Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=[CH:12]3)O1.Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[CH:29]([OH:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:31][CH:29]([C:28]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=[CH:12]2)[CH3:30]
Reactant: CC(O)c1ccncc1Br
Reactant: CC1(C)OB(c2ccc3cc(C#N)ccc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(O)c1ccncc1-c1ccc2cc(C#N)ccc2c1
Temperature: 100 °C

Procedure:
A mixture of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthonitrile 2c (233 mg, 0.835 mmol), 1-(3-bromopyridin-4-yl)ethanol (153 mg, 0.759 mmol, prepared according to the procedure described in Heterocyles 1993, 35, 151-169), sodium carbonate (2M in water, 0.759 mL, 1.518 mmol), bis(triphenylphosphine)palladium(II) chloride (26.6 mg, 0.038 mmol) in DMF (3.035 mL) was heated to 100° C. for 1 hr. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc twice. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified twice via Biotage (20-100% EtOAc/heptane; 25M column). 47 mg of racemic title compound was isolated as white solid, and was subsequently separated by chiral HPLC (ChiralPak AS-H column, 2.1×250 mm, 16 mL/min, 70% heptane 30% ethanol) to 2-(enantiomer-1) (13 mg, 6%) (retention time: 11.74 min) and 2-(enantiomer-2) (12 mg, 6%) (retention time: 19.90 min). 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (d, J=6.3 Hz, 3H), 5.28 (q, J=6.5 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.91 (s, 1H), 8.39 (d, J=5.0 Hz, 1H), 8.55 (s, 1H), 8.70 (d, J=6.2 Hz, 1H). LC-MS (M+1) 275.1, t=1.06 min.
Reaction SMILES: CS(C)=O.[C:5]([O:22]C)(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>O1CCCC1>[C:27]1([C:24](=[O:26])[CH2:25][C:5](=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCCCCCCCCCCCCC(=O)OC
Reactant: CC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCC(=O)CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.88 h

Procedure:
An apparatus as described in Example 1 is charged with 31.7 g of sodium-tert-butylate, 150 g of DMSO and 150 g of tetrahydrofuran (THF) and the mixture is cooled to 0° C. Then a mixture of 89 g of methyl palmitate and 36 g of acetophenone is added dropwise over 45 minutes. The reaction mixture is then stirred for ca. 45-60 minutes at 30° C., the solvent is removed by distillation on a rotary evaporator (bath temperature <60° C.), and the residue is taken up in 1000 ml of water. The aqueous solution is acidified with dilute hydrochloric acid and the precipitate is isolated by filtration, washed with water, and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Cl:14])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[Li+].CC([N-]C(C)C)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Cl:14])=[CH:10][N:11]2[S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=2)(=[O:31])=[O:30])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(Cl)c[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(Cl)cn(S(=O)(=O)c3ccc(C)cc3)c2c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
To a solution of 3-chloro-1H-indole-6-carboxylic acid methyl ester (3.00 g, 17.1 mmol) in 40 mL of THF at −78° C. is added LDA(8.55 mL of a 2.0M solution in hexanes, 17.1 mmol) dropwise. The solution is stirred at −78° C. for 30 minutes p-Toluenesulfonyl chloride (3.43 g, 18.0 mmol) in 15 mL of THF is added dropwise and the resulting solution is stirred at −78° C. for 3 hours. The mixture is warmed to 0° C., quenched with saturated NaHCO3 solution and diluted with H2O and Et2O. The layers are separated. The organic phase is washed with saturated NaHCO3 solution, H2O and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude residue is purified via flash column chromatography eluting with a gradient of 10% EtOAc/hexanes to 30% EtOAc/hexanes to provide the title compound (3.64 g, 10.0 mmol). 1H NMR (CDCl3, 300 MHz) δ8.70 (s, 1H), 8.01 (dd, 1H), 7.80 (d, 2H), 7.70 (s, 1H), 7.60 (d, 1H), 7.38 (m, 2H), 4.00 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][N:7]1[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[N:8]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH3:5][O:4][N:3]([CH3:2])[C:12]([C:11]1[N:7]([CH3:6])[N:8]=[CH:9][CH:10]=1)=[O:14]
Reactant: Cn1nccc1C(=O)O
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccnn1C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (1.30 g) was added to an dimethylformamide (32 mL) solution that contained 1-methyl-1H-pyrazol-5-carboxylic acid (1.21 g), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.38 g) and diisopropylethylamine (3.34 mL) at a room temperature, and the obtained solution was then stirred for 2 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=100:0 to 95:5), so as to obtain the title compound (1.03 g) in the form of a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33])([CH3:28])[CH3:27])#[N:25].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:24]([C:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)[CH:3]=1)=[O:33])([CH3:28])[CH3:27])#[N:25]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 78 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.32 mmol), 3-(1-cyano-1-methylethyl)benzoic acid (62 mg, 0.33 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol), 1-hydroxybenzotriazole (46 mg, 0.34 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 318, the title compound (120 mg, 77%) was obtained as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:33])[N:10]=[C:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[CH:18][CH:17]=3)[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.CI.[CH3:36]CN(C(C)C)C(C)C>C(Cl)Cl>[CH3:36][N:12]1[CH:13]=[C:8]([CH2:7][C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)[C:9](=[O:33])[N:10]=[C:11]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)=[CH:20][CH:21]=1
Reactant: O=c1nc(CCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cc2cncnc2)c(=O)nc1CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.5 %

Procedure:
To the solution of 5-(pyrimidin-5-ylmethyl)-2-(4-(3-(trifluoromethyl)phenoxy)phenethyl) pyrimidin-4(1H)-one (200 mg, 0.442 mmol) in DCM (10 mL) was added MeI (4.42 mL, 4.42 mmol) (1.0 M in DCM) and DIPEA (0.772 mL, 4.42 mmol) at 25° C. The mixture was stirred at room temperature for 2 days. The solvent was removed in vacuo. Purification via MDAP then afforded the title compound (87.6 mg, 40.8% yield) as a white solid. LCMS: rt=1.59 min, [M+H+]=467.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:26])[CH2:7][CH2:8][N:9]([C:23](=[O:25])[CH3:24])[CH:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)C>C(O)C.O>[C:23]([N:9]([CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][C:6]([OH:26])=[O:5])(=[O:25])[CH3:24]
Reactant: CCOC(=O)CCN(C(C)=O)C1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N(CCC(=O)O)C1c2ccccc2-c2ccccc21
Reaction time: 4.5 h
Yield: 42.3 %

Procedure:
1.6 ml of 1N sodium hydroxide was added dropwise to a solution of 435 mg of N-acetyl-N-(9-fluorenyl)-β-alanine ethyl ester in 25 ml of ethanol under ice-cooling. After stirring for 4.5 hours, the reaction solution was condensed. The residue was dissolved in water and, then, washed with ether. The pH value of the water layer was adjusted to 3 to 4 with 5% hydrochloric acid. The precipitate formed was separated by filtration, washed with ice-cold water, and recrystallized from a mixture of ethyl acetate and methanol to give 168 mg of N-acetyl-N-(9-fluorenyl)-β-alanine.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[OH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3/[C:3](=[CH:2]\[C:23]3[CH:24]=[C:19]([OH:18])[CH:20]=[CH:21][CH:22]=3)/[C:9]=12
Reactant: OB(O)c1cccc(O)c1
Reactant: BrC=C1c2ccccc2CCc2cccnc21
Product: Oc1cccc(/C=C2\c3ccccc3CCc3cccnc32)c1
Yield: 63.7 %

Procedure:
Following procedures essentially as described in Example 219, combine 11-bromomethylene-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (250 mg, 0.87 mmol) and (3-hydroxyphenyl) boronic acid (133 mg, 0.96 mmol). Purify to provide product 166 mg (63%) as an off-white solid. LC/MS: 300.1 (M+H). 1H NMR (DMSO, 400 MHz): δ9.22 (s,1H), 8.40 (d,1H), 7.49 (d,1H), 7.34 (d,1H), 7.24 (d,1H), 7.21 (d,3H), 7.15 (s,1H), 7.04 (t,1H), 6.92 (d,1H), 6.90 (d,1H), 6.52 (d,1H), 6.40-6.42 (m,2H), 3.4-2.8 (m,4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O-])(=O)[CH3:12].[Na+].C(=O)C>O.C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[CH:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: NNc1ccc(Cl)cc1
Agent: CC=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC=NNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorophenylhydrazine hydrochloride (5.0 g) and 3.4 g of sodium acetate were dissolved in a mixture of 50 ml of water and 25 ml of ethanol, to which 1.69 g of 80% acetaldhyde aqueous solution were added dropwise at room temperature, and the resulting mixture was stirred for 30 minutes at room temperature. After adding 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried and distilled off to give acetaldehyde 4-chlorophenylhydrazone as an oil.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.Cl.[CH2:15]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH2:16][CH3:17].C(=O)(O)[O-].[Na+]>>[CH2:15]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:10]([CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:11])[CH2:16][CH3:17]
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: CCCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCOC(=O)CNC(=O)C1CC(C)CCC1C(C)C

Procedure:
Following the procedure of Example 2 p-menth-3-oyl chloride (2.0 g., 0.01 moles), was reacted with glycine propyl ester hydrochloride (1.5 g., 0.01 moles) and sodium bicarbonate (1.6 g., 0.02 moles). The crude product was distilled b.p. 170°/0.1 mm. (After distillation the product rapidly solidifies). (Found, C: 68.2; H: 1016; N: 5.0. C16H29NO3 requires, C: 67.8; H: 10.6; N: 4.9.)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH:10]([C:14]([O:27][CH2:28][CH2:29][NH:30]C(OCC2C=CC=CC=2)=O)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[N:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH:10]([C:14]([O:27][CH2:28][CH2:29][NH2:30])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[N:3]=1
Reactant: Cc1cc(C)nc(OC(C(=O)O)C(OCCNC(=O)OCc2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)nc(OC(C(=O)O)C(OCCN)(c2ccccc2)c2ccccc2)n1

Procedure:
A solution of 13.1 g (24.2 mmol) of 2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-benzyloxycarbonylaminoethoxy)-3,3-diphenylpropionic acid in 200 ml of methanol was hydrogenated with hydrogen overnight, under atmospheric pressure and at room temperature, using 800 mg of palladium on activated carbon (10%). The reaction mixture was diluted with methanol to dissolve precipitated product, filtered and concentrated. Yield: 9.6 g of a white solid.
Reaction SMILES: [F:1][CH2:2][C:3]([OH:5])=O.C(Cl)CCl.[I:10][C:11]1[N:15]2[CH:16]=[CH:17][C:18]([C:20]([NH:22][NH2:23])=[O:21])=[CH:19][C:14]2=[N:13][CH:12]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][CH2:2][C:3]([NH:23][NH:22][C:20]([C:18]1[CH:17]=[CH:16][N:15]([C:11]([I:10])=[CH2:12])[C:14](=[NH:13])[CH:19]=1)=[O:21])=[O:5]
Reactant: NNC(=O)c1ccn2c(I)cnc2c1
Reactant: O=C(O)CF
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C=C(I)n1ccc(C(=O)NNC(=O)CF)cc1=N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of fluoroacetic acid (52 mg, 0.66 mmol) in CH2Cl2 (5 ml) was added EDC (127 mg, 0.66 mmol) and DMAP (5 mg, catalytic) and the reaction mixture stirred at room temperature for 15 min. 3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide (prepared as described in Example 329 steps a-c) (100 mg, 0.33 mmol) was added and the reaction mixture stirred at room temperature for 18 h. The reaction mixture was filtered, the precipitate washed with Et2O and dried to afford a crude product which was used directly in the next reaction (101 mg). MS: [M+H]+=363.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:32][CH:33]=2)[CH:21]=1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(-c5cccnc5)cc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-pyridin-3-ylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-pyridin-3-ylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)C)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1
Agent: Cl
Solvent: CO
Product: Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1
Reaction time: 2 h
Yield: 20.2 %

Procedure:
A mixture of 80 parts of intermediate 47, namely N-[4-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]phenyl]acetamide, 150 ml of an aqueous hydrochloric acid solution 2N and 15.8 parts of methanol was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was basified. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 14.1 parts (20.2%) of 4-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]benzenamine (interm. 48).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17](=[O:33])[O:18][CH2:19][CH:20]1[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:15])=[CH:7]2.[OH:34]OS([O-])=O.[K+].O>CN(C=O)C>[CH:22]1[C:21]2[CH:20]([CH2:19][O:18][C:17]([NH:16][C@H:14]([C:8]3[N:9]=[C:10]([C:12]([OH:34])=[O:13])[C:11]4[C:6]([CH:7]=3)=[CH:5][CH:4]=[CH:3][C:2]=4[Cl:1])[CH3:15])=[O:33])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: O=S([O-])OO
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C=O)n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(C(=O)O)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-formylisoquinolin-3-yl)ethylcarbamate (348) (12.0 g, 26.3 mmol, 1.0 eq) in DMF (150 mL), OXONE (30 g, 48.78 mmol, 1.85 eq) was added and the resulting mixture was stirred at RT over night. The mixture was poured into water (600 mL) and then filtered. The solid was dissolved in ethyl acetate (100 mL), and then PE (300 mL) was added dropwise to this solution. The precipitate was collected by filtration to afford (S)-3-(1-(((9H-fluoren-9-yl)methoxy)carbonylamino)ethyl)-8-chloroisoquinoline-1-carboxylic acid (349).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1)=[O:27]>>[CH3:24][NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:30][N:29]=1)=[O:27]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)c1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid methylamide (Stage 15.1.1, 42 mg, 0.160 mmol) to give the title compound as a lightly yellow solid. (HPLC: tR 2.39 min (Method A); M+H=428 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.01 (s, 1H), 8.87-8.80 (m, 1H), 8.71-8.67 (m, 1H), 8.18-8.07 (m, 4H), 8.04-7.98 (m, 1H), 7.65 (s, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 2.83 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16](=[O:24])[CH2:15][CH2:14]1)(=[O:12])=[O:11].Br[CH2:26]Br.C([Li])CCC.CCCCCC.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:14][CH2:15][C:16]2([O:24][CH2:26]2)[CH:17]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:12])=[O:11]
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Reactant: BrCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)CO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
50 mg (0.133 mmol) of ethyl 6-[1-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 0.01 ml (0.146 mmol) of dibromomethane were dissolved in 1 ml of tetrahydrofuran, and 0.18 ml (0.279 mmol) of n-butyllithium/hexane solution (1.58 M) was added dropwise thereto at −78° C., followed by stirring at room temperature for 4 hours. After the reaction solution was cooled with ice, a saturated aqueous ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel thin layer chromatography (solvent; hexane:ethyl acetate=2:1) to give 7 mg of the title compound as a yellow oil (yield: 14%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)=O.[C:14](=O)([O-])[O-].[K+].[K+].CC(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-]>CO>[C:1]([CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[CH:14]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Agent: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-formylazetidine-1-carboxylate (96 g, 0.46 mol) and potassium carbonate (128 g, 0.924 mol) in methanol was added dropwise dimethyl-1-diazo-2-oxopropylphosphonate (67 g, 0.35 mol) in 1.6 L of methanol. The mixture was stirred for 2 h and filtered. The filtrate was concentrated and the residue was diluted with 800 ml of methyl-tert-butyl ether and 1 L of 5% w/w aqueous sodium bicarbonate. The layers were separated and the aqueous layer was washed with methyl-tert-butyl ether (2×500 ml). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography to afford tert-butyl 3-ethynylazetidine-1-carboxylate.