Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O1CCCC1.C(NC(C)C)(C)C>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]([C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7])#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Brc1ccsc1Br
Reactant: C#CCCCCC
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCC#Cc1sccc1Br
Temperature: 70 °C
Yield: 99.4 %

Procedure:
2 ml (18.0 mmol) of 2,3-dibromothiophene, commercially available from Aldrich under the Product No. D4,390-5, and 3.5 ml (27.0 mmol) of 1-heptyne, commercially available from Aldrich under the Product No. 24,4414, were mixed with a solvent of tetrahydrofuran/diisopropylamine (1:1), and 0.23 g (0.36 mmol) of palladium dichlorodiphosphine, 70 mg (0.36 mmol) of copper iodide and 0.1 g (0.36 mmol) of triphenylphosphine were sequentially added thereto. The reaction solution was heated at 70° C. for 8 hours, and washed with an aqueous solution of ammonium chloride. The resulting organic layer was dried over magnesium sulfate, dried under reduced pressure, and purified using silica gel column chromatography, thus obtaining 4.6 g of 2-heptynyl 3-bromothiophene. The compound thus obtained was added with 3.3 ml (23.2 mmol) of trimethylsilylacetylene, commercially available from Aldrich under the Product No. 21,817-0, and then subjected to the above synthesis process, to prepare 2.7 g (9.84 mmol) of 2-heptynyl-3-trimethylsilylethynylthiophene, which was then mixed with 12.8 ml (12.8 mmol) of lithium diisopropylamide (1 M) at about −78° C. The reaction mixture was stirred at the same temperature for 30 minutes, then combined with 2.4 ml (11.8 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-oxaborolane, commercially available from Aldrich under the Product No. 41,714-9, and allowed to react in a bath while the temperature was increased to room temperature. The resultant reaction solution was poured into an aqueous solution of 1 N HCl, treated with chloroform to obtain an organic layer, which was then dried over magnesium sulfate 1 N HCl, treated with chloroform to obtain an organic layer, which was then dried over magnesium sulfate and distilled under reduced pressure, thus obtaining 4.1 g of a compound a in an oil phase. Analysis of the compound 1a produced the following NMR data: 1H NMR (300 MHz, CDCl3), δ(ppm) 0.24 (s, 9), 0.92 (t, 3H, J=7.2 Hz), 1.24-1.64 (m, 18), 2.49 (t, 2H, J=7.0 Hz), 7.47 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: N
Product: CC(C)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 375) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.051 g, 18%). Yellow oil. 1H NMR (300 MHz, DMSO d6) δ 0.80 (d, J=5 Hz, 6H), 1.47 (m, 3H), 4.42 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.50 (m, 1H), 7.65 (m, 2H), 7.83 (m, 2H), 7.93 (m, 2H), 8.18 (s, 1H), 8.60 (bs, 1H). MS (DCI/NH3) m/z 432 (M+H)+, 449 (M+NH4)+. Anal. calc. for C21H22FN3O4S: C, 58.46; H, 5.14; N, 9.74. Found: C, 58.16; H, 5.21; N, 9.57.
Reaction SMILES: OCC1C(O)C(O)C(O)[CH:5]([O:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[CH:18]=CC2C=CC(OC)=CC=2)O1.C[OH:29]>[Pd]>[CH3:5][O:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH:18]=[O:29]
Reactant: CO
Reactant: COc1ccc(C=Cc2sccc2OC2OC(CO)C(O)C(O)C2O)cc1
Agent: [Pd]
Product: COc1ccsc1C=O
Reaction time: 18 h

Procedure:
50 mg of 2-hydroxymethyl-6-{2-[2-(4-methoxy-phenyl)-vinyl]-thiophen-3-yloxy}-tetrahydro-pyran-3,4,5-triol were dissolved in 10 ml of methanol. 20 mg of palladium on activated carbon were added and the solution was stirred under a hydrogen atmosphere for 18 h. The catalyst was filtered off and washed with 60 ml of methanol, and the organic phase was concentrated. The residue was chromatographed on silica gel (ethyl acetate). 18 mg of the product with the molecular weight of 396.46 (C19H24O7S); MS (ESI): 419.05 (M+Na+), 414.10 (M+NH4+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:27]([OH:29])=O)[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:26])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:65]1[CH2:70][CH2:69][CH:68]([N:71]2[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C@H:16]([CH2:17][C:18]3[CH:19]=[C:20]([CH3:26])[C:21]([OH:25])=[C:22]([CH3:24])[CH:23]=3)[C:27](=[O:29])[N:74]3[CH2:73][CH2:72][N:71]([CH:68]4[CH2:69][CH2:70][O:65][CH2:66][CH2:67]4)[CH2:76][CH2:75]3)=[O:14])[CH2:11][CH2:12]2)[N:5]=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:3]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 100 mg (0.21 mmol) (R)-1-carboxy-2-(4-hydroxy-3,5-dimethyl-phenyl)-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate, 74 mg (0.23 mmol) TBTU and 35 μL (0.26 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 35 mg (0.21 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added and the reaction mixture was stirred for a further 5 h at RT. The reaction solution was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](#[N:13])[CH:11]=[CH2:12].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:12][CH2:11][C:10]#[N:13])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(C)c1O
Reactant: C=CC#N
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(CCC#N)cc(C)c1O

Procedure:
In a modification of this Friedel-Crafts reaction, 2,6-di-methylphenol is treated with acrylonitrile in the presence of aluminum chloride to yield 3-(3,5-dimethyl-4-hydroxyphenyl)propionitrile. Upon hydrolysis of this and esterification of the resulting free acid with methanol and p-toluenesulfonic acid, there is obtained methyl 3-(3,5-dimethyl-4-hydroxyphenyl)propionate, M.P. 70°-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[C:10]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:24].[CH3:25][NH:26][OH:27].Cl.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:26]([CH3:25])[O:27][C:10]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)([C:11]([F:14])([F:13])[F:12])[CH:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: CNO
Reactant: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1Br

Procedure:
300 mg 1-(4-Bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (IVa), 80 mg MeNHOH.HCl and 100 mg triethylamine were refluxed in 2 ml of ethanol for 18 hours. After evaporation of the solvent the residue was purified on silica gel giving 210 mg (65%) of 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole (IIIa) as a colorless resin.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:13](F)=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]([S:15]CCC(OCC)=O)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]3[C:13]([S:15][C:5]2=[CH:4][CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: CCOC(=O)CCSc1ccc(Cl)nc1-c1ncccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2sc3cccnc3c2n1
Temperature: 75 °C
Yield: 65.3 %

Procedure:
A 500 mL RBF was charged with ethyl 3-((6-chloro-3′-fluoro-[2,2′-bipyridin]-3-yl)thio)propanoate (16.55 g, 48.6 mmol), THF (Volume: 194 mL) and degassed with nitrogen for 10 minutes, then treated with potassium 2-methylpropan-2-olate (8.17 g, 72.8 mmol) and heated to reflux at 75° C. for 24 hours. The reaction was quenched with aqueous ammonium chloride, extracted 2× with EtOAc. The crude product was purified by column chromatography to give 2-chlorothieno[3,2-b:4,5-b′]dipyridine (7 g, 68% yield).
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:16]=[C:17]([CH:21](Cl)[CH3:22])[CH:18]=[CH:19][CH:20]=1)=[O:14]>O>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]([C:15]1[CH:16]=[C:17]([CH:21]([C:1]#[N:2])[CH3:22])[CH:18]=[CH:19][CH:20]=1)=[O:14]
Reactant: CC(Cl)c1cccc(C(=O)c2cccs2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C#N)c1cccc(C(=O)c2cccs2)c1

Procedure:
To a stirred and hot mixture of 2.7 parts of sodium cyanide in 20 parts of dimethylsulfoxide is added dropwise a solution of 5.8 parts of α-chloro-α-methyl-m-tolyl 2-thienyl ketone in 10 parts of dimethylsulfoxide at 60° C. Another 5 parts of dimethylsulfoxide is added and the whole is stirred for 2.5 hours at 50°-55° C. The reaction mixture is poured onto 35 parts of water and the product is extracted with ether and ethyl acetate. The combined organic layers are washed with water, dried, filtered and evaporated in vacuo. The residue is dissolved in benzene. This solution is washed with water, dried and evaporated in vacuo, yielding m-(2-thenoyl)hydratroponitrile, also named α-cyano-α-methyl-m-tolyl 2-thienyl ketone, as a residue.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][SiH:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])([CH3:4])[CH3:3].[Br-:14]>Cl[Pd]Cl.C(Br)C=C>[CH3:4][Si:2]([C:5]#[C:6][Si:7]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:9])[CH3:10])[Br:14])([CH3:1])[CH3:3]
Reactant: CC(C)[SiH](C#C[Si](C)(C)C)C(C)C
Reactant: [Br-]
Agent: Cl[Pd]Cl
Solvent: C=CCBr
Product: CC(C)[Si](Br)(C#C[Si](C)(C)C)C(C)C
Temperature: 60 °C

Procedure:
(Trimethylsilylethynyl)diisopropylsilane (14 g, 66 mmol) and allyl bromide (˜40 mL) were added to a round-bottom flask equipped with a stir-bar. A septum and bubbler were attached and the solution was purged with N2 for 15 min. PdCl2 (0.06 g, 0.3 mmol, 0.5 mol %) was added and the reaction was heated at 60° C. for 3 hours, or until analysis by GC-MS showed complete conversion to the bromide. After removing the reaction from the heat, pentane (50 mL) was added and the solution was chilled for 20 min. The PdCl2 was removed by filtration through a fine fitted funnel, then solvent was removed using a rotary evaporator, yielding 18.8 g of (trimethylsilylethynyl)diisopropylbromosilane as a light brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(N2CCN(C)CC2)cc1

Procedure:
4-Fluorobenzoic acid methyl ester (34 mmol), 1-methyl-piperazine (75 mmol) and potassium carbonate (34 mmol) are suspended in acetonitrile (30 ml) and stirred under reflux for three days. After evaporation of the solvent, the residue is dissolved in water and extracted three times with ethyl acetate. The extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with (CH2Cl2/MeOH=95:5) as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A pale yellow powder with mp. 117-119° C., Rf=0.20 (CH2Cl2/MeOH=95:5) is obtained.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:15][N:16]2COCC[Si](C)(C)C)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(N)CN>>[CH3:1][N:2]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:27]=[CH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:15][NH:16]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1
Reactant: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: CN(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
To N-methyl-N-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-benzene-1,3-diamine (237 mg, 0.5 mmol) was added 1M TBAF in THF (10.1 mL, 10.1 mmol), followed by ethylenediamine (0.34 mL, 5.04 mmol, 10 equiv). The resulting mixture was heated to 70° C. for 5 h. The reaction was then quenched with saturated NaHCO3 (10 mL) and extracted 3×35 mL EtOAc. The pooled EtOAc phase was washed 5×20 mL H2O, then brine (20 mL), dried with Na2SO4, decanted and concentrated under reduced pressure to a foam. The crude material was purified by silica gel chromatography (9:1 dichloromethane/ethyl acetate) to give N-methyl-N-(3-styryl-1H-indazol-6-yl)-benzene-1,3-diamine as a foam (120 mg, 70% yield). Rf sm 0.73, Rf p 0.27 (dichloromethane:ethylacetate 7:3); 13C NMR (75 MHz, CDCl3) δ 150.3, 148.8, 147.5, 147.5, 143.9, 143.4, 137.5, 131.1, 130.3, 129.3, 128.9, 128.2, 127.9, 126.7, 121.0, 120.5, 117.0, 116.0, 112.6, 109.8, 109.0, 98.3, 40.7; LCMS (ESI) [M+H]/z Calc'd 341. Found 341. Anal. Calc'd: C, 77.62; H, 5.92; N, 16.46. Found: C, 76.16; H, 5.88; N, 15.95.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]2[N:28]([CH2:34][CH3:35])[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]=2[C:25]=1[O:38][CH3:39]>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[N:7][C:2]([NH:23][C:24]2[CH:37]=[CH:36][C:27]3[N:28]([CH2:34][CH3:35])[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]=3[C:25]=2[O:38][CH3:39])=[N:3][CH:4]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccc(OC)cc3-n3cccn3)n1)c2OC

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine, of Example 611c, was reacted with 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-methoxy-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (22%); 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.61 (bs, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 7.96 (d, J=9.06 Hz, 1H), 7.83 (s, 1H), 7.64 (d, J=8.83 Hz, 1H), 7.22 (s, 1H), 7.00 (d, J=8.98 Hz, 1H), 6.95 (d, J=9.09 Hz, 1H), 6.55 (s, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 2.1-1.9 (m, 6H), 1.03 (m, 3H); MS (m/e) 534.47 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][NH2:13].[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24](OCC)=[O:25])[N:23]=2)[CH:20]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24]([NH:13][CH2:12][C:3]3[C:4]([C:8]([F:10])([F:11])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:25])[N:23]=2)[CH:20]=1
Reactant: NCc1c(Cl)cccc1C(F)(F)F
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1c(Cl)cccc1C(F)(F)F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2-chloro-6-(trifluoromethyl)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:11])=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[S:33](Cl)(=[O:35])=[O:34]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[S:33]([O:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([NH:9][C:10](=[O:11])[NH:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:8][C:4]=2[CH:3]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: O=C(NCCN1CCOCC1)Nc1nc2cc(O)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCN1CCOCC1)Nc1nc2cc(OS(=O)(=O)c3c(F)cccc3F)ccc2[nH]1
Temperature: 20 °C
Reaction time: 24 h
Yield: 42.4 %

Procedure:
To a solution of 250 mg of 1-(5-hydroxy-1H-benzimidazol-2-yl)-3-(2-morpholin-4-ylethyl)urea in 16.4 cm3 of aqueous 0.1N sodium hydroxide solution are added 191 mg of 2,6-difluorobenzenesulfonyl chloride. The solution is stirred for 24 hours at a temperature in the region of 20° C. After addition of 40 mg of 2,6-difluorobenzenesulfonyl chloride, the mixture is stirred for 5 hours at a temperature in the region of 20° C. The reaction medium is placed in an ice bath and the precipitate is then filtered off by suction, washed with three times 5 cm3 of ice-cold water and dried under reduced pressure over phosphorus pentoxide. After flash chromatography on a column of silica [eluent: dichloromethane/methanol (93/7 by volume)], 167 mg of 2-{[(2-morpholin-4-ylethyl)carbamoyl]amino}-1H-benzimidazol-5-yl 2,6-difluorobenzenesulfonate are obtained in the form of a pale yellow powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 20.7 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and isopropylamine (44 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (46 mg, 0.12 mmol, yield 21%).
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH:9]([CH3:12])[CH2:10][CH3:11])=[N:7][C:6]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:5][N:4]=1)[NH2:2].[CH3:19][CH:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:19][CH:20]([C:26]1[N:4]2[CH:5]=[C:6]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[N:7]=[C:8]([CH:9]([CH3:12])[CH2:10][CH3:11])[C:3]2=[N:1][N:2]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CCC(C)c1nc(-c2cccnc2)cnc1NN
Product: CCOC(=O)C(C)c1nnc2c(C(C)CC)nc(-c3cccnc3)cn12

Procedure:
In a manner analogous to that described in Example 1, by condensing 2-hydrazino-3-[(RS)-1-methylpropyl]-5-(3-pyridyl)pyrazine with diethyl methylmalonate there is obtained ethyl rac-α-methyl-8-[(RS)-1-methylpropyl]-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 353 (M)+, which by saponification analogously to Example 1 is converted into the above acid which is used directly in the next step.
Reaction SMILES: C(B(CC)[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)C.[C:12]([CH:15]([N:25]1[C:29]2[N:30]=[C:31]([CH2:35][C:36]3[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=3)[NH:32][C:33](=[O:34])[C:28]=2[CH:27]=[N:26]1)[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:14])[CH3:13].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.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:12]([CH:15]([N:25]1[C:29]2[N:30]=[C:31]([CH2:35][C:36]3[CH:37]=[CH:38][C:39]([C:4]4[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=4)=[CH:40][CH:41]=3)[NH:32][C:33](=[O:34])[C:28]=2[CH:27]=[N:26]1)[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:14])[CH3:13]
Reactant: CCB(CC)c1cccnc1
Reactant: CC(=O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc(Br)cc3)nc21
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: C1CCOC1
Product: CC(=O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc(-c4cccnc4)cc3)nc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
71 mg (0.48 mmol) of diethyl-(3-pyridyl)-borane and 16 mg of tetrakistriphenylphosphine-palladium are added under argon to a solution of 177 mg (0.37 mmol) of 1-(1-acetyl-4-phenyl-butyl)-6-(4-bromo-benzyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one in 4 ml of THF, and the mixture is stirred for one hour at 70° C. After 0.522 ml of 2 N Na2CO3 solution have been added, the mixture is stirred for a further 4 hours at 70° C., a further 27 mg (0.185 mmol) of diethyl-(3-pyridyl)-borane and 16 mg of tetrakistriphenylphosphine-palladium are added, and the mixture is stirred for 14 hours under reflux. The solvent is removed in vacuo and the residue taken up in CH2Cl2. The mixture is extracted with 2N HCl, and the aqueous phase is rendered alkaline with 1N NaOH and extracted twice with CH2Cl2. After the mixture has been dried over Na2SO4, the solvent is removed in vacuo. Purification by chromatography (toluene/ethyl/acetate=4:1) gives 110 mg (6.4%) of a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:26])([CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[S:9]1(=[O:25])=[O:24])[C:3]([NH:5][CH3:6])=O.B.O1CCCC1.[ClH:33]>C(OCC)C>[ClH:33].[F:26][C:2]([F:1])([CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[S:9]1(=[O:24])=[O:25])[CH2:3][NH:5][CH3:6]
Reactant: CNC(=O)C(F)(F)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNCC(F)(F)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Reaction time: 2 h

Procedure:
To a stirred solution of 2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropanamide (ca. 1 mmol) at 0° C., was added borane-tetrahydrofuran complex (1 M in THF, 3 mL, 3 mmol). After stirring for 2 h, the mixture was quenched with dilute hydrochloric acid, basified (2 N NaOH) and extracted with ethylacetate. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography (hexanes: ethylacetate, gradient elution) to afford the crude product which was further purified by reverse phase hplc (Xterra RP18 19×150 mm, 5 u, 55% MeOH 45% H2O w/0.05% NH4OH, 20 mL/min). The residue obtained was dissolved in diethyl ether, treated with excess ethereal HCl and lyophilized to afford 2,2-difluoro-3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylpropan-1-amine hydrochloride as a white solid.