Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[C:10]=1[CH2:36][CH2:37][CH3:38])([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[C:10]([CH2:36][CH2:37][CH3:38])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:39])=[O:3])[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCCc1c(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cccc1OC(C)(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1c(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cccc1OC(C)(C)C(=O)O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-{3-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-propyl-phenoxy}-2-methyl-propionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the desired product. Rf=0.22 in 70% ethyl acetate/hexanes; 1H NMR (400 MHz, d6-DMSO) δ7.92 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.67 (d, J=7.6 Hz, 3H), 7.43 (t, J=7.2 Hz, 1H), 7.34 (t, J=7.6 Hz, 2H), 6.95 (t, J=8.4 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.24 (d, J=8.4 Hz, 1H), 4.13 (t, J=6.4 Hz, 2H), 2.87 (t, J=6.4 Hz, 2H), 2.41 (t, J=7.6 Hz, 2H), 2.32 (s, 3H), 1.40 (s, 6H), 1.23 (sextet, J=7.2 Hz, 2H), 0.71 (t, J=7.6 Hz, 3H),
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)nc1
Yield: 88.3 %

Procedure:
2-Bromo-5-methylpyridine (30 g, 174 mmol), phenylboronic acid (25.5 g, 209 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.86 g, 6.98 mmol) and potassium phosphate tribasic monohydrate (120 g, 523 mmol) were added to toluene (600 mL) and water (60 mL). The reaction mixture was degassed with nitrogen for 20 min. Pd2(dba)3 (3.19 g, 3.49 mmol) was added and the reaction mixture was refluxed for 18 h. After cooling, the organic layer was separated and the aqueous layer extracted with 3×50 mL dichloromethane, dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel with 75/25 (v/v) hexane/EtOAc and then distilled on a Kugelrohr apparatus (150° C., 100 mbar) to give 26 g (88%) of 5-methyl-2-phenylpyridine as a white solid. The product was confirmed by NMR and GC/MS. HPLC purity: 99.2%.
Reaction SMILES: C(N)C1C=CC=CC=1.C(O[C:17]([N:19]([CH2:21][C:22]([NH:24][C@H:25]([C:29]([NH:31][C@H:32]([C:34]([NH:36][C@H:37]([P:39](=[O:42])([OH:41])[OH:40])[CH3:38])=[O:35])[CH3:33])=[O:30])[CH2:26][CH2:27][CH3:28])=[O:23])C)=O)C1C=CC=CC=1>>[NH:19]([CH2:21][C:22]([NH:24][C@H:25]([C:29]([NH:31][C@H:32]([C:34]([NH:36][C@H:37]([P:39](=[O:40])([OH:42])[OH:41])[CH3:38])=[O:35])[CH3:33])=[O:30])[CH2:26][CH2:27][CH3:28])=[O:23])[CH3:17]
Reactant: CCC[C@H](NC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: CCC[C@H](NC(=O)CNC)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 5(A)(iii), from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-sarcosyl-L-norvalyl-L-alanyl)-amino]-ethylphosphonic acid there was obtained (1R)-1-(N-sarcosyl-L-norvalyl-L-alanylamino)-ethylphosphonic acid of melting point 277°-279° C. (decomposition); [α]D20 =-96.0°; [α]36520 =-348° (c=0.51% in water).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cc(OCC2CO2)cc1Cl
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(O)COc1cc(Cl)c(C=O)c(Cl)c1

Procedure:
A mixture of 2,6-dichloro-4-(2,3-epoxypropoxy)benzaldehyde (3 gm) and tert-butylamine (20 ml) is heated at 45° for 17 hours. The excess tert-butylamine is removed under reduced pressure (20 mm). The oil is dissolved in 6N hydrochloric acid (25 ml) and heated for 1 hours. The acid solution is added to boiling saturated aqueous sodium carbonate with nitrogen ebullition. The basic solution is extracted with chloroform. The chloroform is dried over anhydrous sodium sulfate, filtered and concentrated to 2,6-dichloro-4-(3-tert-butylamino-2-hydroxypropoxy)benzaldehyde which is used without further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]1[O:34][C:33]2[CH:32]=[CH:31][C:16]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][C:14]=2[O:13]1>C(Cl)(Cl)Cl>[CH2:12]1[O:34][C:33]2[CH:32]=[CH:31][C:16]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:30])=[O:9])[CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][C:14]=2[O:13]1
Reactant: CSc1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 80 %

Procedure:
A solution of 1.20 g (6.95 mmol) of m-chloroperbenzoic acid in 30 ml of chloroform was dropped into a solution of 1.80 g (5.53 mmol) of 4-(3,4-methylenedioxybenzyl)amino-6-methylthioquinazoline in 100 ml of chloroform under cooling with ice and stirring. The obtained mixture was stirred under cooling with ice for several hours, washed with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and filtered. The filtrate was purified by silica gel column chromatography (ethyl acetate/acetone) and recrystallized from chloroform/n-hexane to give 1.51 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[CH2:8]2)[CH2:4][CH2:3]1.Cl.[O:18]([NH2:20])[CH3:19]>>[CH3:19][O:18][N:20]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:8]1
Reactant: CON
Reactant: CN1CCC2(CC1)CC(=O)c1ccccc12
Agent: Cl
Product: CON=C1CC2(CCN(C)CC2)c2ccccc21

Procedure:
The product of Example 138B and the HCl salt of methoxylamine were processed according to the method of Example 135A to provide the product. MS (ESI+) m/z 245 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(OC([N:13]1[CH2:17][CH2:16][C@H:15]([OH:18])[C@H:14]1[C:19](=[O:24])[N:20]([O:22][CH3:23])[CH3:21])=O)(C)(C)C.C(N(CC)CC)C>ClCCl>[CH3:23][O:22][N:20]([CH3:21])[C:19]([CH:14]1[CH:15]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:16][CH2:17][NH:13]1)=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CON(C)C(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1NCCC1OS(C)(=O)=O
Temperature: 0 °C
Yield: 138.8 %

Procedure:
Methane sulphonyl chloride (3.49 g) was added dropwise over 10 minutes to a mixture of compound 65 (7.6 g) and triethylamine (7.7 ml) in dichloromethane (350 ml) and cooled to 0° C. under an argon atmosphere. It was then stirred at 0° C. for another hour. The reation mixture was then applied directly to a silica flash column which was eluted with ethyl acetate to give (2S,3 S)-1-tert-butoxycarbonyl)-2(N-methoxy-N-methylcarbamoyl)-3-methansulfonyloxypyrrolidine (compound 66) as a gum (9.7 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([NH2:30])=[N:22]1.O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:8]1([C:6]2[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:20])([F:19])[F:18])[N:3]=[C:2]([NH:30][C:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:21][N:22]=3)[CH:7]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)c1ccccc1-c1nc(Cl)cc(C2CC2)n1
Reactant: Nc1n[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccccc1-c1nc(Nc2n[nH]c3ccccc23)cc(C2CC2)n1
Temperature: 165 °C
Yield: 15.9 %

Procedure:
A mixture of 4-chloro-6-cyclopropyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (0.08 g, 0.27 mmol) and 1H-indazol-3-ylamine (0.036 g, 0.41 mmol) was heated neat at 160-170° C. for 6 hours. The residue was cooled and dissolved in N-methylpyrrolidinone (2 mL), poured into water (30 mL) and sodium bicarbonate (5 mL) then filtered, washing with water and ether. The collected precipitate and the ether wash were combined and concentrated. Purification by flash chromatography [SiO2, methanol:dichloromethane (2:98)] provided the title compound (0.017 g, 15% yield) as a pale yellow solid. 1H-NMR (500 MHz, DMSO-d6) δ 12.6 (br s, 1H), 10.2 (br s, 1H), 8.00 (d, J=8.1 Hz, 2H), 7.81 (d, J=7.9 Hz, 1H), 7.71 (m, 3H), 7.65 (t, J=7.3 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 2.04 (m, 1H), 1.01 (m, 2H), 0.96 (m, 2H) ppm; LC-MS 396.10 (M+H); Rt (Method A) 3.122 minutes.
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[N:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[CH:19]([N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[N:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[CH:14])=[CH:11][CH:12]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N(N=Nc1ccc(C#C[Si](C)(C)C)cc1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N=NN(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
6 g of 1-(diisopropyltriazenyl)-4-((trimethylsilyl)ethynyl)benzene (19.9 mmol, 1 eq.) are dissolved in 100 ml of MeOH, and 13.7 g of K2CO3 (99.5 mmol, 5 eq.) are added in small portions. The reaction medium is stirred at room temperature for 15 h and then evaporated to dryness and taken up in 100 ml of water and 100 ml of EtOAc. The aqueous phase is extracted four times with 50 ml of EtOAc, after which the organic phase is dried over magnesium sulfate, filtered and then evaporated to give 4.38 g of 1-(diisopropyltriazenyl)-4-ethynylbenzene with a yield of 96%.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH:5]=1.[OH-].[Li+]>O1CCOCC1>[F:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[CH2:14][CH2:13][O:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)c1ccc(OC)c(OCCc2cc(C)ccc2F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1OCCc1cc(C)ccc1F
Reaction time: 0.33 h
Yield: 99 %

Procedure:
The compound of step 1 (530 mg, 1.66 mmol) was dissolved in dioxane (8.3 ml). Lithium hydroxide (8.3 ml of an aqueous 1 M solution) was added and the mixture was kept for 20 min at 60° C. After cooling, the mixture was partitioned between an excess of 2 N hydrochloric acid and EA and the aqueous phase extracted with EA. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was stirred overnight with a mixture of diethyl ether and HEP, filtered, and the solid was dried in vacuo to give 500 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:37][CH2:36][CH2:35][C@:30]2([O:34][CH2:33][CH:32]=[CH:31]2)[C@@H:29]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[Cl-].[Li+].C([O-])=O.[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=1[C@H:32]1[CH2:31][C@@:30]2([CH2:35][CH2:36][CH2:37][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C@H:29]2[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[O:34][CH2:33]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]2(C=CCO2)[C@@H]1c1ccccc1
Reactant: FC(F)(F)Oc1ccc(OCc2ccccc2)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@]2(C[C@H](c3cc(OC(F)(F)F)ccc3OCc3ccccc3)CO2)[C@@H]1c1ccccc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
A mixture of 2-benzyloxy-5-(trifluoromethoxy)iodobenzene (Description 22b, 21.8 g, 55.2 mmol), (5R,6S)-7-(tert-butoxycarbonyl)-6-phenyl-7-aza-1-oxa-spiro[4.5]dec-3-ene (Description 21, 7.0 g, 22.1 mmol), tetra-n-butylammonium chloride (6.18 g, 22.2 mmol), lithium chloride (9.35 g, 0.22 mol) and potassium formate (5.64 g, 67.0 mmol) in dimethylformamide (100 ml) was degassed with a firestone valve (x5) and purged with nitrogen. Palladium acetate (491 mg, 2.2 mmol) was added and the mixture was degassed with a firestone valve (x5). The mixture was stirred at 60° C. for 15 hours, then further 2-benzyloxy-5-(trifluoromethoxy)iodobenzene (Description 22b, 4.32 g, 11.0 mmol), potassium formate (2.78 g, 33.5 mmol) and palladium acetate 260 mg, 1.1 mmol) were added. The mixture was stirred at 60° C. for 22 hours, cooled and filtered. The solvent was evaporated under reduced pressure, water (600 ml) was added and the mixture was extracted with ethyl acetate (2×300 ml). The combined organic fractions were washed with brine (300 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/CH2Cl2 (75:25 increasing to 0:100) then CH2Cl2 /EtOAc (95:5), to give the title compound (9.42 g, 73%). 1H NMR (360 MHz, CDCl3) δ 7.56 (2H, d, J 7.7 Hz), 7.40-7.20 (8H, m), 7.14 (1H, d, J 2.0 Hz), 7.00 (1H, dd, J 8.9, 2.0 Hz), 6.88 (1H, d, J 8.9 Hz), 5.30 (1H, s), 5.08 (2H, s), 4.27 (1H, m), 3.97 (1H, m), 3.87 (2H, m), 2.78 (1H, m), 2.56 (1H, m), 2.15 (1H, m), 1.96 (1H, m), 1.67 (3H, m), and 1.42 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=5)=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[N:18]4[CH:19]=[CH:20][C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:32][CH2:33][CH2:34][N:35]6[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]6)[CH:24]=5)=[CH:22][C:17]4=[N:16][CH:15]=3)[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2ccn3c(-c4ccnc(-c5ccc(F)cc5)c4)cnc3c2)c1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cc(-c3cnc4cc(-c5cccc(OCCCN6CCCCC6)c5)ccn34)ccn2)cc1
Temperature: 60 °C

Procedure:
3-{3-[2-(4-Fluoro-phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridin-7-yl}-phenol (Ex. 1.102) (1 eq, 0.131 mmol, 50 mg), 1-(3-chloropropyl)piperidine monohydrochloride (2.0 eq, 0.262 mmol, 53.7 mg) and potassium carbonate (3.0 eq, 0.394 mmol, 54.4 mg) are dissolved in DMF (4 ml) and heated at 60° C. for 16 h. The reaction mixture is diluted with CH2Cl2 and washed with NaHCO3 and brine. The organic phase is dried over MgSO4, filtered and evaporated to dryness. The reaction mixture is purified by flash chromatography on silica eluting with DCM/MeOH 7/3 to yield 3-[2-(4-fluoro-phenyl)-pyridin-4-yl]-7-[3-(3-piperidin-1-yl-propoxy)-phenyl]-imidazo[1,2-a]pyridine as a yellow solid; [M+H]+=507
Reaction SMILES: [CH3:1][C:2]([CH3:52])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:49])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:48])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][CH2:45][CH2:46][OH:47])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:51])[CH3:50])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:47][CH2:46][CH2:45][NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]12[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]1[C@@H:25]1[C@@:20]([CH3:48])([CH2:21][CH2:22]2)[C@@:19]2([CH3:49])[C@@H:28]([C@:29]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:50])([CH3:51])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:52])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]3)[CH2:27][CH2:26]1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NCCO)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NCCO)CC1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((2-hydroxyethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (60 mg, 0.083 mmol) in DCM (5 mL) stirred at room temp was added TFA (2.5 mL, 32.4 mmol). The reaction mixture was stirred at 30° C. for 2 h. The reaction was evaporated to dryness then diluted with 200 mL DCM. The organic phase was washed with saturated NaHCO3 solution (200 mL*3), water and brine. The organics were dried and concentrated under reduced pressure to afford crude product which was further purified by preparative-HPLC to afford the title compound (35 mg, 63%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ=6.85 (d, J=16.1 Hz, 1H), 5.96 (d, J=16.1 Hz, 1H), 4.49 (dd, J=5.5, 10.5 Hz, 1H), 3.64 (t, J=5.6 Hz, 2H), 3.39 (t, J=5.6 Hz, 2H), 3.37-3.21 (m, 1H), 2.91 (dd, J=4.1, 11.7 Hz, 0H), 2.68-2.50 (m, 2H), 2.33-2.10 (m, 3H), 2.09-0.75 (m, 44H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1>>[N+:11]([C:10]1[C:2]([NH:1][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=2)=[CH:3][C:4]2[O:8][CH2:7][O:6][C:5]=2[CH:9]=1)([O-:13])=[O:12]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: OCCc1ccc(Br)cc1
Product: O=[N+]([O-])c1cc2c(cc1Nc1ccc(CCO)cc1)OCO2

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 45 from 5-amino-6-nitro-1,3-benzodioxol and 4-bromophenylethyl alcohol.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:19][CH2:20][CH2:21]Br>CC#N>[Br:19][CH2:20][CH2:21][O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: FC(F)(F)Oc1ccc(OCCBr)cc1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
To a solution of 4-(trifluoromethoxy)phenol (1 g, 5.61 mmole) in CH3CN (20 mL) was added Cs2CO3 (3.66 g, 11.23 mmole) then 1,2-dibromoethane (2.42 mL, 28.1 mmole). The mixture was heated to reflux. After 3 days the mixture was cooled to RT, filtered through a pad of Celite washing with CH2Cl2, and concentrated. Flash column (Biotage-SNAP-50 g SiO2, 0-10% EtOAc/hexanes) gave the title compound (833 mg, 52%) as a clear liquid. 1H NMR (400 MHz, CDCl3): δ 7.15 (d, J=8.7 Hz, 2 H); 6.95-6.88 (m, 2 H); 4.29 (m, 2 H); 3.64 (t, J=6.29 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH2:20])=[N:16][CH:17]=1>>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:20][CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:22])([F:10])[F:21])=[CH:17][N:16]=2)=[CH:3][CH:4]=1)[CH3:9]
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: CCc1ccc(Br)cc1
Product: CCc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-ethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 295.2 [M+H]+) was prepared from 1-bromo-4-ethyl-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:8]=[N:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl.C(O)(C)C>CO>[NH:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:6]2[N:7]=[N:8][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)nn2)CC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: FC(F)(F)c1ccc(NC2CCNCC2)nn1

Procedure:
A solution of D1 (7.06 g, 20.4 mmol) and hydrochloric acid/isopropanol (6N, 100 ml) in methanol (100 ml) was stirred at room temperature for 2 h. After this period, solvents were evaporated in vacuo and the residue triturated with acetonitrile. The solid product was filtered off and dried to give D2 as the di-hydrochloride salt (6.05 g, 95%). C10H13F3N4 requires 246; Found 247 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=3[C:9]([F:10])([F:11])[F:12])=[O:24])[N:22]=2)[CH:19]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Product: O=C(Nc1ccc(F)cc1C(F)(F)F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 4-fluoro-2-(trifluoromethyl)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1>>[F:38][C:39]1[CH:44]=[C:43]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:15][CH2:16][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:33])([F:35])[F:34])[CH:26]=4)[N:24]=3)[CH2:18][CH2:19]2)[CH:42]=[CH:41][CH:40]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: OB(O)c1cccc(F)c1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cccc(F)c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=515, obsd.=515).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.[F:16]C1C=CC(O)=CC=1>>[F:16][C:15]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(OCc2ncc[nH]2)c1
Reactant: Oc1ccc(F)cc1
Product: Fc1ccc(OCc2ncc[nH]2)cc1

Procedure:
2-(4-Fluoro-phenoxymethyl)-1H-imidazole was prepared following a similar procedure for the preparation of 2-(3-Methoxy-phenoxymethyl)-1H-imidazole (see Example 18) using 4-fluorophenol in place of 3-methoxyphenol to provide a white solid (1.69 g, 85% for 2 steps); ESI MS m/z 193 [C10H9FN2O+H]+.