:30][C:29](=[O:47])[N:28]([CH3:27])[C:33]=5[CH:34]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CN1C(=O)COc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Product: CC1Cc2ccc(-c3ccc4c(c3)N(C)C(=O)CO4)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 129, Step 4 starting from 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one. LCMS (M+H)+: m/z=500.2.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH:19]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.[BH4-].[Na+]>CO>[CH:19]1([CH2:24][CH2:25][NH:26][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NCCC1CCCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCCC3)cc2)nc1
Reaction time: 18 h
Yield: 52.2 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (0.61 g, 2.54 mmol) with 2-Cyclopentyl-ethylamine (0.38 g, 3.3 mmol), 2 g of 3 Å molecular sieves, and 10 mL of methanol. Stir for 18 h under nitrogen. Add sodium borohydride (0.5 g, 13.2 mmol), and stir for 24 h. Filter through Celite, remove the solvent in vacuo. Partition the residue between water (50 mL) and ethyl acetate (100 mL). Dry the organic phase (sodium sulfate), filter, and concentrate in vacuo. Adsorb on silica, and purify on an ISCO® 100 g system (eluting with 95:5:0.5 to 90:10:1 chloroform/ethanol/ammonium hydroxide) to afford 0.45 g of product. HPLC retention time: 5.93 min (98.7% purity), ESMS (M+): 340.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH:13]1[C:23]2[C:24]3[C:16](=[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:18][C:19]=3[CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][CH:13]1[C:23]2[C:24]3[C:16](=[C:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:18][C:19]=3[CH:20]=[CH:21][CH:22]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
A portion (470 mg) of the crude compound obtained in Example 126 was suspended in methylene chloride (4 ml) and to the suspension was added trifluoroacetic acid (4 ml). The mixture was stirred for 1 hour at room temperature. The reaction mixture was made basic with saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate/methanol=9:1) to yield 100 mg (41%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:18](O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H+].[B-:27]([F:31])([F:30])([F:29])[F:28]>C(Cl)Cl>[F:28][B-:27]([F:31])([F:30])[F:29].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S+:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccc(CSCc2ccc(Cl)cc2)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: Clc1ccc(C[S+](Cc2ccccc2)Cc2ccc(Cl)cc2)cc1
Yield: 80 %

Procedure:
5.66 g (20 mmol) of di-(4-chlorobenzyl) sulfide are reacted with 2.6 g (24 mmol) of benzyl alcohol and 8.13 g (50 mmol) of 54% by weight HBF4 in 20 ml of methylene chloride as described in Example 3a). 7.44 g (80% of theory) of di-(4-chlorobenzyl)-benzylsulfonium tetrafluoroborate are obtained as white crystals of melting point 123°-125° C.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([CH3:19])[C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)\[C:4]([CH3:7])([CH3:6])[CH3:5].[H-].[Na+].[CH3:24]I>C1COCC1>[CH3:24][O:1]/[N:2]=[C:3](/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([CH3:19])[C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)\[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: Cn1c(C#N)ccc1-c1ccc(/C(=N/O)C(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO/N=C(/c1ccc(-c2ccc(C#N)n2C)cc1)C(C)(C)C
Reaction time: 0.17 h
Yield: 10.4 %

Procedure:
To a stirred solution of 5-{4-[(1E)-N-hydroxy-2,2-dimethylpropanimidoyl]-phenyl}-1-methyl-1H-pyrrole-2-carbonitrile (0.212 g, 0.75 mmol) in THF (7 mL) was added sodium hydride (0.03 g, 60% in mineral oil, 0.75 mmol) at 0° C. After the mixture was stirred for 10 minutes, methyl iodide (0.8 mL, 1.28 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then quenched with a saturated ammonium chloride solution (20 mL), and extracted several times with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified by a silica gel column (5% ethyl acetate in hexane) to afford 5-{4-[(1E)-N-methoxy-2,2-dimethylpropanimidoyl]phenyl}-1-methyl-1H-pyrrole-2-carbonitrile as a white solid (0.023 g, 10%). MS (ES) m/z 296.0; HRMS: calcd for C18H21N3O+H+, 296.17574; found (ESI, [M+H]+), 296.1753.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[C:6]([CH2:8][C:9](OCC)=[O:10])=O.[CH3:22][NH:23][NH2:24]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH:8]=[C:9]([OH:10])[N:23]([CH3:22])[N:24]=2)[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18]
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Solvent: CCO
Product: COc1cc(-c2cc(O)n(C)n2)cc([N+](=O)[O-])c1OC

Procedure:
10 g of ethyl (3,4-dimethoxy-5-nitrobenzoyl)acetate are suspended in 100 ml of ethanol, treated with 1.7 g of methylhydrazine and heated under reflux for 16 hours. After distillation of about 50 ml of ethanol, the mixture is cooled to 0° and the separated precipitate is filtered under suction. After recrystallization from ethanol there is obtained 3-(3,4-dimethoxy-5-nitrophenyl)-1-methylpyrazol-5-ol in the form of yellow crystals of m.p. 200°-202°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.Br[C:22]1[N:23]=[C:24]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[C:35]([O:42][CH3:43])[CH:34]=2)=[O:32])[N:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=12>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:43][O:42][C:35]1[CH:34]=[C:33]([C:31]([C:24]2[N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]3=[C:22]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:23]=2)=[O:32])[CH:38]=[CH:37][C:36]=1[N+:39]([O-:41])=[O:40]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1cc(C(=O)c2nc(Br)c3ccccn23)ccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)n3ccccc23)cc1

Procedure:
0.447 g (0.003 mol) of 4-methoxyphenylboronic acid, 2.24 g (0.009 mol) of K3PO4.H2O and then 0.131 g (0.011 mol) of tetrakis(triphenylphosphine)palladium(0) are added to 0.850 g (0.023 mol) of (1-bromoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone obtained in example 20 in 30 ml of dioxane under an argon atmosphere. The mixture is heated at reflux for 1 hour. The reaction medium is poured onto water and extracted with ethyl acetate. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by filtration through silica gel, elution being carried out with a dichloromethane/cyclohexane (2/1) mixture and then with dichloromethane. After evaporation, 0.850 g of an orange solid is collected. Melting point: 185° C.; 1H NMR (d6-DMSO): 3.85 (3H, s), 4.06 (3H, s), 7.12 (2H, d), 7.41-7.44 (1H, m), 7.54-7.58 (1H, m), 7.95 (2H, d), 8.08-8.10 (2H, m), 8.34 (1H, d), 8.36 (1H, s), 9.81 (1H, d)
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].F[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1.[OH:29][CH2:30][CH:31]([CH2:33][OH:34])[OH:32].[OH-].[K+].O>ClCCl>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[OH:32][CH:31]([CH2:33][OH:34])[CH2:30][O:29][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Reactant: OCC(O)CO
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCC(O)COc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Temperature: 120 °C
Yield: 0.3 %

Procedure:
To a 3 necked round bottom flask 0.2 g (438.6 mmol) of 9-(4-fluoro-phenyl)-thianthrenium hexafluorophosphate and 10 g of glycerol were added. The suspension was stirred at 120° C. until complete dissolution. Then 50 mg of potassium hydroxide were added and stirred for 10 minutes and the mixture was poured into water. Dichloromethane was added and the organic layer was washed and dried (Na2SO4). Removal of the solvent under vacuum gave a white solid (0.17 g, 73.4%).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[BH4-].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([OH:11])[CH2:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)CC(=O)c1ccccc1S2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2c(c1)CC(O)c1ccccc1S2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10 g of 10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-one are dissolved in 100 ml of dioxane and treated with 3.2 g of sodium borohydride in 5 ml of water. The mixture is subsequently stirred for 20 hours at room temperature. Then the mixture is concentrated under reduced pressure and the residue partitioned between ether and water. The ethereal solution is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. There is obtained 10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-ol as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)/[CH:6]=[C:7](\[CH2:11][CH3:12])/[C:8]([OH:10])=O.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:8](=[O:10])/[C:7](=[CH:6]/[C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([O:2][CH3:1])[CH:4]=2)/[CH2:11][CH3:12])=[CH:19][C:18]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CC/C(=C\c1cccc(OC)c1)C(=O)O
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC/C(=C\c1cccc(OC)c1)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
(2E)-2-(3-methoxybenzylidene)butanoic acid (190 mg, 0.92 mmol), 4-chloro-3-(trifluoromethyl)aniline (189 mg, 0.97 mmol) and DMAP (135 mg, 1.11 mmol) were mixed together and stirred in DCM (15 mL). The reaction mixture was cooled to 0° C. and EDCI (118 mg, 1.29 mmol) was added. The reaction was allowed to warm slowly to rt overnight. The mixture was diluted with DCM and washed with 1N HCl, sat. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, 0-15% EtOAc in hexanes) to give the title compound (216 mg). 1H NMR (400 MHz, d6-DMSO): δ 10.44 (s, 1H), 8.29 (d, 1H), 8.05-8.02 (dd, 1H), 7.68 (d, 1H), 7.39-7.35 (m, 1H), 7.22 (s, 1H), 6.99 (d, 1H), 6.95-6.93 (m, 2H), 3.77 (s, 3H), 2.54 (q, 2H), and 1.08 (t, 3H).
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)[CH2:2][CH3:3].[OH-].[Na+]>CO.O>[CH2:26]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]1[C:6]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:27][CH3:28]
Reactant: CCCN(CCC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CCC)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a solution of methyl 3-(dipropylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (50 mg, 0.13 mmol) in methanol (15 mL) was added a solution of sodium hydroxide (10 mg, 0.25 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was dissolved in water (20 mL) and adjusted to pH 5 with hydrochloric acid (3N). The resulting solution was extracted with dichloromethane (4×20 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 3-(dipropylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (22.4 mg, 46%).