Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][N:9]=1.[O:24]=[C:25]1[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[CH2:27][CH2:26]1.N1C2C(=NC=CC=2)N(O)N=1.Cl.C(N=C=NCCCN(C)C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C@@H:2]1[CH2:7][N:6]([C:31]([CH:28]2[CH2:29][CH2:30][C:25](=[O:24])[CH2:26][CH2:27]2)=[O:32])[CH2:5][CH2:4][N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][N:9]=1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccccc12
Reactant: O=C1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)C2CCC(=O)CC2)CCN1c1nnc(-c2ccccc2)c2ccccc12

Procedure:
(R)-1-(2-methylpiperazin-1-yl)-4-phenylphthalazine (JK-10) (509 mg, 1.67 mmol), 4-oxocyclohexanecarboxylic acid (261 mg, 1.84 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (273 mg, 2.01 mmol) (HOAt), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (385 mg, 2.01 mmol), sodium bicarbonate (281 mg, 3.34 mmol), and DMF (6 mL) were stirred at rt for 22 hours. The reaction was taken up in ethyl acetate (80 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-70% ethyl acetate gave an off-white solid, compound 69. MS (M+H)+=429.2.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)c1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 85.4 %

Procedure:
To a solution of methyl 4-(1,4-dioxaspiro[4.5]dec-8-yl)benzoate (480 mg, 1.73 mmol) in 8 mL of THF was added 4 mL of 1 N of aqueous HCl solution. The mixture was stirred at rt for 21 h and concentrated. The residue was partitioned between 50 mL of Et2O and 50 mL of 1 N aqueous NaHCO3 solution. The organic layer was separated, dried over MgSO4, and concentrated. Chromatography on a Biotage 40S cartridge using 1:9 v/v EtOAc/hexanes as the eluant afforded 343 mg (85%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=[CH:8][CH:9]([CH3:11])[CH3:10])[C:5]([OH:7])=[O:6].[C:13]([OH:16])(=[S:15])[CH3:14]>>[C:13]([S:15][CH:8]([CH:4]([CH2:3][CH:2]([CH3:12])[CH3:1])[C:5]([OH:7])=[O:6])[CH:9]([CH3:11])[CH3:10])(=[O:16])[CH3:14]
Reactant: CC(C)C=C(CC(C)C)C(=O)O
Reactant: CC(O)=S
Product: CC(=O)SC(C(C)C)C(CC(C)C)C(=O)O

Procedure:
E and Z 2-(2-methylpropyl)-4-methyl-pent-2-enoic acid (7 g) in thioacetic acid (50 ml) was heated at 100° C. under reflux for 72 h. The excess thioacetic acid was removed in vacuo and the residue dissolved in dichloromethane which was extracted with aqueous saturated sodium hydrogen carbonate (3×200 ml). The aqueous phase was separated, acidified to pH1 with concentrated hydrochloric acid and extracted with fresh dichloromethane. The organic extract was dried over sodium sulphate and concentrated in vacuo to a gum which was chromatographed on silica in 15% ethyl acetate in dichloromethane to afford 2-(RS)-(1-(RS)-S-Acetyl mercapto-2-methylpropyl)-4-methyl pentanoic acid (2.0 g) as a colourless oil δ(CDCl3) 0.86-1.08 (12H, m, 2×CH(CH3)2); 1.32-1.46 (1H, m, CH); 1.48-1.78 (2H, m, CH2); 1.92-2.12 (1H, m, CH); 2.36 and 2.39 (3H, each s, CH3COS); 2.65 and 2.9 (1H, each m, CH); 3.65 and 3.78 (1H, each m, CHS).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/S(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[N+:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[C-:23].CCO>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:23][NH:22][C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:8][CH:9]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)/C=C/c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]ccc1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Under N2, at 0° C. 60% NaH in mineral oil (3.11 g, 78 mmol) was added to a solution of (E)-1-chloro-4-(2-tosylvinyl)benzene (19 g, 64.9 mmol) in dry THF (300 mL). After 5 minutes ethyl 2-isocyanoacetate (7.76 mL, 71.4 mmol) was added and the reaction mixture stirred at room temperature. After 18 h EtOH (50 mL) was added and the solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc (400 mL) and H2O (400 mL). The organic phase was washed with (100 mL), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product (16.55 g, “102%”) was used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[O:13])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14][Mg]Br.C(OCC)(=O)C.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([OH:13])[CH3:14])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1O
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)c1cc(Br)cc(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (4.1 mmol) of 5-bromo-3-formyl-2-hydroxy-benzoic acid was dissolved in 100 mL of anhydrous THF under nitrogen. The solution was cooled in an ice-bath and 13.6 ml of a 3 M solution of methyl magnesium bromide was added. The mixture was stirred for 16 h, slowly warming to room temperature. The resulting solution was distributed between ethyl acetate and dilute aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and evaporated to afford 1.09 g of 5-bromo-2-hydroxy-3-(1-hydroxy-ethyl)-benzoic acid as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.76 (d, 1H), 7.72 (d, 1H), 4.98 (q, 1H), 1.30 (d, 3H), MS: m/z 258.9+261.0 (M+H+).
Reaction SMILES: [OH-].[K+].[C:3]([N:5]=[C:6]([NH2:8])[NH2:7])#[N:4].CC(C)=O.[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[S:19])=[CH:16][CH:15]=1>O.C(O)(=O)C>[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:7][C:6]([NH:5][C:3]#[N:4])=[NH:8])=[S:19])=[CH:16][CH:15]=1
Reactant: N#CN=C(N)N
Reactant: Cc1ccc(C(=S)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C(=S)NC(=N)NC#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Potassium hydroxide, 13.02 g (0.2 mole) is dissolved in 40 ml of water and 10.51 g (0.125 mole) of dicyanodiamide is added, followed by the addition of 50 ml of acetone. The mixture is cooled to 0° C and the 4-methylthiobenzoyl chloride from Step 1A, above, is added dropwise. The mixture is stirred at 0° C for 1 hour and placed in the refrigerator overnight. The mixture is poured into 500 ml of water and the water is then acidified with an excess of acetic acid. The product forms a precipitate which is filtered, washed with water followed by ether and air dried to give 12.1 g of 1-(4'-methylthiobenzoyl)-3-cyanoguanidine, m.p. 314° C dec.
Reaction SMILES: S(S([O-])=O)([O-])=[O:2].[Na+].[Na+].[N+](NC1C=CC=CC=1)([O-])=O.[CH2:19]([S:21][CH2:22][C:23]1[CH:36]=[CH:35][C:26]2[NH:27][C:28]([NH:30][C:31](=[O:34])[O:32][CH3:33])=[N:29][C:25]=2[CH:24]=1)[CH3:20].CO>C(O)C.O.[OH-].[NH4+].C(O)(=O)C>[CH2:19]([S:21]([CH2:22][C:23]1[CH:36]=[CH:35][C:26]2[NH:27][C:28]([NH:30][C:31](=[O:34])[O:32][CH3:33])=[N:29][C:25]=2[CH:24]=1)=[O:2])[CH3:20]
Reactant: O=S([O-])S(=O)[O-]
Reactant: CCSCc1ccc2[nH]c(NC(=O)OC)nc2c1
Agent: O=[N+]([O-])Nc1ccccc1
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCS(=O)Cc1ccc2[nH]c(NC(=O)OC)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the residue dissolved in 100 ml 95% ethanol is added sodium dithionite (9.4 g, 54 mmol) dissolved in 60 ml water and 15 ml concentrated ammonium hydroxide. After refluxing for 5 minutes, portions of sodium dithionite (1 g in 10 ml water and 2 ml ammonium hydroxide) are added until the orange nitroaniline color disappears. The reaction mixture is reduced to one-half volume by evaporation, basified with 20 ml 10% sodium hydroxide, and extracted with chloroform (X 5). The chloroform washings are dried (Na2SO4) and evaporated. The residue, 3.3 g (16.1 mmol) of the thiopseudourea from Example 1, part D, 6 drops of acetic acid, and 50 ml of methanol are refluxed for 2 hours. After stirring overnight at room temperature, the product crystallizes out, is filtered off and digested with 50 ml hot methanol to yield the title compound, 2.77 g, m.p. 228°-235°(d).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:12]1[C:20]2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=[C:16]([Cl:23])[C:15]=2[N:14]=[C:13]1[CH2:24][Cl:25])[CH3:11])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+].C(Cl)Cl>C1COCC1>[Cl:23][C:16]1[C:15]2[N:14]=[C:13]([CH2:24][Cl:25])[N:12]([C@@H:10]([CH3:11])[CH2:9][OH:8])[C:20]=2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1nc(Cl)c2nc(CCl)n([C@@H](C)CO[Si](C)(C)C(C)(C)C)c2c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nc(Cl)c2nc(CCl)n([C@@H](C)CO)c2c1C
Temperature: -78 °C
Yield: 100 %

Procedure:
1-((1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-4-chloro-2-(chloromethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridine (440 mg, 1.09 mmol) was dissolved in 10 mL of THF and the yellow solution was cooled to −78° C. under an atmosphere of N2. A 1.0 M solution of tetrabutylammonium fluoride in THF (1.42 mL) was slowly added, and the reaction was allowed to warm to 0° C. overnight. The reaction was then treated with 20 mL of saturated NaHCO3 and 20 mL of CH2Cl2. The layers were separated and the organic portion was washed with brine (4×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give (2S)-2-[4-chloro-2-(chloromethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl]propan-1-ol (314 mg) as a tan solid. The tan solid was dissolved in 10 mL of anhydrous THF. The resulting yellow solution was cooled to 0° C. under an atmosphere of N2. Solid potassium tert-butoxide (116 mg, 1.42 mmol) was then added and the reaction was stirred at 0° C. for 1 hour and was then allowed to warm to ambient temperature. After 2 hours, the reaction mixture was partitioned between 20 mL of CH2Cl2 and 20 mL of saturated NaHCO3 solution. The layers were separated and the organic portion was washed sequentially with 20 mL of saturated NaHCO3 solution and 20 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give (4S)-9-chloro-4,6,7-trimethyl-3,4-dihydro-1H-pyrido[3′,4′:4,5]imidazo[2,1-c][1,4]oxazine (270 mg) as an orange solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.[Cl-].[NH4+]>CCCCCC.CCOCC.O1CCCC1>[CH2:14]1[O:15][C:16]2([CH2:21][CH2:20][C:19]([OH:22])([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH2:18][CH2:17]2)[O:23][CH2:13]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccncc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2ccncc2)CCC2(CC1)OCCO2
Yield: 67.2 %

Procedure:
Thirty-five ml of ether was cooled to -78° C., to which 20 ml of a 1.6 mol n-butyl lithium solution in hexane was added. Next, 5 g of 4-bromopyridine was dissolved in 30 ml of ether and the solution was added to the mixture. Then, a solution of 5 g of 1,4-cyclohexanedione monoethyleneacetal in 30 ml of tetrahydrofuran was added to the mixture. After completion of the reaction, the reaction solution was poured into saturated ammonium chloride aqueous solution. The mixture was extracted with chloroform and the extract was purified to give 5 g of 4-hydroxy-4-(4-pyridyl)cyclohexanone ethyleneacetal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH2:11][S:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])=[CH:21][C:15]=3[N:14]=2)[CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:34]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([CH2:11][S:12]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])=[CH:21][C:15]=3[N:14]=2)=[O:34])[CH:4]=1
Reactant: COc1cnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cnc(CS(=O)c2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)cc1OC

Procedure:
A solution of the product in methylene chloride is obtained by the procedure described in Example 2 by oxidation of 0.76 g of 2-[(4,5-dimethoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole with 19 ml of a 0.1M solution of m-chloroperoxybenzoic acid in 30 ml of methylene chloride at -40° C., after extraction. After drying the solution over magnesium sulfate, the drying agent is filtered off, the filtrate is concentrated and the residue is crystallized from methylene chloride/diisopropyl ether. 0.64 g (82% of theory) of the title compound is obtained in the form of colorless crystals of m.p. 160°-162° C. (decomp.).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:20]=4[S:19](=[O:29])(=[O:28])[N:18]=3)[C:7]2=[O:30])[CH2:3][CH2:2]1.Br[CH2:32][C:33]#[N:34].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([O:27][CH2:32][C:33]#[N:34])=[CH:26][C:20]=4[S:19](=[O:28])(=[O:29])[N:18]=3)[C:7]2=[O:30])[CH2:2][CH2:3]1
Reactant: N#CCBr
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc2n1NCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#CCOc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Yield: 95.5 %

Procedure:
The product of Example 320C (0.050 g, 0.117 mmol) in N,N-dimethylformamide (2 mL) was reacted with 2-bromoacetonitrile (16 μL, 0.230 mmol), potassium carbonate (0.15 g, 0.46 mmol) and tetrabutylammonium iodide (catalytic) at 25° C. for 1 day. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate/hexane (1:1), filtered and washed with water to give title compound (52 mg, 95%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O-:12])(=[O:11])=[O:10].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)CCN(C)C.[CH:49]([O:51][CH2:52][CH2:53]Cl)=[CH2:50]>CS(C)=O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O-:12])(=[O:11])=[O:10].[CH:49]([O:51][CH2:52][CH2:53][O:15][C:16]1[CH:21]=[CH:20][C:19]([S+:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH2:50]
Reactant: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: C=COCCCl
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1C(F)(F)F
Solvent: CS(C)=O
Product: C=COCCOc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
4-Hydroxyphenyldiphenylsulfonium 2-trifluoromethylbenzenesulfonate (8.01 g), potassium carbonate (2.74 g), and N,N,N′,N′-tetramethylethylenediamine (0.18 g) were dissolved in dimethyl sulfoxide (36 g). Subsequently, chloroethyl vinyl ether (5.31 g) was added to the resultant solution, followed by heating to 80° C. and stirring for 15 hours. The resultant reaction mixture was cooled to 30° C. or lower. After removal of solid matter through filtration, water (40 g) was added to the filtrate, and the aqueous layer was washed thrice with hexane (30 g). Dichloromethane (30 g) and water (60 g) were added to the washed aqueous layer, followed by stirring for extraction of a target substance into the dichloromethane layer. The organic layer was repeatedly washed with distilled water until the pH of the separated aqueous layer became 7. The solvent was removed by means of a rotary evaporator, to thereby yield 3.7 g of an oily substance. Through 1H-NMR analysis and ion chromatography, this substance was identified to be 4-vinyloxyethoxyphenyldiphenylsulfonium 2-trifluoromethylbenzenesulfonate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]([CH3:27])([CH3:26])[CH2:9][C:10]([CH2:16][C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[F-].[K+].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1.C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:12][C:11]([F:14])([F:13])[C:10]([CH2:16][C:17]1[NH:25][C:20]2=[CH:21][N:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)([OH:15])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:3]=[CH:4][C:5]=1[O:28][CH3:29])([CH3:27])[CH3:26]
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccccc2)cc1C(C)(C)CC(O)(Cc1cc2ccncc2[nH]1)C(F)(F)F
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of 4-(5-bromo-2-methoxyphenyl)-1,1,1-trifluoro-4-methyl-2-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)pentan-2-ol (188 mg, 0.4 mmol), Pd(OAc)2 (9 mg, 0.04 mmol), DCyBPP ((2-dicyclohexylphosphino)biphenyl, 28 mg, 0.08 mmol), and KF (93 mg, 1.6 mmol) in 3 mL of THF at room temperature was treated with phenylboronic acid (74 mg, 0.6 mmol). The reaction mixture was microwaved for 20 minutes at 120° C., cooled to room temperature, diluted with 20 mL of ethyl acetate and filtered through diatomaceous earth. The filtrate was washed with 5 mL of 1.0 M aqueous sodium hydroxide solution, water, and 5 mL of brine. The organic phase was dried over magnesium sulfate, filtered, and the solvent evaporated in vacuo. The residue was purified silica gel chromatography to provide 75 mg (40% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N+:16]([O-])=O.[H][H]>CO.[Pd]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH2:16]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnccc1Nc1cccc(F)c1F
Agent: [Pd]
Solvent: CO
Product: Nc1cnccc1Nc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
To a solution of N-(2,3-difluorophenyl)-3-nitropyridin-4-amine in 200 mL of methanol under an atmosphere of nitrogen was added 10% Pd/C (0.75 g). The atmosphere was replaced with hydrogen gas and the reaction mixture stirred under balloon pressure for 14 hours at RT. The reaction mixture was filtered over Celite which washed with methanol (3×30 mL). The filtrate was concentrated in vacuo to give a brown solid. The crude product was triturated with petroleum ether (3×50 mL) to afford N4-(2,3-difluorophenyl)pyridine-3,4-diamine (4.0 g, 90% yield) as light brown solid; LC-MS: 222.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[N+:18]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pt]>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: [Pt]
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from (4-chloro-5-ethoxy-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example A21) (7.04 g, 22.2 mmol) by hydrogenation with 5% Pt/C according to the general procedure J (method a). Obtained as a light yellow solid (6.32 g, 99%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][N:10]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11](=[O:23])[N:12]2[C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[CH:6]=1)=[O:4].[CH:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)([CH3:42])[CH3:41]>C(Cl)Cl>[Cl:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:46]2[CH2:47][CH2:48][N:43]([CH:40]([CH3:42])[CH3:41])[CH2:44][CH2:45]2)[CH:14]=[C:13]2[C:8]=1[CH2:9][N:10]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:11](=[O:23])[N:12]2[C:15]1[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(=O)CBr)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: CC(C)N1CCNCC1
Solvent: ClCCl
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(=O)CN4CCN(C(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reaction time: 1.5 h

Procedure:
To a solution of 7-(bromoacetyl)-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (38 mg, 0.059 mmol) in CH2Cl2 (1 mL) was 1-isopropylpiperazine (15 mg, 0.118 mmol) at rt. The reaction mixture was stirred for 1.5 h, then the solvent was removed in vacuo. The resulting crude material was purified by preparative thin layer chromatography using 10% MeOH in CH2Cl2 as an eluent to give the title compound. Mass spectrum (ESI): 691.2 (M+1).
Reaction SMILES: [C:1]1([CH2:13][CH2:14][NH:15][S:16]([CH2:19][C:20]([O:22]C)=O)(=[O:18])=[O:17])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[NH2:24][OH:25]>>[OH:25][NH:24][C:20](=[O:22])[CH2:19][S:16]([NH:15][CH2:14][CH2:13][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1)(=[O:18])=[O:17]
Reactant: COC(=O)CS(=O)(=O)NCCc1ccc(-c2ccccc2)cc1
Reactant: NO
Product: O=C(CS(=O)(=O)NCCc1ccc(-c2ccccc2)cc1)NO

Procedure:
In a manner similar to Example 1 (b), methyl 2-({[2-(biphen4-yl)ethyl]amino}sulfonyl)acetate was reacted with hydroxylamine to give the title compound as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O[C:21](=O)[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23])C.CC(C)([O-])C.[K+].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.O>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:21]2[C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])=[CH:10][C:11]=1[F:17])#[N:14]
Reactant: N#Cc1ccc(Nc2ncccc2N)cc1F
Reactant: CCOC(=O)C(=O)NC1CC1
Agent: CC(C)(C)[O-]
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc(-n2c(C(=O)NC3CC3)nc3cccnc32)cc1F
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[(3-aminopyridin-2-yl)amino]-2-fluorobenzonitrile (C15) (3.9 g, 17 mmol) and ethyl(cyclopropylamino)(oxo)acetate (P1) (4.03 g, 25.6 mmol) in 1-methylpyrrolidin-2-one (17 mL) was added potassium tert-butoxide (2.88 g, 25.7 mmol). The reaction mixture was stirred at 120° C. for 30 minutes, cooled to room temperature, and treated with 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P) (˜50% weight solution, 20.3 mL, 32 mmol). After the reaction mixture had been stirred at 120° C. for 18 hours, it was allowed to cool. Water (10 mL) was added and stirring was continued for 10 minutes. Saturated aqueous sodium bicarbonate solution (20 mL) was introduced, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, filtered, and concentrated in vacuo Silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 2.29 g, 7.13 mmol, 42%. LCMS m/z 322.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=4.7, 1.4 Hz, 1H), 8.17 (dd, J=8.2, 1.5 Hz, 1H), 7.79-7.85 (m, 1H), 7.69 (br s, 1H), 7.38-7.45 (m, 3H), 2.83-2.90 (m, 1H), 0.87-0.93 (m, 2H), 0.68-0.73 (m, 2H).