Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[N:21]=[C:20]1[CH2:28][CH2:29][CH2:30][CH3:31])C1C=CC=CC=1.CC[OH:34]>[Pd]>[CH2:28]([C:20]1[N:19]([C:10]2[CH:9]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([OH:34])=[CH:15]3)[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[N:21]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCO
Reactant: CCCCc1nc2cccnc2n1-c1c(OCc2ccccc2)ccc2ccccc12
Agent: [Pd]
Product: CCCCc1nc2cccnc2n1-c1cccc2cc(O)ccc12
Reaction time: 72 h

Procedure:
A solution of 3-(benzyloxy-naphthalen-1-yl)-2-butyl-3H-imidazo[4,5-b]-pyridine (1500 g) in EtOH (75 mL) was added to a mixture of Pd/C (3.56 g) in EtOH (50 mL). The mixture was hydrogenated on a paar shaker at 50 psi for 72 hours. The reaction mixture was filtered through celite and concentrated in vacuo to give 1.13 grams of an amorphous solid. 1H NMR (250 MHz, CDCl3): d 8.48 (d, 1 H), 8.24 (d, 1 H), 7.52 (m), 7.37 (dd, 1 H), 7.26 (d, 2 H), 6.68 (dd, 2 H), 6.60 (s, 1 H), 2.67 (t, 2 H), 170 (m, 2 H), 1.23 (m, 2 H), 0.78 (t, 3 H).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.O>CS(C)=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][C:8]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16]
Reactant: [C-]#N
Reactant: Fc1ccc(CBr)cc1OCC(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(F)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
900 mg (13.8 mmol) of KCN were added to a solution of 3.3 g (11.5 mmol) of 4-bromomethyl-1-fluoro-2-(2,2,2-trifluoro-ethoxy)-benzene in 30 ml of dry dimethylsulfoxide. The reaction mixture was stirred for 1 hour at room temperature. Water was added and the product was extracted with diethyl ether. The solvent was removed under vacuum and the crude residue was purified by flash chromatography (hexane/ethyl acetate 8:2 v:v). 1.4 g (52% yield) of the title compound were isolated as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][C:10]=1[O:18][CH3:19])C1C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[NH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:18][CH3:19])[CH:11]=1
Reactant: [H][H]
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(CCN)ccc1O

Procedure:
0.5 g of palladium on charcoal (10%) were added to 5 g (19.5 mmol) of 2-[4-(benzyloxy)-3-methoxyphenyl]ethylamine [cf.: Heterocycles, Vol. 28, 297-298 (1989)] in 100 ml of tetrahydrofuran and the mixture was hydrogenated under atmospheric pressure. After the uptake of hydrogen had ended, the mixture was filtered and the filtrate was freed from the solvent.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.N1C=CC=CC=1>Cl>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The product from (e) (2 g) was heated with pyridine hydrochloride (20 g) at 170°-180° C. for 6 hours. The mixture was cooled, diluted with dilute hydrochloric acid, and extracted with ether. The ether extracts gave an oily solid which was purified by preparative thin layer chromatography using silica as the adsorbent and 6% ethanol-chloroform as the solvent.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:5][C:4]=2[N:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[C:31]([N:28]1[CH2:29][CH2:30][CH:25]([O:24][C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:13]([CH2:20][O:21][CH2:22][CH3:23])=[N:12][C:11]=4[C:2]([NH2:1])=[N:3][C:4]=3[CH:5]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:32]
Reactant: CCOCc1nc2c(N)nc3cc(OC4CCNCC4)ccc3c2n1CC(C)(C)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OC4CCN(C(C)=O)CC4)ccc3c2n1CC(C)(C)O
Reaction time: 16 h

Procedure:
1-[4-Amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (from Part A) was slurried in dichloromethane (11 mL). Acetic anhydride (0.105 mL, 1.03 mmol) was added and the reaction was stirred for 16 hours. The reaction mixture was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-25% CMA in chloroform). The resulting solid was covered with diethyl ether for one week. Filtration of the solid provided 0.130 g of 1-[7-[(1-acetylpiperidin-4-yl)oxy]-4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as red-tan crystals, mp 162-164° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)[CH:7]=1>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCCC1>[C:8]12([C:6]3[CH:7]=[C:2]([C:2]4[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([C:8]56[CH2:9][CH:10]7[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]7)[CH2:17]5)[CH2:15]6)[CH:7]=4)[CH:3]=[CH:4][C:5]=3[O:18][CH3:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2
Reactant: COc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 79.9 %

Procedure:
Next, 0.03 g of Pd(OAc)2 and 3.5 g of 1-(5-bromo-2-methoxyphenyl) adamantane were added to the mixture, followed by 25 mL of tetrahydrofuran in order to improve agitation, and the mixture was heated at reflux for approximately 24 hours. The resulting mixture was then evaporated to dryness and poured into 103 mL of 0.015 N HCl. Next, 150 mL of dichloromethane and 100 mL of water were added to yield a mixture consisting of a solid, an aqueous layer and an organic layer. The mixture was then filtered to separate the solid, the aqueous layer was discarded, and the organic layer was washed with 200 mL of water and decanted again. This process was repeated twice on the filtered solid. The three collected organic layers were evaporated to dryness, washed in methanol, and dried to yield 2.1 g of 3,3′-diadamantyl-4,4′-dimethoxybiphenyl (yield: 39.9%). Analytical data: Melting point: 288.1-289.1° C.; Elemental analysis: C 83.63%, H 8.73%; 1H-NMR (300 MHz, CDCl3): δ 1.78 (broad s, 12H), 2.08 (broad s, 6H), 2.15 (broad s, 12H), 3.86 (s, 6H), 6.92 (dm, 2H, J=8.1 Hz), 7.34 (dd, 2H, J=2.4, 8.1 Hz), 7.39 (d, 2H, J=2.4 Hz); 13C-NMR (75.4 MHz, CDCl3): δ 29.2, 37.1, 37.2, 40.6, 55.1, 111.9, 125.0, 125.5, 134.0, 138.5, 157.8; MS (EI, 70 eV): m/z=484 (6), 483 (36), 412 (1,100), 410 (5), 347 (8), 135 (22), 107 (7), 93 (14), 79 (17), 67 (9), 55 (6); IR (Selected absorption bands): 2992, 2964, 2898, 2850, 1603 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)=[O:6]>[Pd].CO>[NH2:18][C:17]1[CH:16]=[CH:15][C:4]([C:5]([NH:7][CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Reaction time: 16 h

Procedure:
3-chloro-N-(1-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 80; 270 mg, 1 mmol), 10% Palladium on Carbon (30 mg) and Methanol (50 mL) were combined and stirred at 25 )C under Hydrogen at 5 bar pressure for 16 hours.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][N:26]=[C:25]([CH3:28])[C:24]=2[CH:29]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]3[O:27][N:26]=[C:25]([CH3:28])[C:24]=3[CH:29]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1noc2ccc(N)cc12
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc2onc(C)c2c1
Reaction time: 0.08 h
Yield: 48.4 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (128 mg, 0.567 mmol) in dichloromethane (3 mL) was added pyridine (110 μL, 1.35 mmol) and the mixture was stirred under N2 for 5 min, after which time 5-amino-3-methyl-1,2-benzisoxazole [26] (80 mg, 0.54 mmol) was added. The resulting mixture was stirred for 4 h at, room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (88 mg, 48%), single spot at Rf 0.58 (1:1 hexane:ethyl acetate). mp 162.8-163.2° C., HPLC purity 99+% (tR 2.26 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.80 (1H, dd, J=7.9, 1.3 Hz), 7.55 (1H, dd, J=8.1, 1.1 Hz), 7.38 (2H, m), 7.17 (1H, t, J=8.1 Hz), 7.10 (1H, dd, J=8.8, 2.2 Hz), 6.72 (1H, s, N−H), 2.72 (3H, s), 2.50 (3H, s). LCMS: 320.00 (M−CH3). FAB-MS (MH+, C15H13ClN2O3S): calcd 337.0413, found 337.0422.
Reaction SMILES: [CH3:1][CH:2](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)[N:11]=2)=[CH:6][CH:5]=1.[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C=O)C>[N:38]([CH:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][C:21]([CH3:23])([CH3:24])[NH:20][C:19]([CH3:25])([CH3:26])[CH2:18]3)[N:11]=2)=[CH:6][CH:5]=1)=[N+:39]=[N-:40]
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1)N=[N+]=[N-]

Procedure:
The title compound was prepared from toluene-4-sulfonic acid 1-methyl-2-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-ethyl ester and sodium azide in DMF.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(=O)C)[CH2:14][C@H:13]2[CH2:21][CH2:22][O:23]C(=O)C)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:21][CH2:22][OH:23])=[O:11])=[CH:27][CH:28]=1)([O-:3])=[O:2]
Reactant: CC(=O)OCC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CCO
Reaction time: 0.5 h

Procedure:
(2R,4S)-1-p-Nitrobenzyloxycarbonyl-2-(2-acetoxyethyl)-4-acetylthiopyrrolidine (204 mg) was dissolved in 5 ml of methanol and 1 ml of 1N sodium hydroxide solution was added thereto at room temperature under nitrogen stream, followed by stirring for 30 minutes. 1H Hydrochloric acid (1.2 ml) was added to the reaction mixture. The resulting mixture was diluted with ethyl acetate, washed with brine five times, dried over anhydrous sodium sulfate and evaporated to give an oily residue, which was purified by silica gel thin layer chromatogaraphy to give (2R,4S)-1-p-nitrobenzyloxycarbonyl-2-(2-hydroxyethyl)-4-mercaptopyrrolidine.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:59][CH3:60])=[C:53]([CH3:58])[CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:59][CH3:60])=[C:53]([CH3:58])[CH:54]=4)[O:49][C:48]=3[C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1C
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)c(=O)c2cc1C
Yield: 91.8 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(7-methoxy-6-methyl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (46 mg, 0.090 mmol) was reacted to give the title compound (34 mg, 92%). LCMS (Method E): RT=3.85 min, [M+H]+=412. 1H NMR (400 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.38-7.25 (m, 7H), 7.18 (s, 1H), 7.05 (d, J=9.6 Hz, 2H), 3.90 (s, 3H), 2.35-2.26 (m, 2H), 2.25-2.10 (m, 5H), 2.06-1.87 (m, 3H), 1.64-1.53 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([S:10]([C:13]([CH3:21])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[N:22]1[C:26]2=[N:27][C:28]([CH2:33][OH:34])=[CH:29][C:30]([O:31][CH3:32])=[C:25]2[NH:24][C:23]1=[O:35].CN(C)C=[O:39]>C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[C:33]([C:28]1[N:27]=[C:26]2[N:22]([C:3]3[CH:4]=[C:5]([S:10]([C:13]([CH3:21])([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH3:14])(=[O:12])=[O:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])[C:23](=[O:35])[NH:24][C:25]2=[C:30]([O:31][CH3:32])[CH:29]=1)([OH:39])=[O:34]
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)cc(CO)nc32)cc1S(=O)(=O)C(C)(C)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)cc(C(=O)O)nc32)cc1S(=O)(=O)C(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[2-chloro-4-methoxy-5-(1-methyl-1-phenylethylsulfonyl)-phenyl]-5-hydroxymethyl-7-methoxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) in N,N-dimethylformamide (2 mL) was added manganese(IV) oxide (0.4 g), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with ethyl acetate, and the insoluble material was removed by filtration. The filtrate was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue were added tert-butanol (1.5 mL), water (0.15 mL), sodium dihydrogen phosphate dihydrate (10 mg), 2-methyl-2-butene (18 mg) and a solution of sodium chlorite (20 mg) in water (0.3 mL) successively, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added 1 mol/L hydrochloric acid and water, and the precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give the title compound (19 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([NH:18]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[I:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([NH2:18])[CH2:16][CH2:17]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(I)cc2)CC1
Reaction time: 24 h

Procedure:
3 mL (38.76 mmol) of trifluoroacetic acid are added to a solution of 1 g (2.78 mmol) of tert-butyl [1-(4-iodophenyl)cyclopropyl]carbamate in 40 mL dichloromethane and stirred for 24 h. Then the solvent is eliminated by rotary evaporation and the residue is combined with toluene and then again eliminated by rotary evaporation. This residue is then added to a solution of 0.39 g (2.8 mmol) of potassium carbonate in 20 mL of water and stirred for 30 minutes at RT. The aqueous phase is extracted with dichloromethane, the organic phase is dried with sodium sulfate and the solvent is eliminated by rotary evaporation. Yield: 0.7 g (97% of theory); C9H10IN (M=259.09); calc.: molecular ion peak (M+H)+: 260; found: molecular ion peak (M+H)+: 260.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[C:18]([C:22]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=2[C:24]#[N:25])[CH:19]=[N:20][CH:21]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]([C:18]2[CH:19]=[N:20][CH:21]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:17]=2)=[C:23]([CH:26]=1)[C:24]#[N:25]
Reactant: N#Cc1cc(F)ccc1-c1cncc(Br)c1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: CC(C)(O)c1ccn2c(-c3cncc(-c4ccc(F)cc4C#N)c3)cnc2c1F
Yield: 51.9 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (145 mg, 0.75 mmol) and 2-(5-bromopyridin-3-yl)-5-fluorobenzonitrile (208 mg, 0.75 mmol) were coupled following the procedure in Example 23 to afford 5-fluoro-2-{5-[8-fluoro-7-(2-hydroxyprop-2-yl)imidazo[1,2-α]pyridin-3-yl]pyridin-3-yl}benzonitrile (152 mg, 52%) as a white solid: δH (500 MHz, DMSO) 1.59 (6H, s), 5.57 (1H, s), 7.23 (1H, dd, J 7 and 7), 7.80 (1H, ddd, J 9, 9 and 3), 7.91-7.94 (1H, m), 7.99 (1H, s), 8.08 (1H, dd, J 9 and 3), 8.41 (1H, dd, J 2 and 2), 8.58 (1H, d, J 7), 8.82 (1H, s), 9.01 (1H, s); m/z (ES+) 391 (100%, [MH]+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11]>O1CCCC1.O.[OH-].[Na+]>[CH3:7][C:8]1[C:9]([CH2:10][OH:11])=[CH:14][CH:15]=[CH:16][N:17]=1
Reactant: COC(=O)c1cccnc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncccc1CO

Procedure:
To a slurry of lithium aluminum hydride (500 mg, 13.2 mmol) in anhydrous tetrahydrofuran (45 mL) at 0° C. under nitrogen was added dropwise a solution of methyl 2-methylnicotinate (17, 1.0 g, 6.6 mmol) in anhydrous tetrahydrofuran (5 mL). After 1 h the suspension was diluted with water (1 mL) and 6 N NaOH solution (5 mL). The precipitate was removed by vacuum filtration and the filtrate was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to provide the title compound as a light yellow oil: 1H NMR (300 MHz) 8.37 (d, J=4.9 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.14 (dd, J=7.6 Hz, 4.9 Hz, 1H), 4.72 (s, 2H), 2.95-2.74 (bs, 1H), 2.53 (s, 3H) ppm.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=O)C.[O:12]1[CH2:17][CH2:16]C(=O)[CH2:14][CH2:13]1>>[O:12]1[CH2:17][CH2:16][CH:4]([N:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:14][CH2:13]1
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)N1CCNCC1
Product: C1CN(C2CCOCC2)CCN1
Yield: 39 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 10 using 1-ethoxycarbonylpiperazine (50 g) and 2,3,5,6-tetrahydropyran-4-one (34 g), the title compound (21 g) was obtained. boiling point: 95-100° C./5 mmHg
Reaction SMILES: N#N.[Na].C([O:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=1)(=O)C.[NH4+].[Cl-]>CO>[OH:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[N:13]=1
Reactant: COC(=O)c1coc(COC(C)=O)n1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1coc(CO)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), sodium (1.32 g, 57.42 mmol) was added portionwise to MeOH (145 mL). Methyl 2-(acetoxymethyl)oxazole-4-carboxylate (23.30 g, 116.99 mmol) was then added and the reaction mixture was stirred for 1 h at rt. Sat. aq. NH4Cl (760 mL) was then added and the mixture was extracted with EA (2×760 mL). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a white solid: TLC: rf (9:1 hept-EA)=0.33. LC-MS-conditions 06: tR=0.31 min, [M+H]+=158.15.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15]([OH:17])=O)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62])[CH2:57][CH2:58][CH3:59]>CN(C=O)C>[CH2:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][N:66]([C:15](=[O:17])[C@@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:11]2[N:10]=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:12]=2)[CH2:65][CH2:64]1)=[O:62])[CH2:57][CH2:58][CH3:59]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)O
Reactant: CCCCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](Cc2cn(Cc3ccccc3)nn2)NC(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a solution of 836 mg (S)-3-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-2-tert-butoxycarbonylamino-propionic acid in 20 ml DMF were added 0.61 ml N-ethylmorpholine, 0.79 g TOTU and 449 mg Piperazine-1-carboxylic acid butyl ester. After stirring for 2 h the reaction mixture was concentrated, diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 1.14 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[Si]([O:21][CH2:22][C@@H:23](/[N:29]=[CH:30]/[C:31]([F:34])([F:33])[F:32])[CH2:24][C:25]([F:28])([F:27])[CH3:26])(C(C)(C)C)(C)C.[Cl-].[NH4+]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:30]([NH:29][C@@H:23]([CH2:24][C:25]([F:27])([F:28])[CH3:26])[CH2:22][OH:21])[C:31]([F:34])([F:33])[F:32])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(F)(F)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(F)(F)C[C@@H](CO)N[C@@H](c1ccc(Br)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a −78° C. solution of 1,4-dibromobenzene (330 mg) in THF (5.2 mL) was added 2.5M n-BuLi in hexanes (0.52 mL) and the solution was aged for 30 minutes. Then, a solution of (2S)-1-((tert-butyl(dimethyl)silyl)oxy)-4,4-difluoro-N-((1E)-2,2,2-trifluoroethylidene)pentan-2-amine (333 mg) in THF (5.2 mL) was added. The mixture was stirred at −78° C. for 45 minutes, then poured over cold saturated ammonium chloride, extracted with ethyl acetate (2×), washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated under vacuum. The residue was dissolved in THF (10 mL) cooled in an ice/water bath and n-tetrabutylammonium fluororide (1M in THF, 1.5 mL) was added. The mixture was stirred at 0° C. for 1 h, poured over cold water, extracted with ethyl acetate (2×), washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated under vacuum to afford (2S)-2-(((1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)-4,4-difluoropentan-1-ol.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH:23]([CH2:25][C:26]([O:28]CC)=[O:27])[C:22]4[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=4[CH2:20][C:19]=3[CH:35]=2)[CH:5]=1>CCO>[CH3:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH:23]([CH2:25][C:26]([OH:28])=[O:27])[C:22]4[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=4[CH2:20][C:19]=3[CH:35]=2)[CH:5]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3cc(C)ccn3)cc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)O)C3)c1

Procedure:
1.0 N NaOH (0.144 mL, 0.144 mmole) was added to a solution of ethyl (±)-10,11-dihydro-3-[3-(4-methyl-2-pyridylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (35 mg, 0.08 mmole) in EtOH(5 mL) at RT. The mixture was warmed overnight in an oil bath set at 32° C., then was concentrated. The residue was dissolved in H2O (3 mL), and the solution was acidified with 20% TFA. ODS chromatography (5-10% CH3CN/H2O containing 0.1% TFA) followed by concentration and lyophilization gave the title compound as a white powder: MS (ES) m/e 417.3(M+H)+. Anal. Calcd for C26H28N2O3.2.0 TFA.1.0 H2O: C, 54.38; H, 4.87; N, 4.23. Found: C, 54.66; H, 6.4.53; N, 4.32.