Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[N:18]([CH2:19][CH2:20][NH2:21])[CH:13]([CH2:14][CH2:15]2)[CH:12]=1.Br[C:23]1[CH:24]=[C:25]([O:33][CH3:34])[CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][CH:29]=[CH:28]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:34][O:33][C:25]1[CH:26]=[C:27]2[C:32](=[C:23]([NH:21][CH2:20][CH2:19][N:18]3[CH:16]4[CH2:15][CH2:14][CH:13]3[CH:12]=[C:11]([C:2]3[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=3)[CH2:17]4)[CH:24]=1)[N:31]=[CH:30][CH:29]=[CH:28]2
Reactant: NCCN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Reactant: COc1cc(Br)c2ncccc2c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(NCCN2C3C=C(c4ccc5ccccc5c4)CC2CC3)c2ncccc2c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A mixture of 0.17 g, (0.61 mmol) 2-[3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethylamine, 0.13 g (0.55 mmol) 8-bromo-6-methoxyquinoline, 30 mg (0.03 mmol) Pd2(dba)3, 20 mg (0.08 mmol) 2-(di-t-butylphosphino)biphenyl and 10 mL PhMe is stirred at 23° C. for 16 h. The reaction mixture is poured into 100 mL of H2O and extracted 3×50 mL EtOAc. The combined organics are washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered, and the volatiles are evaporated. The crude product is subjected to flash chromatography on SiO2, eluting with EtOAc to EtOAc/2M NH3 in MeOH (40/1), to give the title compound as an off-white solid. This solid is dissolved in 4 mL of absolute EtOH and treated with 0.01 g (0.14 mmol) (CO2H)2 to give 0.07 g (0.13 mmol, a 23% yield) of the oxalate salt of the title compound as a dark green solid: mp: 179-182 C; MS (ES) m/z 436 (MH)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][CH2:19][C@H:18]([N:22]([CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[C:23]2[N:24]=[N:25][N:26]([CH3:28])[N:27]=2)[C:17]2[CH:44]=[C:45]([CH2:52][CH3:53])[C:46]([C:48]([F:51])([F:50])[F:49])=[CH:47][C:16]1=2)=O)(C)(C)C>ClCCl>[F:42][C:40]([F:41])([F:43])[C:32]1[CH:31]=[C:30]([CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=1)[CH2:29][N:22]([C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1)[C@H:18]1[CH2:19][CH2:20][CH2:21][NH:15][C:16]2[CH:47]=[C:46]([C:48]([F:49])([F:50])[F:51])[C:45]([CH2:52][CH3:53])=[CH:44][C:17]1=2
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
Add trifluoroacetic acid (1 mL) to a solution of (S)-5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid tert-butyl ester (2.04 g, 3.13 mmol) in dichloromethane (1 mL). Stir for 30 minutes at room temperature. Dilute the mixture with dichloromethane (40 mL) and wash with saturated aqueous sodium bicarbonate solution (40 mL). Dry organic layer over anhydrous sodium sulfate and filter. Remove the solvent under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-30%), to provide the title compound (0.318 g, 98%). MS (ES+): 567 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26]([CH3:32])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][C:26]([CH3:32])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Cc1ccc2c(N)cccc2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=Nc1cccc2nc(C)ccc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 175 mg (0.60 mmol) of (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 103 mg (0.63 mmol) of 5-amino-2-methylquinoline and 0.3 ml of titanium tetraethoxide are reacted to give (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 230 mg of resultant crude imine are cyclized in the same way as in Example 1 at −30° C. using 5 ml (5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 135 mg of product.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:12][C:13](=[O:33])[C:14]([OH:32])([CH3:31])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)O)[CH3:11].C([SiH](CC)CC)C>C(Cl)Cl>[CH2:10]([O:12][C:13](=[O:33])[C:14]([OH:32])([CH3:31])[CH2:15][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)[CH3:11]
Reactant: CCOC(=O)C(C)(O)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Boron trifluoride etherate was added to a 0° C. solution of 3-(4-Benzyloxy-phenyl)-2,3-dihydroxy-2-methyl-propionic acid ethyl ester (12.9 g, 38.96 mmol) and triethylsilane (28 mL, 175.3 mmol, d=0.728) in anhydrous CH2Cl2, then the reaction is allowed to gradually warm to ambient temperature over 3 h. The reaction is quenched with a saturated aqueous solution of sodium bicarbonate and extracted with additional CH2Cl2. The organic layer is dried, concentrated, and separated by chiral chromatography to provide the title compound (11.7 g, 96%). 1H NMR (400 MHz, CDCl3): δ 7.44-7.33 (m, 5H), 7.12 (d, 2H, J=6.85 Hz), 6.90 (d, 2H, J=6.85 Hz), 5.04 (s, 2H), 4.22-4.14 (m, 2H), 3.03 (d, 1H, J=13.69 Hz), 2.87 (d, 1H, J=13.69 Hz), 1.48 (s, 3H), 1.27 (t, 3H, J=7.34 Hz). Rf=0.60 in 50% acetone in hexanes.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)[N:10]2[CH2:14][C@@H:13]3[O:15][C:16]4[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=4[O:18][C@H:12]3[CH2:11]2)=CC=1.Cl.O.C(Cl)(Cl)[Cl:37]>C(O)=O>[ClH:37].[N+:23]([C:22]1[C:16]2[O:15][C@@H:13]3[C@H:12]([CH2:11][NH:10][CH2:14]3)[O:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)([O-:25])=[O:24]
Reactant: COc1ccc(C(c2ccc(OC)cc2)N2C[C@@H]3Oc4cccc([N+](=O)[O-])c4O[C@H]3C2)cc1
Reactant: ClC(Cl)Cl
Agent: Cl
Solvent: O
Solvent: O=CO
Product: O=[N+]([O-])c1cccc2c1O[C@H]1CNC[C@@H]1O2

Procedure:
A solution of (±)-(trans)-2-[bis(4-methoxyphenyl)methyl]-2,3,3a,9a-tetrahydro-5-nitro-1H-[1,4]benzodioxino[2,3-c]pyrrole (1.12 g) in formic acid (10 ml) was heated under reflux with 10M hydrochloric acid (0.5 ml), water (1 ml) and chloroform (5 ml) for 70 minutes. The maroon mixture was cooled and partitioned between chloroform (20 ml) and water (10 ml). The chloroform layer was re-extracted with water (10 ml) and the aqueous solutions were sequentially washed with chloroform (20 ml), combined and evaporated to ca. 2 ml, when crystals formed. These were triturated with warm propan-1-ol (5 ml), cooled to 20° for 1 hour and harvested to give a first crop of the title compound (0.58 g). Concentration of the mother liquor gave a small second crop (0.03 g). Recrystallisation of the first crop from slightly aqueous propan-1-ol gave purer title compound (0.54 g) m.p. ca. 280° (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]12[CH2:17]C[CH:15]1[CH2:14][NH:13][CH2:12]2.C(N(CC)CC)C>O1CCOCC1>[CH:15]12[CH2:17][CH:11]1[CH2:12][N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:14]2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CC2CNCC12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CC3CC3C2)nc1
Temperature: 65 °C
Yield: 97.5 %

Procedure:
A mixture of 0.5 g (3.15 mmol) of 2-chloro-5-nitropyridine, 0.452 g (3.78 mmol) of 3-aza-bicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621) and 1.32 mL (6.94 mmol) of triethylamine in 10 mL of dioxane, is heated at 65° C. for 4 h. The reaction mixture is then poured into 50 mL of ice water. The mixture is stirred until the ice has melted completely, then a yellow precipitate is collected by filtration and is dried at reduced pressure. In this way we isolate 0.63 g of the expected product in the form of a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.C([O:15][C:16]([C:18]1[C:27]2[C:26]3[N:28]=[CH:29][N:30]=[CH:31][C:25]=3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=O)C.O>C(Cl)Cl.[NH4+].[Cl-]>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16]([C:18]1[C:27]2[C:26]3[N:28]=[CH:29][N:30]=[CH:31][C:25]=3[CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][CH:19]=1)=[O:15]
Reactant: CCOC(=O)c1c[nH]c2c1-c1ncncc1CCC2
Reactant: Nc1ccccc1F
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccc1F)c1c[nH]c2c1-c1ncncc1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 2-fluoroaniline (108 mg, 0.972 mmol) in CH2Cl2 (2.0 mL) at 0° C. under N2 is slowly added AlMe3 (0.49 mL, 2.0 M in toluene). The resulting solution is stirred at room temperature for 1 h. Next, 3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethyl ester (50 mg, 0.194 mmol) is added in one portion. The resulting mixture is then stirred at reflux for 2 h. After cooling, the reaction mixture is carefully diluted with saturated aq NH4Cl (˜5 mL) and some H2O. The mixture is stirred vigorously for 15 min. and then extracted three times with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 40:1 CHCl3—MeOH followed by 30:1 CHCl3—MeOH and finally 20:1 CHCl3—MeOH afforded 45 mg (72%) of 3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid (2-fluoro-phenyl)-amide as a light yellow solid. Electrospray mass spectrum: m/z 321 [M−1].
Reaction SMILES: [H-].[Na+].[F:3][C:4]([CH3:10])([CH3:9])[C:5](OC)=[O:6].[C:11](#[N:13])[CH3:12].Cl>C1COCC1.O>[F:3][C:4]([CH3:10])([CH3:9])[C:5](=[O:6])[CH2:12][C:11]#[N:13]
Reactant: COC(=O)C(C)(C)F
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(F)C(=O)CC#N
Temperature: 70 °C
Yield: 69.7 %

Procedure:
To a stirred suspension of 60% NaH/mineral oil (12.48 g, 0.31 mol) in dry THF at 75° C. was added dropwise methyl 2-fluoro-2-methylpropanoate (24 g, 0.2 mol) in dry acetonitrile (16 mL, 0.31 mol) over the course of 45 min. The resulting pale yellow suspension was heated at 70° C. overnight, whereupon analysis by TLC indicated a single new product. After cooling to rt, the mixture was poured into water, acidified to pH˜2 with 2N HCl, and extracted with diethyl ether (1 L). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-30% EtOAc in petroleum ether to afford 4-fluoro-4-methyl-3-oxopentanenitrile as a colorless oil (18 g, 72% yield). LC-MS (ESI) m/z 128 (M−H)+.
Reaction SMILES: [NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1.[CH:37](=O)[CH3:38].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:33]([Cl:34])=[CH:32][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:37][CH3:38])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc([N+](=O)[O-])cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-(4-nitrobenzylamino)pentyl)-piperidin-4-yl)methyl)benzamide (1.5 g) as starting compound, acetaldehyde (0.21 ml) and sodium cyanoborohydride (0.24 g) were reacted and treated in the same manner as in Example 136 to give 0.6 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(4-nitrobenzyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][C@H:3]1[C:6]([O:8][CH3:9])=[O:7].[C:10]1([CH2:16][S:17](Cl)(=[O:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:9][O:8][C:6]([C@@H:3]1[CH2:4][CH2:5][N:2]1[S:17]([CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:19])=[O:18])=[O:7]
Reactant: COC(=O)[C@@H]1CCN1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCN1S(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
(2S)-Methyl azetidine-2-carboxylate hydrochloride from Reference Example 1 (361.4 mg, 2.26 mmol, 1.0 eq) was dissolved in dry dichloromethane (10.0 mL) and treated with α-toluenesulfonyl chloride (458.1 mg, 2.40 mmol, 1.1 eq). After cooling to about 0° C. under argon atmosphere, diisopropylethylamine (420 μL, 2.41 mmol, 1.1 eq) was added and the reaction mixture was stirred at about room temperature overnight. The solvent was evaporated and the residue was subjected to flash chromatography (in dichloromethane) to give 431.2 mg (71 % yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 2.29-2.51 (m, 2H); 3.21-3.29 (m,1H); 3.81 (s, 3H); 4.02 (q,1H, J=8.6); 4.32 (d, 1H, J=9.4, 6.9); 4.46 (d, 1H, J=14.6); 4.86 (dd, 1H, J=9.4, 6.9); 7.34-7.43 (m, 3H); 7.46-7.54 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:16](Cl)=[O:17].CCN(C(C)C)C(C)C.[N:28]1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][CH:35]=2)[S:30][C:29]=1[C:37]1[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=1[NH2:39]>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:16]([NH:39][C:38]1[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=1[C:29]1[S:30][C:31]2[C:36]([N:28]=1)=[CH:35][CH:34]=[CH:33][N:32]=2)=[O:17]
Reactant: Nc1ccccc1-c1nc2cccnc2s1
Reactant: O=C(Cl)c1nc(-c2ccccc2)sc1CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccccc1-c1nc2cccnc2s1)c1nc(-c2ccccc2)sc1CCCCl
Reaction time: 16 h
Yield: 26 %

Procedure:
A suspension of 5-(3-chloropropyl)-2-phenylthiazole-4-carbonyl chloride (906 mg, 3.2 mmol), DIPEA (1.1 mL, 6.4 mmol), and 2-(thiazolo[5,4-b]pyridin-2-yl)aniline b (585 mg, 2.6 mmol) in CH3CN (12 mL) was stirred for 16 h. The resulting ppt was collected by filtration, rinsed with CH3CN and dried. The crude product was purified by MPLC eluting with DCM/MeOH (0-5% gradient) to give 5-(3-chloropropyl)-2-phenyl-N-(2-(thiazolo[5,4-b]pyridin-2-yl)phenyl)thiazole-4-carboxamide (316 mg, 26% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:26]([C:27]([OH:29])=[O:28])=[C:16]3[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[O:19][C:15]3=[CH:14][CH:13]=2)[N:4]=1.[C:30]([O:36][CH2:37]Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:26]([C:27]([O:29][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28])=[C:16]3[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:20])[O:19][C:15]3=[CH:14][CH:13]=2)[N:6]=1
Reactant: CCOC(=O)c1c(C)oc2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)O)c12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)oc2ccc(Oc3nc(OC)cc(OC)n3)c(C(=O)OCOC(=O)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.7 %

Procedure:
A mixture comprising 0.40 g of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-3-ethoxycarbonyl-2-methylbenzofuran-4-carboxylic acid, 0.26 g of chloromethyl pivalate and 0.21 g of potassium carbonate in 20 ml of N,N-dimethylformamide, was stirred at room temperature for 6 hours, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 0.43 g (yield: 84%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:10][C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.[B].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48]Cl)=[CH:46][CH:45]=1>CN(C)C=O>[F:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][N:10]2[C:11]3[C:12](=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:16]=3)[N:23]=[C:9]2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:46][CH:45]=1
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3[nH]2)c1
Reactant: Fc1ccc(CCl)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: [B]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of 2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (Compound of Example 1) (80 mg), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine resin (PS-BEMP, 2.2 mmol/g) (181 mg) and N,N-dimethyl formamide (3.2 ml) was shaken at room temperature for 1 hour. To the mixture was added 4-fluorobenzyl chloride (46 mg), and the mixture was further shaken at room temperature for 15 hours. The resin was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to a preparative HPLC, and the desired fraction was concentrated. The concentrate was distributed into dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic layer was filtered by means of a PTFE filter tube, and concentrated under reduced pressure to obtain 1-(4-fluorobenzyl)-2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridine (84 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:10]=[C:11](O)[C:12]2[CH2:18][N:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=3)[CH2:16][CH2:15][C:13]=2[N:14]=1.[Cl-].[Cl:30]C(=[N+](C)C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:30][C:11]1[C:12]2[CH2:18][N:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[CH:20]=3)[CH2:16][CH2:15][C:13]=2[N:14]=[C:9]([C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:10]=1
Reactant: CC(Cl)=[N+](C)C
Reactant: Cc1cccc(C)c1-c1nc(O)c2c(n1)CCN(c1cc(C(C)C)nn1C)C2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(C)c1-c1nc(Cl)c2c(n1)CCN(c1cc(C(C)C)nn1C)C2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (2.38 g, 6.3 mmol) in DCM (50 mL) at 0° C., was added (1-chloro-ethylidene)-dimethylammonium chloride (Vilsmeier reagent) (2.421 g, 18.91 mmol). The reaction was stirred at 0° C. for 5 min, then at r.t. for 30 min. Saturated aqueous NaHCO3 was added to quench the reaction. The mixture was extracted with DCM three times. The combined organic layers was dried over Na2SO4. After filtration and concentration, the resulting residue was purified via silica gel FCC (0-100% EtOAc/heptane) to give 4-chloro-2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, CD2Cl2) δ ppm 7.19-7.27 (m, 1 H), 7.11 (d, J=7.6 Hz, 2 H), 5.80 (s, 1 H), 4.16 (s, 2 H), 3.72 (s, 3 H), 3.32 (t, J=5.9 Hz, 2 H), 3.16 (t, J=5.8 Hz, 2 H), 2.88 (dt, J=13.9, 6.9 Hz, 1 H), 2.11 (s, 6 H), 1.23 (d, J=6.8 Hz, 6 H). MS (ESI+) m/z 396.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1.[O-:27]P([O-])([O-])=O.[K+].[K+].[K+]>O.[Pd]>[OH:27][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1
Reactant: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(Br)cnc23)C1
Reactant: O=P([O-])([O-])[O-]
Agent: [Pd]
Agent: [K+]
Solvent: O
Product: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(O)cnc23)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 1-[(6-bromo-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 186 (24 mmol, 1 eq, 10 g) in 100 ml of water are added successively palladium on activated carbon (10%, 1.2 mmol, 0.05 eq, 1.2 g) and K3PO4 (48 mmol, 2 eq, 10.25 g). The mixture is degassed and stirred vigorously at 130° C. for 8 hours. After cooling to room temperature, the reaction mixture is filtered on celite and a 5 N hydrochloric acid solution (10 ml) is added (until pH 7). The water is removed under reduce pressure and the crude is triturated with hot THF. After filtration and evaporation of THF, 1-[(6-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one x149 is obtained (1.9 g).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH:10]1[O:12][CH2:11]1.C(N(CC)CC)C>CO>[Br:8][CH2:9][CH:10]([OH:12])[CH2:11][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: Sc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: OC(CBr)CSc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophenol, 11.0 g (0.10 mole), was added dropwise over a period of one hour, to a cold (0° C.) mixture of 13.69 g [8.5 ml (0.1 mole)] 1-bromo-2,3-epoxypropane (epibromohydrin), 1.5 ml [1.09 g (0.02 moles)] triethylamine and 1.5 ml methanol. The reaction mixture was then allowed to come to room temperature and was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in ether, washed several times with water and once with brine. The organic phase was dried over magnesium sulfate, filtered and concentrated to give 22.7 g of the above-identified product as an amber oil.