Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[N:13]=1.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>CS(C)=O.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:21])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][CH:15]=2)[N:13]=1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Product: C[Si](C)(C)C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 107.3 %

Procedure:
To a solution of 5-(2-chloro-6-fluorophenyl)-2-(4-iodophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.200 g, 0.483 mmol) in DMSO (2 mL) was added ethynyl(trimethyl)silane (0.071 g, 0.724 mmol), copper iodide (0.005 g, 0.007 mmol), bis(triphenylphosphine) palladium(II) chloride (0.200 g, mmol) and TEA (2.0 mL). The reaction mass was stirred at RT for 24 h. The reaction mass was quenched in water and neutralized with dilute acetic acid and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.200 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 2.31 (s, 9H), 7.44-7.47 (m, 3H), 7.54-7.71 (m, 3H), 7.94-8.01 (m, 1H), 77.95 (br s, 1H). MS (m/z): 384.29 (M−H)−.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[CH:16][C:17]=3[O:22][CH3:23])[N:12]=2)=[CH:7][C:6]=1[CH3:26].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH3:23][O:22][C:17]1[CH:16]=[C:15]([O:24][CH3:25])[CH:14]=[C:13]2[C:18]=1[C:19](=[O:21])[NH:20][C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:6]([CH3:26])[CH:7]=1)=[N:12]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCBr)c(C)c3)nc2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCN4CCCC4)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-[4-(2-bromo-ethoxy)-3-methyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.70 g, 1.67 mmol) in anhydrous DMF (9 mL) was added pyrrolidine (0.55 mL, 6.68 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 20 hours. Solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel 230-400 mesh; 9% methanol in dichloromethane as eluent) to give the title compound as an off-white solid. Yield: 0.62 g (90.6%). MP 230-231° C. 1H NMR (400 MHz, CDCl3): δ 9.96 (br s, 1H), 7.91-7.89 (m, 2H), 6.93 (d, J=7.6 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 4.21 (t, J=6.0 Hz, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 2.98 (t, J=6.0 Hz, 2H), 2.69 (br s, 4H), 2.32 (s, 3H), 1.84-1.81 (m, 4H). MS (ES−) m/z 408.13 (M−1, 100%), MS (ES+) m/z 410.14 (M+1, 75%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([F:51])[C:48]([F:52])=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[C:49]([F:51])[C:48]([F:52])=[CH:47][C:46]=3[Cl:53])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Fc1cc(Cl)c(CBr)cc1F
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cc(F)c(F)cc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-4,5-difluorobenzene and isolated as colorless gum (6.2 mg, 34%). MS (m/e): 443.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:33]([CH2:35][CH3:36])[CH3:34]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:33]([CH2:35][CH3:36])[CH3:34])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCC(C)Br
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)CC)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (3) (400 mg, 1.18 mmol), anhydrous Cs2CO3 (574 mg, 2.36 mmol), and KI (40 mg, 0.24 mmol) in DMF (10 mL) is added 2-bromobutane (508 μL, 4.72 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (30 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 10-40% EtOAc in heptane) to give a pure product (12) as white solid (395 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])[CH3:19]>C(O)(=O)C.Cl.O.C(O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][N:9]=[C:21]([C:22](=[O:24])[CH3:23])[C:18](=[O:20])[CH3:19]
Reactant: Cc1ccccc1N
Reactant: O=N[O-]
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(=O)C(=NNc1ccccc1C)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 2-methylaniline (1000 mg, 9.34 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (774 mg, 11.21 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2299 mg, 28.04 mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(2-methylphenyl)hydrazono]pentane-2,4-dione (1000 mg, 49%). LCMS: m/z=219 [M++H].
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([OH:21])[CH2:20][O:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([CH:23]=[O:24])=[CH:5][NH:6]2.CC(=CC)C.Cl([O-])=[O:31].[Na+].O.OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([OH:21])[CH2:20][O:19][CH2:18]3)=[CH:13][CH:12]=2)=[C:9]([F:22])[CH:8]=[C:7]2[C:3]=1[C:4]([C:23]([OH:31])=[O:24])=[CH:5][NH:6]2
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(O)COC4)cc3)c(F)c12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: O=C(O)c1c[nH]c2cc(F)c(-c3ccc(C4(O)COC4)cc3)c(F)c12
Temperature: 0 °C
Reaction time: 5 h
Yield: 10.4 %

Procedure:
A solution of 4,6-difluoro-5-[4-(3-hydroxyoxetan-3-yl)phenyl]-1H-indole-3-carbaldehyde (38 mg, 0.12 mmol) was dissolved in acetonitrile (1 mL) and warm tert-butanol (0.3 mL). The reaction mixture was treated with 2-methyl-2-butene (0.3 ml), cooled to 0° C., and treated with a solution of sodium chlorite (199 mg, 2.36 mmol) and sodium phosphate monobasic hydrate (332 mg, 2.41 mmol) in water (1 mL) via addition funnel. The ice bath was removed, and the reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction mixture was diluted with water (2 mL) and NH4Cl (2 mL). The product was extracted with EtOAc (3×20 mL). The organic layer was concentrated in vacuo to give the crude product, which was purified using prep-HPLC to give the title compound (4.3 mg). MS (ES+) 346.0 (M+H)+. Retention time: 2.04 min. Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. Flow: 2.0 mL/min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:5][N:4]=1>CO.[Ni]>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:5][N:4]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To the solution of 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (500 mg, 1.79 mmol) in MeOH (50 mL) was added Raney-Ni (50 mg). The reaction mixture was stirred at room temperature under H2 for 2 h. Then the solid was filtered off, and the solvent was removed to afford 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine in 89% yield (400 mg). m/z 251 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].O[CH:5]=[C:6]1[C:10]([CH3:12])([CH3:11])[O:9][C:8]([CH3:14])([CH3:13])[C:7]1=[O:15]>C(Cl)(Cl)Cl>[CH3:13][C:8]1([CH3:14])[C:7](=[O:15])[C:6](=[CH:5][NH:3][CH2:1][CH3:2])[C:10]([CH3:12])([CH3:11])[O:9]1
Reactant: CC1(C)OC(C)(C)C(=CO)C1=O
Reactant: CCN
Solvent: ClC(Cl)Cl
Product: CCNC=C1C(=O)C(C)(C)OC1(C)C
Yield: 65 %

Procedure:
Ethylamine gas was bubbled through a solution of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)furanone (4.0 g, 24 mmol) in 50 mL of chloroform at room temperature for 15 min. The solvents were evaporated and the residue was recrystallized from hexanes to give 3.0 g (65%) of dihydro-2,2,5,5-tetramethyl-4-ethylaminomethylene-3(2H)furanone as a light brown solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:11][CH2:12][O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([OH:24])=[O:23])[CH2:17]2)[CH:7]=[CH:8][CH:9]=1>[Pd].CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:11][CH2:12][O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([C:22]([OH:24])=[O:23])[CH2:17]2)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C(=CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2C)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc(C(CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2C)c1
Yield: 14.9 %

Procedure:
The acid prepared in Example 30 (2.0 g, 4.5 mmol) was dissolved into methanol (50 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (65% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a solid residue which was recrystallised from a mixture of acetone and ethyl acetate to give 0.30 g (23%) of the title compound.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:6][S:7]([N:10]([C:18]2[C:19]([F:28])=[C:20]([C:24]([F:27])=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])S(CC2CC2)(=O)=O)(=[O:9])=[O:8])[CH2:5][CH2:4]1>C1COCC1.CO>[CH:3]1([CH2:6][S:7]([NH:10][C:18]2[C:19]([F:28])=[C:20]([C:24]([F:27])=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])(=[O:8])=[O:9])[CH2:5][CH2:4]1
Reactant: O=C(O)c1c(F)ccc(N(S(=O)(=O)CC2CC2)S(=O)(=O)CC2CC2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(F)ccc(NS(=O)(=O)CC2CC2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
A solution of 1N NaOH (2.78 mL, 2.78 mmol) was added to a solution of crude 3-(1-cyclopropyl-N-(cyclopropylmethylsulfonyl)methylsulfonamido)-2,6-difluorobenzoic acid (380 mg, 0.928 mmol) in 4:1 THF/MeOH (5 mL, 0.2M). The reaction mixture was stirred at room temperature for 1 hour, after which most of the organic solvents were removed. 1N HCl (3 mL) was slowly added to the mixture to acidify to a pH of 1. The acidified aqueous layer was extracted with ethyl acetate (75 mL). The ethyl acetate extract was washed with water (2×20 mL), brine (20 mL), dried (Na2SO4), filtered and concentrated. Trituration of the residue with Et2O afforded 3-(cyclopropylmethylsulfonamido)-2,6-difluorobenzoic acid as a solid (139 mg, 51%). 1H NMR (400 MHz, d6-DMSO) δ 9.76 (s, 1H), 7.60-7.54 (m, 1H), 7.22-7.16 (m, 1H), 3.10 (d, J=7.0 Hz, 2H), 1.10-0.99 (m, 1H), 0.58-0.53 (m, 2H), 0.36-0.31 (m, 2H); m/z (APCI-neg) M-1=289.9.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[C:10]([CH:18](N(C)C)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]=1[OH:28])([CH3:7])([CH3:6])[CH3:5].C(OC)(C)(C)C>O.S1(CCCC1)(=O)=O>[NH2:2][C:1]1[O:28][C:9]2[C:8]([C:4]([CH3:6])([CH3:5])[CH3:7])=[CH:13][C:12]([C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:11][C:10]=2[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN(C)C(c1ccccc1)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)c1cc(C(C)(C)C)c2oc(N)c(-c3ccccc3)c2c1
Temperature: 120 °C
Yield: 99.5 %

Procedure:
A solution of 0.98 g (20,0 mmol) of sodium cyanide in 2.0 ml of water is added to a solution of 3.39 g (10,0 mmol) of 2,4-di-tert-butyl-6-(dimethylaminophenyl-methyl)-phenol [compound (201), Table 2, prepared according to Example 2a in WO-A-99/67232] in 10 ml of sulfolane. The reaction mixture is then maintained at 120° C. for one hour. After cooling to room temperature, the reaction mixture is poured into 80 ml tert-butyl-methylether and washed three times with water. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. The residue yields 3.20 g (99%) of 2-amino-3-phenyl-5,7-di-tert-butyl-benzofurane (compound (301), Table 3), m.p. 174-178° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH2:17])[C:6](=[O:16])[NH:7]2.Cl.N[OH:20].O>C(O)CCC>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[N:17][OH:20])[C:6](=[O:16])[NH:7]2
Reactant: Nc1nc2c(Cl)cc(C(F)(F)F)cc2[nH]c1=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: O=c1[nH]c2cc(C(F)(F)F)cc(Cl)c2[nH]c1=NO
Temperature: 25 °C
Yield: 68.8 %

Procedure:
An adaptation of the method of Harsanyi et al., Liebigs Ann. Chem. 190 (1973), was used. A mixture of 5-chloro-7-trifluoromethyl-3-aminoquinoxalin-2(1H)-one (35 mg, 0.13 mmol) and hydroxylamine hydrochloride (20 mg, 0.29 mmol; Aldrich Co.) in 2 mL of 1-butanol was heated to reflux. The resulting suspension was stirred under reflux for 12 h. The resulting suspension was cool to 25° C., and added H2O (5 mL). A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 25 mg (69%) of 5-chloro-7-trifluoromethyl-3-(hydroxyimino)-1,4-dihydroquinoxalin-2-one (tentatively named as this since the regiochemistry is not sure) as a pale yellow solid of a new compound: mp dec.>235° C. 1H NMR (300 MHz, DMSO-d6) δ 11.199 (br s, 1H, NH), 10.932 (br s, 1H, NOH), 10.411 (br s, 1H, NH), 7.604 (s, 1H, H-7), 7.317 (s, 1H, H-5). LRMS: 279 (M+, 100%), 249 (50%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7]C)=[O:6].[CH:14](O)=O>>[CH3:13][C:3]1[C:2]2[NH:1][CH:14]=[N:12][C:11]=2[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N)c(N)c1C
Reactant: O=CO
Product: Cc1c(C(=O)O)ccc2nc[nH]c12
Temperature: 70 °C

Procedure:
Methyl 3,4-diamino-2-methylbenzoate (synthesized in reagent preparation 22) (0.18 g, 1.0 mmol) was taken up in formic acid (8.0 mL) and refluxed for 4 hours. The solution was then concentrated in vacuo. The material was taken up in methanol (2.5 mL) and tetrahydrofuran (5.0 mL) and treated with 2M aqueous lithium hydroxide (2.5 mL) and heated to 70° C. for 12 hours. This solution was made acidic using concentrated aqueous hydrochloric acid, then extracted with 10% methanol in ethyl acetate (2×50 mL). The combined organic layers were dried (magnesium sulfate), filtered and concentrated to give 0.055 g of 7-methyl-1H-benzimidazole-6-carboxylic acid. 1H NMR (400 MHz, d6-DMSO): 9.34 (s, 1H), 7.94 (d, 1H), 7.64 (d, 1H), 2.85 (s, 3H). MS (EI) for C9H8N2O2: 177 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[OH:16])=O)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29]/[C:5](/[C:4]1[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=1[CH2:1][CH3:2])=[C:7]1\[C:8](=[O:16])[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[S:11]\1)[CH3:28]
Reactant: CCN
Reactant: CCc1ccccc1C(=O)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1CC
Yield: 2 %

Procedure:
Prepared as in Example 1 from 2-(2-ethyl-benzoyl)benzo-[b]thiophen-3-ol, phosphorus(V) chloride and an aqueous 25% ethylamine solution with a yield of 2% of theory. M.p. 76°-77° C. (diisopropyl ether/petroleum ether 1:2).
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].I[CH:15]([CH2:17][CH3:18])[CH3:16].C(N1C=C(I)C(C2SC=CC=2)=N1)(CC)C>CN(C)C=O.CC(OC)(C)C.O>[CH:15]([N:4]1[C:3]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[C:2]([I:1])[CH:6]=[N:5]1)([CH2:17][CH3:18])[CH3:16]
Reactant: CCC(C)I
Reactant: Ic1c[nH]nc1-c1cccs1
Agent: CCC(C)n1cc(I)c(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: CCC(C)n1ncc(I)c1-c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution of 4-iodo-3-(2-thienyl)-1H-pyrazole (7.1 mmol) in 57 mL dry N,N-dimethylformamide under argon atmosphere at 0° C. was added sodium hydride (8.5 mmol, 60% dispersion in mineral oil) in portions. The reaction mixture was stirred at 0° C. for 15 min, then 2-iodobutane (10.6 mmol) was added dropwise. After 14 h at room temperature, water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 2.7 g of a mixture of 1-sec-butyl-4-iodo-3-(2-thienyl)-1H-pyrazole and 1-sec-butyl-4-iodo-5-(2-thienyl)-1H-pyrazole (80:20; 88% yield). The mixture was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100 and cyclohexane:toluene 100:0 to 0:100) to afford 1.16 g 1-sec-butyl-4-iodo-3-(2-thienyl)-1H-pyrazole (48% yield) and 71 mg of 1-sec-butyl-4-iodo-5-(2-thienyl)-1H-pyrazole (3% yield).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[N:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23][CH:22]=1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:25]3[CH:26]=[N:21][CH:22]=[N:23][CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: OB(O)c1cncnc1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3cncnc3)c2c1
Yield: 34 %

Procedure:
This compound was prepared from 6b using 5-pyrimidinylboronic acid according to method P. Yellow powder; Yield: 34%; mp>340° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 7.00 (d, J=2.6 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H), 7.36 (dd, J=9.0, 2.6 Hz, 1H), 7.98-8.02 (m, 2H), 8.08 (s, 1H), 8.11 (dd, J=13.1, 2.2 Hz, 1H), 9.11 (s, 2H), 9.37 (s, 1H), 10.07 (s, 1H), 10.24 (s, 1H); MS (ESI) m/z 332 ([M−H]−), 334 ([M+H]+); Anal. Calcd for C19H12FN3O2: C, 68.47; H, 3.63; N, 12.61. Found: C, 65.37; H, 3.98; N, 11.30.
Reaction SMILES: CC1C=CC(Cl)=CC=1C=O.Cl[C:12]1[N:13]=[N:14][C:15]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[CH3:25])=[CH:16][CH:17]=1.[CH:26]([NH:28][NH2:29])=O>C(O)CCC>[CH3:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[C:15]1[CH:16]=[CH:17][C:12]2[N:13]([CH:26]=[N:28][N:29]=2)[N:14]=1
Reactant: Cc1ccc(Cl)cc1-c1ccc(Cl)nn1
Reactant: NNC=O
Agent: Cc1ccc(Cl)cc1C=O
Solvent: CCCCO
Product: Cc1ccc(Cl)cc1-c1ccc2nncn2n1

Procedure:
As described in Example 35, 2-methyl-5-chlorobenzaldehyde is converted to 3-chloro-6-(2-methyl-5-chlorophenyl)pyridazine. A mixture of the preceding compound and formylhydrazine in n-butanol is refluxed for 24 hours to give the product of the example.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([CH:28]=O)[C:24]([CH3:30])=[N:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:45]CCCl>>[ClH:45].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([N:15]3[CH2:20][CH2:19][N:18]([CH2:28][C:25]4[C:24]([CH3:30])=[N:23][N:22]([CH3:21])[C:26]=4[CH3:27])[CH2:17][CH2:16]3)=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: Cc1nn(C)c(C)c1C=O
Reactant: COc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc(-c2nccnc2N2CCN(Cc3c(C)nn(C)c3C)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
Couple 3′-(4-methoxyphenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.103 g, 0.400 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (0.0727 g, 0.526 mmol) using sodium triacetoxyborohydride (0.167 g, 0.788 mmol) in DCE (5 mL). Stir at room temperature for 18 hr, and add the reaction mixture to an SCX column. Elute with 2 M ammonia in methanol. Purify by silica gel chromatography, eluting with 0:100 to 20:80 methanol:DCM. Dissolve the residue in methanol and add ammonium chloride (1.3 mL of a 0.2 M solution of ammonium chloride in methanol, 0.26 mmol). Stir overnight, concentrate, add diethyl ether and stir overnight. Isolate the solid product by filtration and vacuum dry overnight to give the title compound (100 mg, 58%). MS (ES): m/z=393 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=O)[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[F:27][C:28]([F:38])([F:37])[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([NH:34][C:33]2[CH:35]=[CH:36][C:30]([O:29][C:28]([F:27])([F:37])[F:38])=[CH:31][CH:32]=2)=[O:26])[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2ccc(OC(F)(F)F)cc2)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 (95 mg, 0.256 mmol) with 4-(trifluoromethoxy)aniline (54 mg, 0.307 mmol) in the presence of EDCI hydrochloride (98 mg, 0.512 mmol) and DMAP (47 mg, 0.384 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 68 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.23-0.26 (m, 2H), 0.43-0.47 (m, 2H), 1.13-1.15 (m, 1H), 3.73 (d, J=6.6 Hz, 2H), 3.78 (s, 3H), 6.92-6.96 (m, 1H), 7.04 (t, J=7.8 Hz, 1H), 7.22-7.25 (m, 1H), 7.35-7.38 (m, 3H), 7.44 (d, J=16.2 Hz, 1H), 7.77-7.81 (m, 2H), 7.86 (d, J=16.2 Hz, 1H), 8.01 (d, J=4.2 Hz, 1H), 10.47 (s, 1H); ESI-MS (m/z) 530.37 (MH)+.