Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[F:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][C:13]=1[F:19].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)[CH:15]=[CH:14][C:13]=1[F:19]
Reactant: C#Cc1cncc(OC)c1
Reactant: Fc1ccc(I)cc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1cncc(C#Cc2ccc(F)c(F)c2)c1
Temperature: 60 °C
Yield: 93.8 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (110 mg, 0.15 mmol), copper (I) iodide (57 mg, 0.30 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (400 mg, 3.0 mmol) to a solution of 1,2-difluoro-4-iodobenzene (0.43 mL, 3.6 mmol) in triethylamine (6.3 mL, 45.0 mmol) and heat at 60° C. for 20 h. Cool to room temperature and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 65:35 hexanes:ethyl acetate, followed by a second silica gel chromatography, eluting with 100:0 to 80:20 dichloromethane:ethyl acetate, to give the title compound as a white solid (690 mg, 94%).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:11]([NH2:14])(=[O:13])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:14][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)(=[O:13])=[O:12])=[O:24])=[CH:18][CH:17]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCCC2
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)CCCC2
Yield: 56 %

Procedure:
The title compound was prepared by the method of Example 1 in 56% yield from 5,6,7,8-tetrahydro-2-naphthalenesulfonamide and 4-chlorophenylisocyanate, m.p. 163°-165° C.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][C:9](/[CH:13]=[C:14]4/[C:15](=[O:23])[NH:16][C:17]5[C:22]/4=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:10][CH:11]=3)[N:6](COCC[Si](C)(C)C)[N:5]=2)[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][C:9](/[CH:13]=[C:14]4/[C:15](=[O:23])[NH:16][C:17]5[C:22]/4=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:10][CH:11]=3)[NH:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1nc(C2CC2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(C3CC3)n[nH]c2c1
Yield: 21.1 %

Procedure:
A mixture of (E)-3-((3-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (47 mg, 0.11 mmol) and tetrabutylammonium fluoride (1.0 M in THF, 10 mL, 10 mmol) in anh. THF (30 mL) was refluxed under Ar for 18 h. The reaction mixture was then concentrated to a brown oil, which was diluted with H2O, extracted (2% MeOH in DCM), washed (H2O (2×), brine), dried (Na2SO4, and MgSO4) and concentrated under reduced pressure. The material was suspended in DCM, collected by filtration and washed with xs. DCM to afford the title compound as a yellow solid (7.0 mg, 21%). 1H NMR (400 MHz, CD3OD) δ ppm 7.90 (d, J=8.53 Hz, 1H), 7.86 (s, 1H), 7.78 (s., 1H), 7.65 (d, J=8.03 Hz, 1H), 7.42 (d, J=8.78 Hz, 1H), 7.23 (t, J=8.03 Hz, 1H), 6.92 (d, J=7.78 Hz, 1H), 1H), 6.87 (t, J=7.65 Hz, 1H), 2.26-2.36 (m, 1H), 1.04-1.11 (m, 4H); MS ESI 302.1 [M+H]+, calcd for [C19H15N3O+H]+ 302.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[N:12][OH:13])[CH3:11])=[CH:5][CH:4]=1.[ClH:14].[BH3-]C#N.[Na+]>CO>[ClH:14].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][OH:13])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(C)=NO)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)NO)cc1
Reaction time: 8 h

Procedure:
23.7 g (0.13 mol) of 4-methoxyphenylacetone oxime were dissolved in 200 ml of methanol and the solution was brought to pH 3 with dilute hydrochloric acid. 8.3 g (0.13 mol) of NaBH3CN were then introduced in portions, the pH being kept at 3 by simultaneous addition of dilute hydrochloric acid. The mixture was subsequently stirred overnight at room temperature, the pH was brought to 1 with hydrochloric acid and the mixture was evaporated. The aqueous residue was extracted with methylene chloride (3×100 ml). The combined organic phases were washed with water (3×25 ml), dried over Na2SO4 and evaporated. Yield 23.3 g (80% of theory), melting point 124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Na].Br[CH:11]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:12]([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:11]([C:12]([OH:14])=[O:13])[C@H:15]([CH2:16][CH3:17])[CH3:18])=[CH:4][CH:3]=1
Reactant: CCC(C)C(Br)C(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: [Na]
Product: CC[C@H](C)[C@H](Nc1ccc(Cl)cc1)C(=O)O

Procedure:
N-(4-chlorophenyl)isoleucine is prepared by the reaction of 4-chloroaniline with the sodium salt of α-bromo-3-methylpentanoic acid neat at 100°.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:6]=CC=CC=1.[N:20]12CCC(C[CH2:25]1)[C@@H:22](O)[CH2:21]2>C(OCC)(=O)C>[C:13]1([CH2:12][C:11]([O:10][C@@H:8]2[CH:7]3[CH2:1][CH2:6][N:20]([CH2:21][CH2:22]3)[CH2:25]2)=[O:19])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cc1ccccc1)OC(=O)Cc1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)O[C@H]1CN2CCC1CC2
Yield: 93.3 %

Procedure:
Phenylacetic acid anhydride (prepared as described in J. Org. Chem., 1588, 30, 1965) (15 g) was added to a suspension of (R)-3-quinuclidinol (5 g) in ethyl acetate (250 ml) at room temperature. After 178 hour the solvent was evaporated and the residue dissolved in hydrochloric acid (2M). This was washed with ethyl acetate, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated to give the title compound as a yellow oil (9 g, 66%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.P(=O)(O)(O)O>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN1CCCCC1=O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: CN1CC=C(c2c[nH]c3ccccc23)CC1

Procedure:
Using the same procedure of Example 1, 1-methyl-piperidone and 1H-indole were condensed in refluxing acetic acid in the presence of phosphoric acid to obtain 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole melting at 228°~229° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].C([O-])([O-])=O.[K+].[K+].II>CC(O)(C)C>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]2[NH:13][CH2:12][CH2:11][N:14]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: NCCN
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CSc1ccc(C2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(methylthio)benzaldehyde (1-Im-1, 10 g, 1.0 eq) in 1000 mL of t-BuOH, ethylene diamine (1.1 eq) was added. The mixture was stirred at rt under Ar for 30 min, then K2CO3 (3.0 eq) and I2 (1.25 eq) were added to the mixture. This mixture was stirred at 70° C. for 3 h, then was quenched with aqueous Na2SO3 until the color of iodine disappeared, then extracted with CHCl3. The organic layer was washed with NaHCO3 and brine and dried with Na2SO4. The solvent was removed to give 2-(4-(methylthio)phenyl)-4,5-dihydro-1H-imidazole (compound 2-Im-1).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[F:39][C:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:43]([C:40]3([F:39])[CH2:42][CH2:41]3)=[O:44])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: O=C(Cl)C1(F)CC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3(F)CC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, 1-fluorocyclopropanecarbonyl chloride (20 mg, 165 μmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions, and the mixture was stirred for 12 h. The reaction mixture was then concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (29.5 mg, 89% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C>[F:14][C:11]([F:12])([F:13])[C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:22](=[O:24])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2c(=O)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 113.2 %

Procedure:
To a suspension of 2-amino-5-(trifluoromethyl)benzoic acid (2 g, 9.75 mmol) in acetonitrile (10.0 ml) was added pyridine (2.31 g, 2.37 ml, 29.2 mmol) and a solution of triphosgene (1.74 g, 5.85 mmol) in acetonitrile (10.0 ml) at 50° C. The reaction mixture was stirred for 2 h at 50° C. Then additional triphosgene (579 mg, 1.95 mmol) was added and heating to 50° C. was continued overnight. The solvent was removed and water was added. The mixture was extracted with EtOAc and the combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was triturated in dichloromethane for 3 h. The solid was filtrated off and washed two times with dichloromethane to afford the crude title compound (1.53 g, 45%) as off-white solid. MS (ESI): 230.3 (M−H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9]1([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Cc1ccccc1Cl
Product: Cc1ccccc1N(c1ccccc1)c1ccccc1
Reaction time: 21 h
Yield: 103.3 %

Procedure:
According to the general procedure A, 2-bromotoluene (188 mg, 1.10 mmol) reacted with diphenylamine (169 mg, 1.00 mmol) to give the title compound (258 mg, 99%) as a white solid at room temperature for 4 h. Reaction of 2-chlorotoluene (70 mg, 0.55 mmol) with diphenylamine (85 mg, 0.50 mmol) proceeded at 80° C. for 21 h to give the title compound (134 mg, 99%). 1H-NMR (400 MHz, CDCl3): δ 7.14-7.27 (m, 8H), 7.01-6.92 (m, 6H), 2.06 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 147.46, 145.37, 136.49, 131.67, 129.61, 128.99, 127.33, 125.95, 121.50, 121.33, 18.56. GC/MS(EI): m/z 259 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([CH2:17][C:18](OCC)=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH:17][C:18]2=[O:19]
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Product: O=c1cc(-c2ccccc2)[nH]c2ccc(Br)cc12
Temperature: 150 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of 4-bromoaniline (7.0 g, 40.7 mmol), ethyl benzoylacetate (14.09 mL, 81.4 mmol), and polyphosphoric acid (15.95 g, 162.7 mmol) was heated without solvent to 150° C. for 3 h. After 3 h, the reaction was cooled to RT, and the mixture was quenched with 4 N HCl (200 mL), which caused an orange cake to form. This solid was filtered, and to this was added 2N NaOH (200 mL). The majority of the solid did not dissolve, and was filtered off. The solid was washed with water (200 mL) and a mixture of 1:1 acetone/DCM (200 mL), and stored under vacuum overnight to give 6.52 g (53% yield) of ˜95% (by LC-MS) pure 6-bromo-2-phenylquinolin-4(1H)-one. Further purification can be accomplished by recrystallization with n-butoxyethanol to yield analytically pure material. 1H NMR (400 MHz, DMSO-d6) ppm: 11.87 (br s, 1H), 8.18 (d, J=2.4 Hz, 1H), 7.82 (m, 3H), 7.73 (d, J=8.8 Hz, 1H), 7.60 (m, 3H), 6.39 (d, J=1.6 Hz, 1H). LRMS (CI, [M+H]) Calc'd=300.1. found=300.1.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[OH-].[Li+]>O1CCCC1.CO>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccc(F)cc1)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccc(F)cc1)CCC3
Yield: 50.7 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(4-fluorobenzyl)-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (0.34 g, 0.78 mmol) in tetrahydrofuran (15 mL) and methanol (15 mL) was treated with 1 M aqueous lithium hydroxide solution (20 mL) at room temperature for 66 h. The mixture was concentrated in vacuo and the residue acidified with concentrated hydrochloric acid. The resulting precipitate was collected via vacuum filtration, washed with water, and air-dried to provide 168 mg (51%) of the title compound as a green solid: mp 199-201° C. (dec). 1H NMR (DMSO-d6) δ 13.10 (bs, 1H), 7.18 (m, 2H), 6.95 (m, 2H), 6.50 (s, 1H), 5.55 (s, 2H), 4.62 (s, 2H), 2.95 (t, J=6.6 Hz, 2H), 2.83 (t, J=7.0 Hz, 2H), 2.50 (s, 3H), 1.98 (quintet, J=7.3 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[OH:27].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:27][C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=2[F:19])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Oc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2cccc(F)c2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 56.2 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.17 g of 2,3-difluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.17 g of 4-(2-butynyloxy)-6-(2,3-difluorophenoxy)pyrimidine (the present compound (39)).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)=[O:30])[CH2:25][CH2:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:35]3[CH:36]=[C:31]([C:29]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[O:30])[CH:32]=[CH:33][CH:34]=3)=[N:7][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: CN1CCN(C(=O)c2cccc(B(O)O)c2)CC1
Product: CN1CCN(C(=O)c2cccc(-c3cnc4c(n3)N(Cc3c(F)ccc(F)c3Cl)CCN4)c2)CC1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 3-(4-Methylpiperazine-1-carbonyl)phenylboronicacid, pinacol ester using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[O:17]1[CH2:20][C:19](=[O:21])[CH2:18]1.CC(=O)OCC>C1COCC1>[Br:1][C:2]1[C:7]([C:19]2([OH:21])[CH2:20][O:17][CH2:18]2)=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Br)c1
Reactant: O=C1COC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1(c2c(Cl)ccnc2Br)COC1
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a solution of 2-bromo-4-chloropyridine (14 g, 70 mmol) in dry THF (200 mL) was added LDA (42.0 mL, 84.0 mmol, 2.0 M) dropwise at −70° C. After stirring for 0.5 h at this temperature, a solution of oxetan-3-one (6.6 g, 90 mmol) in dry THF (40 mL) was added slowly and the reaction mixture was stirred at 0° C. for an additional 1 h. Saturated aqueous NH4CI (50 mL) and EA (200 mL) were added. The mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude material was purified by SGC eluting with DCM) to afford 148a as a yellow solid (8.8 g, 45%). MS: [M+H]+ 266.0.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:29]=[CH:28][C:15]3[N:16]([CH3:27])[C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=4)=[N:18][C:14]=3[CH:13]=2)[CH:10]=1)=[O:4].[CH3:30][NH2:31]>>[Br:26][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17]2[N:16]([CH3:27])[C:15]3[CH:28]=[CH:29][C:12]([O:11][C:9]4[CH:10]=[C:5]([C:3]([NH:31][CH3:30])=[O:4])[CH:6]=[N:7][CH:8]=4)=[CH:13][C:14]=3[N:18]=2)=[CH:25][CH:24]=1
Reactant: CN
Reactant: COC(=O)c1cncc(Oc2ccc3c(c2)nc(Nc2ccc(Br)cc2)n3C)c1
Product: CNC(=O)c1cncc(Oc2ccc3c(c2)nc(Nc2ccc(Br)cc2)n3C)c1

Procedure:
To a solution of methyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate in added methylamine and the resulting mixture was stirred at ambient temperature for 16 h. It was then concentrated and purified by preparative chromatography to yield (5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy)-(3-pyridyl))-N-methylcarboxamide. MS: MH+=452.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[CH:6]=[C:7]([OH:22])[C:8]2[N:12]=[C:11]([CH3:13])[N:10](C(OC(C)(C)C)=O)[C:9]=2[CH:21]=1)=[O:4].[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:36])=[C:29]2[C:34]=1[O:33][CH2:32][CH2:31][CH:30]2O>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH3:36])=[C:29]2[C:34]=1[O:33][CH2:32][CH2:31][CH:30]2[O:22][C:7]1[C:8]2[N:12]=[C:11]([CH3:13])[NH:10][C:9]=2[CH:21]=[C:5]([C:3]([N:2]([CH3:1])[CH3:23])=[O:4])[CH:6]=1
Reactant: Cc1ccc(F)c2c1C(O)CCO2
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C(=O)OC(C)(C)C
Product: Cc1nc2c(OC3CCOc4c(F)ccc(C)c43)cc(C(=O)N(C)C)cc2[nH]1
Yield: 32 %

Procedure:
The title compound was prepared as a white solid in 32% yield (38 mg) from 1,1-dimethylethyl 6-[(dimethylamino)carbonyl]-4-hydroxy-2-methyl-1H-benzimidazole-1-carboxylate (100 mg, 0.31 mmol, STEP 2 in Example 9) and 8-fluoro-5-methylchroman-4-ol (0.23 g, 1.2 mmol, STEP 1-3) by the same manner in STEP 3-2 of Example 9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH:16]([C:21]#[N:22])[C:17]([O:19]C)=[O:18])[CH2:12][N+:13]([O-:15])=[O:14].[OH-].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH:16]([C:21]#[N:22])[C:17]([OH:19])=[O:18])[CH2:12][N+:13]([O-:15])=[O:14]
Reactant: COC(=O)C(C#N)C1(C[N+](=O)[O-])C(=O)Nc2ccc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#CC(C(=O)O)C1(C[N+](=O)[O-])C(=O)Nc2ccc(Cl)cc21

Procedure:
To a solution of methyl [5-chloro-3-(nitromethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl](cyano)acetate, intermediate 27 (5.00 g; 15.45 mmol) in MeOH (150 ml) was added a potassium hydroxide solution in water (9.27 ml; 5.00 M; 46.34 mmol). After stirring for 2.5 l the solvent was evaporated. The residue was taken up with ethyl acetate and the organic phase extracted with 1N HCl, dried (MgSO4) and the solvent removed in vacuo to give the crude [5-chloro-3-(nitromethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl](cyano)acetic acid (4.89 g, quant.). This was a mixture of diastereomers, which was sufficiently pure for subsequent reaction (HPLC purity 93%).
Reaction SMILES: C([O:4][C:5]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(C)=O>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:9][C:8]1[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][C:5]([OH:4])=[CH:17][C:16]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:15]
Reactant: CCOC(=O)COc1c(-c2ccccc2)cc(OC(C)=O)cc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1c(-c2ccccc2)cc(O)cc1-c1ccccc1
Temperature: 100 °C
Yield: 55.9 %

Procedure:
Ethyl 4-acetoxy-2,6-diphenylphenoxyacetate (7.2 g, 18.5 mmol) was dissolved in wet toluene (400 ml) and a catalyst (25 g SiO2 treated with a solution of 2 g 4-toluenesulfonic acid in 10 ml acetone and evaporated in vacuo) was added. The mixture was stirred and heated at 100° C. for 6 h, cooled and filtered through a column of silica gel (50 g). Elution with benzene afforded 3.6 g (56%) of (2,6-diphenyl-4-hydroxy-phenoxy)-acetic acid ethyl ester as white crystals, which were recrystallized from benzene/petroleum ether. M.p. 91–93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:23]=[C:24]([N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:25]2[N:26]([C:28]([CH3:31])=[N:29][N:30]=2)[N:27]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[N:9]2[C:22]2[CH:23]=[C:24]([N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[C:25]3[N:26]([C:28]([CH3:31])=[N:29][N:30]=3)[N:27]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Reactant: Cc1nnc2c(N(C)C(=O)OC(C)(C)C)cc(Cl)nn12
Solvent: ClCCl
Solvent: CO
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(N(C)C(=O)OC(C)(C)C)c3nnc(C)n3n1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 110 using 4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 85.6) and tert-butyl (6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)(methyl)carbamate (Step 112.5). tR: 5.60 min (HPLC 1); tR: 1.29 min (LC-MS 2); ESI-MS: 549 [M+H]+ (LC-MS 2); Rf=0.56 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.09 (m, 2H) 1.19-1.25 (m, 2H) 1.43 (s, 9H) 1.90 (s, 3H) 2.52 (s, 3H) 3.44 (s, 3H) 3.79-3.88 (m, 1H) 6.45 (s, 1H) 7.33-7.38 (m, 2H) 7.43-7.48 (m, 2H) 8.30 (s, 1H).