Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[CH:20]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[N:29]=[N:30][C:31](Cl)=[CH:32][CH:33]=2)=[O:27])[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[N:29]=[N:30][C:31]([N:15]3[CH2:16][CH2:17][CH:12]([C:10](=[O:11])[NH:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:18])[F:19])[CH2:13][CH2:14]3)=[CH:32][CH:33]=2)=[O:27])[CH2:22][CH2:21]1
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(C(=O)Nc3ccccc3C(F)(F)F)CC2)nn1
Yield: 89 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use piperidine-4-carboxylic acid (2-trifluoromethylphenyl)amide in place of piperidin-4-yl-(2-trifluoromethylphenyl)amine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 89% yield. 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=7.9 Hz, 1H), 7.96 (d, J=9.4 Hz, 2H), 7.58-7.48 (m, 3H), 7.24-7.18 (m, 1H), 6.97 (d, J=9.5 Hz, 1H), 4.53-4.49 (m, 2H), 3.54-3.47 (m, 2H), 3.18-3.00 (m, 2H), 2.66-2.57 (m, 1H), 2.07-1.99 (m, 2H), 1.93-1.79 (m, 2H), 1.49-1.43 (m, 2H), 0.73-0.67 (m, 1H), 0.45-0.39 (m, 2H), 0.07-0.02 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 172.4, 163.2, 159.9, 144.6, 134.9, 132.9, 126.9, 126.2, 126.1, 125.2, 124.9, 122.2, 112.2, 44.4, 43.8, 39.6, 34.5, 27.9, 43.8, 8.6, 4.2. MS (ES+) m/z 462 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4]([OH:20])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)=[C:6]([F:8])[CH:7]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CN1CCCC1=O>[Cl:1][C:2]1[C:3](=[O:21])[N:4]([O:20][CH3:22])[C:5]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:17])[F:18])[N:11]([CH3:19])[N:10]=2)=[C:6]([F:8])[CH:7]=1
Reactant: Cn1nc(-c2c(F)cc(Cl)c(=O)n2O)c(Cl)c1OC(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN1CCCC1=O
Product: COn1c(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc(Cl)c1=O
Yield: 62.5 %

Procedure:
0.20 g of 3-chloro-6-(4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazol-3-yl)-5-fluoro-1-hydroxy-[1H]-pyridin-2-one (Example P32) is introduced into 2 ml of N-methylpyrrolidone (NMP) at 22° C. and 0.16 g of anhydrous potassium carbonate is added. With stirring, 0.10 g of methyl iodide in 0.5 ml of NMP is then added dropwise. The reaction mixture is stirred for 2 hours at 22° C. and then partitioned between 20 ml of water and diethyl ether. The separated ethereal phase is washed with brine, dried over sodium sulfate, filtered and concentrated to dryness by evaporation in vacuo. 0.13 g of the desired crude product is obtained in the form of a yellow oil which, after purification by means of flash chromatography (silica gel; eluant: n-hexane/ethyl acetate 1/1 (v/v)), yields 0.08 g of pure product in the form of a colourless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(O)[CH3:14])[C:7]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:6]=3[C:5]=2[CH:4]=1.C(N(S(F)(F)[F:33])CC)C>C(Cl)Cl>[F:33][C:13]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:14])[CH2:12][N:8]1[C:9]2[CH:10]=[CH:11][C:3]([CH2:2][OH:1])=[CH:4][C:5]=2[C:6]2[CH2:25][N:24]([CH3:26])[CH2:23][CH2:22][C:7]1=2
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1CCc2c(c3cc(CO)ccc3n2CC(C)(O)c2cccnc2)C1
Solvent: ClCCl
Product: CN1CCc2c(c3cc(CO)ccc3n2CC(C)(F)c2cccnc2)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 2 %

Procedure:
1-(8-Hydroxymethyl-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol (700 mg, 1.99 mmol) was dissolved in 70 mL DCM and cooled to 0° C. Diethylaminosulfur trifluoride (800 mg, 4.9 mmol) in DCM (5 mL) was added dropwise at the same temperature and stirred for 45 min. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with saturated bicarbonate and extracted with DCM. The organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 14 mg of [5-(2-fluoro-2-pyridin-3-yl-propyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl]-methanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.6 (s, 1H), 8.57 (d, 1H), 7.6 (d, 1H), 7.35 (s, 1H), 7.2 (m, 1H), 7.125 (m, 2H), 4.72 (s, 2H), 4.3 (m, 2H), 3.6 (q, 2H), 2.8 (m, 1H), 2.7 (dd, 2H), 2.6 (m, 1H), 2.52 (s, 3H), 1.75 (d, 3H). Separation by chiral HPLC provides enantiomers II-213a-b.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[N:18]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[N:17]=[C:16]([CH2:24][CH3:25])[C:14]=2[N:15]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:9][C:10]1[N:11]=[C:12]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)[C:13]2[N:18]([CH2:19][CH2:20][O:21][CH2:22][CH3:23])[N:17]=[C:16]([CH2:24][CH3:25])[C:14]=2[N:15]=1
Reactant: CCOCCn1nc(CC)c2nc(Cl)nc(Cl)c21
Reactant: Cc1ccnc(N)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CCOCCn1nc(CC)c2nc(Cl)nc(Nc3cc(C)ccn3)c21
Temperature: 0 °C
Yield: 97 %

Procedure:
A mixture of 2-amino-4-picoline (4.32 g, 40 mmol) and 5,7-dichloro-1-(2-ethoxyethyl)-3-ethyl-1H-pyrazolo[4,3-d]pyrimidine from step 4 (5.78 g, 20 mmol) was treated with THF (25 mL) and cooled to 0° C. The mixture was stirred and treated with 1 M LiN(TMS)2 in THF (40 mL, 40 mmol) at a rate such that the temperature was kept below 5° C. The mixture was stirred for 30 min and was then treated with 10% citric acid solution until pH 6-7 was achieved. The mixture was partially concentrated under reduced pressure. The mixture was then stirred at 5° C. for 1 h. The resulting solid was collected by suction filtration and washed with water (40 mL). The solid was dried in a vacuum oven at a temperature less than 60° C. to afford 7.0 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:20](=O)[CH3:21])[CH2:6][C:7](=O)[CH2:8][C@@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])C.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([CH3:32])[CH:26]=1.O>C(O)(=O)C>[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([N:29]2[C:7]([CH2:8][C@@H:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH3:10])=[CH:6][C:5]([C:4]([OH:3])=[O:23])=[C:20]2[CH3:21])=[C:27]([CH3:32])[CH:26]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: CCOC(=O)C(CC(=O)C[C@H](C)OCc1ccccc1)C(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1-n1c(C[C@H](C)OCc2ccccc2)cc(C(=O)O)c1C
Temperature: 110 °C
Reaction time: 15 h
Yield: 74.1 %

Procedure:
To a solution of (6S)-2-acetyl-6-(benzyloxy)-4-oxoheptanoic acid ethyl ester (2.5 g, 7.8 mmol) in acetic acid (8 ml), 4-chloro-2-methylaniline (1.1 g, 7.8 mmol) was added, and the mixture was stirred at 110° C. for 15 hours. 15 ml of water was poured to the reaction mixture, and after the organic layer was extracted with diethyl ether, it was washed with 1N aqueous sodium hydroxide solution, water, a saturated aqueous ammonium chloride solution and saturated brine, and dried with sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crudely purified by silica gel column chromatography. Subsequently, the product was dissolved in a 5M aqueous sodium hydroxide solution (30 mL) and methanol (40 mL), and the mixture was stirred at 100° C. for 4 hours. After the reaction, 2M hydrochloric acid (80 mL) was added under ice-cooling to neutralize it, and it was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine and dried with sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.3 g, 73%).
Reaction SMILES: [CH:1]([O-:3])=O.[NH4+].[C:5]1([CH2:11][N:12]2C(=O)C(C(C)C)[N:14](C)[S:13]2(=[O:23])=[O:22])C=CC=[CH:7][CH:6]=1>CO.[Pd]>[CH2:5]([CH:11]1[NH:12][S:13](=[O:23])(=[O:22])[NH:14][C:1]1=[O:3])[CH2:6][CH3:7]
Reactant: O=C[O-]
Reactant: CC(C)C1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: CCCC1NS(=O)(=O)NC1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a suspension of 3.5 g of 10% Pd/C in 150 ml of methanol containing ammonium formate (15 g) was added a solution of 2-phenylmethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (7.1 g) in 50 ml of methanol. The mixture was stirred at room temperature for 7 hours, filtered through a pad of CELITE® and the residue was washed with methanol. The combined filtrate was concentrated in vacuo to afford 4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide 2-ammonium salt (Formula IV: R1 =H; R2 =isopropyl; R3 =CH3 ; as ammonium salt).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]#[N:14])=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:15]I>C1C=CC=CC=1.[OH-].[Na+].[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][N:11]1[CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([C:13]#[N:14])=[CH:10]1
Reactant: CI
Reactant: Cc1ccc(-c2c[nH]cc2C#N)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(-c2cn(C)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
To a solution of 4-(4-methylphenyl)pyrrole-3-carbonitrile (2.0 g) in a mixture of benzene (40 ml) and 50% aqueous sodium hydroxide solution (10 ml) was added methyliodide (1.56 g) and tetrabutylammonium iodide (4.06 g) in that order in an ice bath. The mixture was stirred for 3 hours at ambient temperature and extracted twice with diethyl ether. The combined organic layers were washed with aqueous hydrochloric acid and then water, dried, and concentrated in vacuo to yield 1-methyl-4-(4-methylphenyl)pyrrole-3-carbonitrile (2.03 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:13][CH:12]=1
Reactant: Cc1ccc(N)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1ccc(N)c(-c2ccc(Cl)cc2)c1

Procedure:
2-bromo-4-methylaniline and 4-chlorobenzene boronic acid were combined to form 2-(4-chlorophenyl)-4-methylaniline,
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:12]=[C:13]([C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Product: CCOC(=O)c1ccc(-c2coc(-c3ccc(Cl)cc3)n2)cc1
Yield: 49 %

Procedure:
In the same manner as in Example 1, 4-chlorobenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(4-chlorophenyl)-4-oxazolyl)benzoate. The product was recrystallized from ethanol. Yield: 49%. Pale yellow prisms. Melting Point: 153 to 154° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH:28][CH2:29][CH2:30][CH3:31])[CH2:26][CH3:27]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([CH2:21][N:28]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:26][CH3:27])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3nc(CCl)co3)ncn2-c2cccc(Cl)c2C1=O
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1coc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 34.2 %

Procedure:
0.30 g (0.00082 mol) of 7-chloro-3-(4-chloromethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one was dissolved in 40 ml of tetrahydrofuran, treated with 2.3 ml (0.01 65 mol) of dipropylamine and boiled at reflux for 20 hrs. The solution was completely freed from the solvents, the residue was chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent and recrystallized from ethyl acetate/n-hexane. There was obtained 0.12 g (34%) of 7-chloro-3-(4-dipropylaminomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 105°-107°.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH2:10][CH2:9]1)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH:23]1[C:24]2[C:20](=[CH:19][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:8]([NH:7][CH3:6])[CH2:9][CH2:10]3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc3[nH]ccc3c2)c2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CNC1CCN(c2ccc3[nH]ccc3c2)c2ccccc21
Temperature: 0 °C
Yield: 5.4 %

Procedure:
[1-(1H-Indol-5-yl)-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic acid tert-butyl ester (1.2 g, 4.3 mmol) was dissolved in 30 mL THF and the mixture was cooled to 0° C. Lithium aluminum hydride (0.70 g, 4.6 mmol) suspended in 5 mL THF was added, and the mixture was warmed to room temperature with stirring, and then heated to reflux for three hours. The mixture was cooled room temperature, diluted with THF (25 mL), and then cooled to 0° C. Hydrous sodium sulfate (36 g) was slowly added with stirring, and the mixture was stirred for 30 minutes, then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (methylene chloride/methanol/ammonium hydroxide 90:9:1) to give 0.064 g of [1-(1H-indol-5-yl)-1,2,3,4-tetrahydro-quinolin-4-yl]-methyl-amine, MS (M+H)=278.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[C:7]2[C:12](=O)[CH:11]3[CH2:14][CH2:15][N:8]2[CH2:9][CH2:10]3)=[CH:4][CH:3]=1.[OH-].[K+].O.[NH2:21][NH2:22]>C(O)CO>[NH:8]1[CH2:15][CH2:14][CH:11]([C:12]2[CH:7]=[C:6]([C:5]3[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:22][N:21]=2)[CH2:10][CH2:9]1
Reactant: O=C1C(=Cc2ccc(Cl)cc2)N2CCC1CC2
Reactant: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Clc1ccc(-c2cc(C3CCNCC3)n[nH]2)cc1
Temperature: 110 °C
Yield: 85 %

Procedure:
A mixture of 2-(4-chlorobenzylidene)quinuclidin-3-one (35.0 g), potassium hydroxide (15.0 g) and hydrazine hydrate (11.0 cm3) in ethylene glycol(100 cm3) was heated at 110° C. for 15 minutes to produce a dear, dark brown solution. Hydrazine hydrate and water were distilled from the solution over 1 hour at 110° C. to 195° C. The brown solution was then heated at reflux for 3 hours. The mixture was cooled to room temperature and diluted with water (300 cm3). The resulting white precipitate was collected and washed with water (500 cm3) and ethyl acetate (200 cm3). The white powder was dried in vacuo to give the title compound (31.5 g, 85%), m.p. 174°-176° C.; δH (250 MHz; d6 -DMSO) 1.52 (2H, apparent qd, J=12 and 4, 2×NCH2CHAHB), 1.85 (2H, apparent d, J=10, 2×NCH2CHAHB), 2.56 (2H, apparent td, J=12 and 2, 2×NCHAHB), 2.71 [1H, tt, J=8.1 and 4.5, (CH2)2CH], 2.99 (2H, apparent d, J=12.1, 2×NCHAHB), 6.48 (1H, s, N=C--CH=C), 7.44 (2H, d, J=8.6, 2×ArH o to Cl; and 7.79 (2H, d, J=8.6, 2×ArH m to Cl); δC (90 MHz; d6 -DMSO) 39.9 (t), 34.2 (d), 46.2 (t), 98.9 (d), 126.8 (d), 128.7 (d), 131.7 (s), 132.4 (broad, s), 147.5 (broad, s) and 151.1 (broad, s); m/z (CI+, NH3) 262 (M+ +H; 60%) and 139 (100).
Reaction SMILES: [CH2:1]1[CH2:5][C:4]2([CH2:12][C:10](=[O:11])[NH:9][C:7](=[O:8])[CH2:6]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:24][CH2:23]1>CN(C)C=O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][N:9]2[C:7](=[O:8])[CH2:6][C:4]3([CH2:5][CH2:1][CH2:2][CH2:3]3)[CH2:12][C:10]2=[O:11])[CH2:27][CH2:26]1
Reactant: Fc1ccccc1N1CCN(CCCl)CC1
Reactant: O=C1CC2(CCCC2)CC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CC2(CCCC2)CC(=O)N1CCN1CCN(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A mixture of 3,3-tetramethylene glutarimide (6.9 mg) and potassium carbonate (40 mg) in dimethylformamide (0.5 mL) was stirred at room temperature for 30 minutes. 1-(2-Chloroethyl)-4-(2-fluorophenyl)piperazine (10.0 mg) was added and the resulting solution was heated at 120° C. for 3 hours. The solvent was removed and the residue was purified by thin-layer chomatography (silica gel, eluting with hexane/ethyl acetate, 1:1), giving the title compound as a white solid (6.2 mg, 40%). 1H NMR (300 MHz, CDCl13) δ7.07-6.87 (m, 4H), 3.96 (t, 2H, J=6.6 Hz), 3.05 (t, 4H, J=4.8 Hz), 2.67 (t, 4H, J=4.7 Hz), 2.59 (s, 4H), 2.54 (t, 4H, J=6.6 Hz), 1.73-1.68 (m, 4H), 1.55-1.50 (m, 4H). ESI-MS m/z 374 (MH+).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH2:8]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]2[CH:20]=1)[CH2:9][C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.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>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([C:11]#[C:10][CH2:9][CH2:8][C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[CH:20]=2)[N:3]=1
Reactant: Cc1nc(I)cs1
Reactant: C#CCCc1cn2ccccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1nc(C#CCCc2cn3ccccc3n2)cs1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (6.5 mg, 0.03 mmol) and triethylamine (2.33 mL, 13.60 mmol), were added 4-iodo-2-methylthiazole (150 mg, 0.68 mmol) and Pd(PPh3)2Cl2 (39 mg, 0.03 mmol) under N2. A yellow suspension is obtained and after a few minutes of stirring at room temperature, was added a solution 2-(but-3-ynyl)-imidazo[1,2-a]pyridine (115 mg, 0.68 mmol) in triethylamine (0.5 mL) under N2. Immediately the color of the reaction times to black. The mixture was stirred at room temperature for 4 h and 50° C. overnight under N2. Triethylamine was removed under reduce pressure. The crude product was purified by flash chromatography (Prepacked 25 g silicagel column from DCM/MeOH: 100/0 to 97/3 as eluent) to afford 25 mg of 2-(4-(2-methylthiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine (Yield: 14%) as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[N:15]=[N+:16]=[N-:17].C(N(C(C)C)CC)(C)C.[Cl:27][C:28]1[N:29]=[C:30]([C:35](Cl)=[O:36])[NH:31][C:32]=1[CH2:33][CH3:34]>ClCCl>[N:15]([C@H:3]1[C@@H:2]([NH:1][C:35]([C:30]2[NH:31][C:32]([CH2:33][CH3:34])=[C:28]([Cl:27])[N:29]=2)=[O:36])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1)=[N+:16]=[N-:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](N=[N+]=[N-])C1
Reactant: CCc1[nH]c(C(=O)Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])nc1Cl
Reaction time: 2.5 h
Yield: 78.4 %

Procedure:
tert-Butyl cis(±)-4-amino-3-azidopiperidine-1-carboxylate obtained in Example (81a) (about 0.29 mmol) was dissolved in dichloromethane (4 mL). Diisopropylethylamine (0.2 mL, 1.15 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carbonyl chloride obtained in Example (81b) (about 0.29 mmol) were added, followed by stirring for 2.5 hours. Dichloromethane was added to the reaction solution, and the organic layer was washed with 1 N hydrochloric acid, a 1 N aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=90/10, 70/30, 55/45) to obtain 90.4 mg of the title compound (78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36]([O:42][CH:43](Cl)[CH3:44])(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]>CN(C=O)C.CCOC(C)=O>[C:36]([O:42][CH:43]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH3:44])(=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCC(=O)OC(C)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(=O)OC(C)n1cc(C(=O)c2c(F)ccc(NS(=O)(=O)CCC)c2F)c2cc(-c3ccc(Cl)cc3)cnc21
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a suspension of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.3 g, 0.61 mmol) in anhydrous DMF (2.5 mL) was added KOH (69 mg, 1.23 mmol). The reaction was stirred at 10° C. for 30 min, followed by adding a solution of 1-chloroethyl pentanoate (0.1 g, 0.61 mmol) in anhydrous DMF (0.5 mL) dropwise over 30 min. The mixture was stirred at 10° C. for another 16 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=7/1) to give the crude product. The crude product was recrystallized in PE/EtOAc (10/1) to give the title compound as a white solid (0.14 g, 37.8%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][CH:7]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])[CH:10]([CH3:16])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C(=O)Nc1cccc(F)c1
Solvent: C1CCOC1
Product: CC(C(=O)O)C(=O)Nc1cccc(F)c1

Procedure:
Prepared according to Procedure B using ethyl 3-(3-fluorophenylamino)-2-methyl-3-oxopropanoate (21.0 g, 87.8 mmol) in THF (80 mL) to give 3-(3-fluorophenylamino)-2-methyl-3-oxopropanoic acid as a white solid. Mass Spectrum (ESI) m/e=212.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]2[N:14]=[N:15][C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:18]=2)=O)=[CH:4][CH:3]=1.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=CC=CC=1C1C(C2C=CC(Cl)=CC=2)=CC2N(C(CC3CCCCC3)=NN=2)N=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:14]3[N:15]=[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])[C:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:18][C:13]3=[N:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1
Agent: Clc1ccc(-c2cc3nnc(CC4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)cc1
Yield: 53.7 %

Procedure:
The title compound (50 mg, 54%) as a white powder was prepared from 2-(4-chlorophenyl)-N′-(6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3-yl)acetohydrazide (96 mg, 0.2 mmol) and triphenylphosphine dichloride (220 mg,0.66 mmol) according to the procedures described for 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(cyclohexylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine (Example 7B). HPLC/MS (method A): retention time=4.12 min, (M+H)+=465.2.