Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([Cl:9])=[C:7](Cl)[S:6](=[O:11])[N:5]=1)[CH3:2].[CH3:12][O-:13].[Na+]>CO>[CH2:1]([O:3][C:4]1[C:8]([Cl:9])=[C:7]([O:13][CH3:12])[S:6](=[O:11])[N:5]=1)[CH3:2]
Reactant: CCOC1=NS(=O)C(Cl)=C1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC1=NS(=O)C(OC)=C1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.2 %

Procedure:
To the solution of 3-ethoxy-4,5-dichloroisothiazole-1-oxide (0.12 g, 0.00056 mol) in methanol (1 ml) cooled in an ice-bath was added a solution of sodium methoxide (0.032 g, 0.00060 mol) methanol (1 ml). The solution was warmed to ambient temperature and stirred overnight. The solution was concentrated to dryness in vacuo and the residue was partitioned between chloroform (10 ml) and water (5 ml). The aqueous layer was washed with chloroform (10 ml) and the combined organic layers were washed with saturated sodium chlorate solution (2 ml) dried over sodium sulfate, filtered, and concentrated to dryness to give 0.14 g orange liquid. This liquid was chromatographed on a column of E. Merck silica gel 60. From the fraction eluted with n-butylchloride, there was obtained 0.06 g of a mixture of starting material and 3-methoxy-4,5-dichloroisothiazole-1-oxide. From the fractions eluted with methylene chloride, there was obtained 0.03 g (25%) of the title compound. TLC (methylene chloride silica): Rf=0.43 (identical to product of Step B above.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N+:10]([O-])=O)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].C(OCC)(=O)C>[Pd].CO>[NH2:10][C:5]1[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CCNc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNc1cccnc1N

Procedure:
A mixture of 3-ethylamino-2-nitro-pyridine (400 mg), 10% palladium on carbon (40 mg) and 1:1 ethyl acetate:methanol (30 mL) were placed in a Parr apparatus under hydrogen (50 psi) for 50 min. The mixture was filtered through Celite, concentrated, and the product triturated with hexane to give 2-Amino-3-ethylaminopyridine as a brown solid. More material was recovered from the filtrate. 1H NMR (CDCl3): δ 7.59 (d, J=4.94 Hz, 1H), 6.81 (d, J=6.32 Hz, 1H), 6.71 (dd, J=4.94, 7.69 Hz, 1H), 3.12 (q, J=7.14 Hz, 2h), 1.31 (t, J=7.14 Hz, 3H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[BrH:1].[CH2:19]([NH:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCCOCCCCc1ccccc1
Product: Br
Product: c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A mixture comprising 7.34 g (25.53 mmol) 4-(6-bromohexyloxy)butylbenzene and 10.3 ml (94.30 mmol) benzylamine is heated at 125° C. for 8 hr. The benzylamine in excess is distilled off and the residue dissolved in 30 ml methyl ethyl ketone. To the resulting solution, heated to 50° C., is added a solution of 7.43 ml 47% HBr in 50 ml H2O, then it is allowed to stir for 15 min and decanted. The organic phase is evaporated to dryness an the thus obtained residue triturated with Et2O and filtered to yield 5.9 g (59.8%) N-benzyl-6-(4-phenylbutoxy)hexylamine hydrobromide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:42])=[C:16]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:43][Br:44]>>[Br-:44].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:42])=[C:16]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([CH2:25][CH2:26][CH2:27][N+:28]([CH3:43])([CH3:30])[CH3:29])=[O:31])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CBr
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCC[N+](C)(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Product: [Br-]

Procedure:
The title compound was prepared from N-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-dimethylamino-butyramide (Ex. 16, 25 mg, 0.044 mmol) and MeBr (ca. 30% in EtOH, 0.15 mL) using a similar method to that employed for Example 15 (30 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33]>>[Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=1
Reactant: O=C(N1CCc2c(F)cc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1cccc(F)c1
Product: O=C(N1CCc2c(F)cc(Cl)c(NCc3cccc(F)c3)c2CC1)C(F)(F)F
Yield: 27.9 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-9-fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (130 mg, 0.3 mmol) with 3-fluorobenzylamine (100 □L, 0.89 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 and 4:1) followed by SCX chromatography to give 7-chloro-9-fluoro-6-(3-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (35 mg, 28%). MS (ES+) m/z: 401 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[C:29]([CH3:36])[C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 85%).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)C.C(O)C.[OH-].[Na+]>O>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH:11]([N:12]1[CH2:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2sccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCC(c1ccccc1Cl)N1CCc2sccc2C1)C(=O)O
Yield: 43.4 %

Procedure:
8-(2-Chlorophenyl)-8-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester (0.86 g, 1.92 mmol) was added to a solution of ethanol (32 mL) and sodium hydroxide (0.53 g, 13.4 mmol) in water (10.4 mL). The mixture was heated to reflux for 6.5 hours. The solution was concentrated under reduced pressure and water (43 mL) was added to the residue. Any starting material was extracted with ethyl acetate/heptane (1/10, 43 mL). The heptane extract was discarded. The remaining aqueous solution was adjusted with 10 N hydrochloric acid solution to pH=6. The product was extracted with CH2Cl2 (3×40 mL), dried over Na2SO4, concentrated and purified by column chromatography (silica gel, ethyl acetate/heptane=1/10 to 1/3) to provide 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethyloctanoic acid (Compound Im, 0.35 g, 43.8% yield, 99.6% purity by HPLC) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 10.43 (br, 1H), 7.52 (d, 1H, J=7.50 Hz), 7.39 (d, 1H, J=8.10 Hz), 7.28-7.15 (m, 2H), 7.03 (d, 1H, J=5.0 Hz), 6.69 (d, 1H, J=5.0 Hz), 4.24 dd, 1H, J=9.3, 4.2 Hz), 3.83 (d, 1H, J=14.40 Hz), 3.51 (d, 1H, J=14.40 Hz), 2.92-2.73 (m, 4H), 1.99-1.81 (m, 2H), 1.46-1.41 (m, 2H), 1.28-1.15 (m, 6H), 1.13 (s, 6H). (t, 3H, J=7.2 Hz), 1.15-1.08 (m, 2H), 1.07 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 184.02, 138.85, 135.16, 133.87, 133.42, 129.60, 129.17, 128.17, 126.92, 125.52, 122.74, 63.53, 50.54, 47.90, 42.29, 40.70, 32.95, 30.52, 25.75, 25.64, 25.26, 24.96. HRMS (FIA-ESI): Calculated for C23H30ClNO2S (M+H)+: 420.1759, found 420.1779. CHN analysis: Calculated; 65.77 C, 7.20 H, 3.33 N, found; 60.77 C, 6.68 H, 3.11 N. Best fit for CHN: C23H30ClNO2S+HCl
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1([N:16]=[C:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CCCCCC>[CH:10]1([NH:16][C:17]([NH:9][CH:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C=NC1CCCCC1
Reactant: NC1CCCCCCC1
Solvent: CCCCCC
Product: O=C(NC1CCCCCCC1)NC1CCCCC1
Yield: 88 %

Procedure:
Cyclooctylamine, 0.382 g (3.00 mmol), 0.40 mL (0.39 g, 3.1 mmol) of cyclohexylisocyanate in 20 mL of hexane, on standing for one day provides 0.664 g (88%) of 1-cyclohexyl-3-cyclooctylurea as white needles, mp 194.0-194.5° C. An infrared spectrum [3344 (s, NH), 3334 (s, NH), 1624 (vs, C═O), 1564 (vs. amide II) cm−1] and mass spectrum [FAB-MS m/z calcd. for C15H28N2O: 252, obsd: 253 (M+H+)] confirms the identity of this material.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C(N(C(C)C)CC)(C)C.[CH2:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:25]#[CH:26]>C(Cl)(Cl)Cl>[CH2:24]([N:27]1[CH2:32][CH2:31][N:30]([CH2:3][C:4]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[CH2:29][CH2:28]1)[C:25]#[CH:26]
Reactant: C#CCN1CCNCC1
Reactant: Oc1ccc(CCl)c2cccnc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN1CCN(Cc2ccc(O)c3ncccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a mixture of 5-chloromethyl-8-hydroxyquinoline hydrochloride (A2) (323 mg, 1.407 mmol) and diisopropylethylamine (0.26 ml, 1.477 mmol, 1.05 eq) in 6 ml CHCl3 at 0° C., N-propargylpiperazine obtained in step 2(iii) above was added (173 mg, 1.407 mmol, 1 eq). The mixture was stirred for 24 h at room temperature. 10 ml of CHCl3 was then added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The crude product was purified by FC to give the title compound (HLA20) as a white solid. (337 mg, 86% yield). H1 NMR (250 MHz, CDCl3), 2.23 (m, 1H), 2.54 (s, 8H), 3.28 (d, J=2.44 Hz, 2H), 3.80 (s, 2H), 7.08 (m, 1H), 7.36 (d, J=10.59, 1H), 7.46 (dd, J=8.55, 4.18 Hz, 1H), 8.67 (dd, J=8.56, 1.55 Hz, 1H), 8.78 (dd, J=4.18. 1.51 Hz, 1H); 13C NMR (100 MHz, CDCl3) 46.77, 51.98, 52.87, 60.55, 73.05, 78.92, 108.60, 121.40, 124.58, 127.87, 128.87, 134.10, 138.68, 147.50, 151.78.
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[C:21](Cl)(=[O:23])[CH3:22].Cl[Sn](Cl)(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[C:21]([C:4]1[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[S:1][C:5]=1[NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([Br:16])=[CH:14][CH:15]=1)(=[O:9])=[O:8])(=[O:23])[CH3:22]
Reactant: O=S(=O)(Nc1cc2ccccc2s1)c1ccc(Br)cc1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1c(NS(=O)(=O)c2ccc(Br)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
To a suspension of compound 361-A (9.21 g, 25.0 mmol) in DCM (50 mL), cooled in an ice-bath, was added an ice-cold solution of acetyl chloride (2.30 mL, 32.3 mmol), followed by SnCl4 (27.9 mmol) in DCM (200 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was quenched with saturated NH4Cl solution (125 mL), filtered over a pad of celite, dried over MgSO4, filtered and concentrated under vacuum. The residue was dissolved in refluxing EtOAc (75 mL), filtered hot and the filtrate allowed to cool. The solid was filtered and washed EtOAc (10 mL). Another batch of product was obtained by evaporation of the mother liquor, dissolving the residue in refluxing EtOAc (25 mL), filtering hot and allowing the filtrate to cool. The solid was filtered and washed with EtOAc (2 mL). The combined batches of solid were air-dried to afford 8.54 g of compound 361-B as a tan-orange powder. 1H-NMR (DMSO-d6) δ: 2.57 (s, 3H), 7.40-7.24 (m, 2H), 7.83-7.70 (m, 5H), 8.14 (d, 1H); MS: m/z 408.1 (M-H)−.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:38]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[C:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH:56]([NH2:58])[CH3:57])=[CH:51][CH:50]=2)=[CH:43][CH:42]=1)[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[C:48][C:49]2[CH:50]=[CH:51][C:52]([CH2:55][CH:56]([NH:58][C:1](=[O:6])[CH2:2][CH2:3][CH3:4])[CH3:57])=[CH:53][CH:54]=2)=[CH:43][CH:42]=1)[CH3:39]
Reactant: CCCC(=O)O
Reactant: CCOc1ccc(C#Cc2ccc(CC(C)N)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(=O)NC(C)Cc1ccc(C#Cc2ccc(OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.41 mg (0.10 mmol) butanoic acid are dissolved in 300 μL DMF together with 32.1 mg (0.10 mmol) TBTU and 50.0 μL (0.30 mmol) DIPEA and the mixture is stirred at r.t. for 5 min. 27.9 mg (0.10 mmol) 1-(4-((4-ethoxyphenyl)ethynyl)phenyl)propan-2-amine (I64) are added and the reaction mixture is stirred at 40° C. over night. The mixture is filtered through a plug of alox, eluted with DMF/MeOH (9/1) and the solvent is removed in vacuo. The residue is purified by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]#[N:18]>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#CCOc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
Mix 4-bromophenol (1.4 mmol) in acetonitrile (5 ml) and water (2 ml), add K2CO3 (3 mmol) and bromoacetonitrile (1.5 mmol) at room temperature under inert atmosphere. Heat the mixture to 80° C. for 16 h. Analyze by LC/MS for final product. Evaporate the solvent and add water. Extract product with DCM (3×) and combine and evaporate organic phases to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:4].[H-].[Na+].[CH3:21]I.[ClH:23]>CN(C)C=O.O.CCOCC>[ClH:23].[CH3:1][N:2]([CH3:21])[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CNC(=O)CCCCCc1cccc2cncn12
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCCCCc1cccc2cncn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.45 g of 5-[5-(N-methylcarbamoyl)pentyl]imidazo[1,5-a]pyridine in 25 ml of dimethylformamide is treated with 0.011 mole of sodium hydride (obtained by washing 0.53 g of 50% NaH dispersion in mineral oil with hexane) and warmed briefly on a steam bath. Methyl iodide (1.56 g) is added to the cooled yellow solution. The mixture is stirred at room temperature for 2 hours, diluted with water and extracted first with a 1:1 mixture of ethyl acetate and ether and subsequently with chloroform. The residue obtained on evaporation of the combined extracts to dryness is dissolved in ether and treated with ethanolic hydrochloric acid. The precipitated salt is collected, recrystallized first from acetonitrile/ethyl acetate and then from ethanol/ether to yield 5-[5-(N,N-dimethylcarbamoyl)pentyl]imidazo[1,5-a]pyridine hydrochloride melting at 166°-71°.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[O:23][N:22]=[C:21]([CH:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25])[N:20]=1.CO>CCCCCCC>[CH3:28][CH:27]([CH3:29])[CH2:26][CH:24]([NH:25][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:21]1[N:20]=[C:19]([CH3:18])[O:23][N:22]=1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(N)CC(C)C)no1
Solvent: CCCCCCC
Solvent: CO
Product: Cc1nc(C(CC(C)C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 5-methyl-α-(2-methylpropyl)-1,2,4-oxadiazole-3-methanamine (CAN 1155538-06-9) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/8% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 385.2234 (M+H)+, αD20 (MeOH)=−24.8°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[NH:16][CH:17]=[C:18]([C:20](F)(F)F)[N:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:25].C(O)(=O)C>CCOC(C)=O.CCCCCC>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[NH:16][CH:17]=[C:18]([C:20]#[N:25])[N:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1OC1CCCC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COc1ccc(-c2nc(C#N)c[nH]2)cc1OC1CCCC1
Yield: 35 %

Procedure:
A mixture of 2-(3-cyclopentyloxy-4-methoxyphenyl)-4-trifluoromethyl-imidazole (1.04 g, 3.18 mmol) and 5% aqueous ammonium hydroxide (300 ml) was heated to reflux for 24 hours. The reaction mixture. was cooled and carefully neutralised with acetic acid. The mixture was extracted with methylene chloride (3×150 ml) and the volatiles removed in vacuo to afford the crude product. Flash chromatography (SiO2; EtOAc:hexane (2:3)) produced the 2-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanoimidazole (320 mg, 35%) as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31]C1C=CC=CC=1C=O>>[F:31][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[O:9]1
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Reactant: O=Cc1ccccc1F
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2ccccc2F)Oc2ccc(O)cc21

Procedure:
2-(2-Fluorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of 2′,5′-dihydroxyacetophenone and 1.4 ml of 2-fluorobenzaldehyde. The product was recrystallised from acetic acid. 1H NMR (400 MHz, d6-DMSO) δ: 9.45 (s, 1H), 7.67 (m, 1H), 7.47 (m, 1H), 7.32-7.25 (m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.04 (dd, 1H, J 8.9, 3.0 Hz), 6.95 (d, 1H, J 8.9 Hz), 5.77 (dd, 1H, J 13.5, 2.8 Hz), 3.26 (dd, 1H, J −16.9, 13.5 Hz), 2.76 (dd, 1H, J −16.9, 2.8 Hz).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(=O)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with piperidin-4-one (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C34H39Cl2N4O3 [(M+H)+] 621.2394, observed 621.2395.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[C:14]([F:16])[C:11]([CH:12]=O)=[C:10]([F:17])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:25]O.[CH3:27][CH2:28][OH:29]>O>[C:12]([C:11]1[C:14]([F:16])=[CH:15][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:28](=[O:29])[CH3:27])[N:7]=2)=[CH:9][C:10]=1[F:17])#[N:25]
Reactant: NO
Reactant: Nc1nccc(-c2cc(F)c(C=O)c(F)c2)n1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1nccc(-c2cc(F)c(C#N)c(F)c2)n1
Temperature: 100 °C
Yield: 36 %

Procedure:
To a suspension of 4-(2-amino-4-pyrimidinyl)-2,6-difluorobenzaldehyde (5.69 g, 24.2 mmol) in EtOH (50 mL) and water (150 mL), were added sodium carbonate (2.82, 26.6 mmol) and hydroxylamine hydrochloride (1.85 g, 26.6 mmol), and the resulting mixture was stirred at 100° C. until the starting material was consumed as judged by LCMS (˜2 hours). The reaction mixture was concentrated, and the resulting tan solid was washed with water and filtered. The aqueous washings were extracted with EtOAc, and the combined organic layers were concentrated. The concentrated organic extract and the filter cake were combined and suspended in acetic anhydride (used as solvent, ˜150 mL), and the reaction mixture was stirred at 100° C. until the oxime intermediate was completely converted to the nitrile (˜5 days). The reaction mixture was concentrated and co-evaporated with EtOH, and the resulting solid was triturated with CH3OH to afford the title compound (2.4 g, 36%) as a sandy tan solid. The filtrate was treated with saturated aqueous NaHCO3 and K2CO3, and the basic solution was stirred overnight at room temperature converting the bis-acetyl by-product to the title compound. The basic solution was filtered, and the filtrate was concentrated. The resulting solid was triturated with CH3OH and washed with water to afford the title compound (1.05 g, 16%) as a sandy tan solid. LC-MS (ES) m/z=275 [M+H]+.