Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1(/[CH:17]=[C:18](\[C:27]2[CH:28]=[N:29][C:30]([S:33][CH3:34])=[CH:31][CH:32]=2)/[C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl.CCOC(C)=O>[CH:12]1(/[CH:17]=[C:18](\[C:27]2[CH:28]=[N:29][C:30]([S:33]([CH3:34])=[O:9])=[CH:31][CH:32]=2)/[C:19]([NH:21][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CSc1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cn1
Reaction time: 4.5 h

Procedure:
A solution of mCPBA (85% pure, 64 mg, 318 μmol) in CH2Cl2 (1 mL) was added over 5 min to a stirred solution of (E)-3-cyclopentyl-2-(6-methylsulfanylpyridin-3-yl)-N-thiazol-2-ylacrylamide (EXAMPLE 5, 110 mg, 318 μmol) in CH2Cl2 (5 mL) at 0° C. After 4.5 h at 0° C., the reaction mixture was diluted with EtOAc (40 mL). The resulting solution was washed with H2O-saturated aqueous NaHCO3 (1:1, 2×20 mL) and brine (20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (EtOAc then THF) provided the title compound: RTA=3.32 min; m/z (ES+)=362.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCc3ccccc3)nc(Cl)nc21

Procedure:
2-Chloro-6-(benzylamino)-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 15 for preparation), benzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: I[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CCC(I)C(=O)N2
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(N=[N+]=[N-])C(=O)N2
Reaction time: 2 h
Yield: 85.1 %

Procedure:
3-Iodo-7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (4.074 g, 12.85 mmol) and sodium azide (4.178 g, 64.3 mmol, 5 eq.) were dissolved in 50 mL of dimethylformamide and heated with stirring at 60° for 2 hours. The solvent was evaporated under vacuum at room temperature and the residue redissolved in 150 mL of ethyl acetate and washed with water (3×50 mL) and brine (1×50 mL). The organic layer was separated, dried over MgSO4, filtered and evaporated to dryness under vacuum to yield 2.538 g (10.94 mmol, 85%) of product. 1H NMR (200 MHz, CDCl3): 2.2-2.7 (m,3H), 2.90 (m,1H), 3.75 (s,3H), 3.80 (m,1H), 6.75 (m,2H), 6.95 (d,8 Hz, 2H), 8.22 (br s,1H). FAB-MS: calculated for C11H12N4O2 232; found 233 (M+H,30%).
Reaction SMILES: [C:1]([CH:9]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([F:22])[CH:15]=2)[C:11](=[O:23])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>B(Br)(Br)Br.C(Cl)Cl>[C:1]([CH:9]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:22])[CH:15]=2)[C:11](=[O:23])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CC(C(=O)c3ccccc3)CC2=O)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccccc1)C1CC(=O)N(c2ccc(O)c(F)c2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-benzoyl-1-(3-fluoro-4-methoxyphenyl)pyrrolidin-2-one (Step 2, 1.0 g, 3.2 mmol) in 20 mL of 1 M BBr3/CH2Cl2 was stirred at RT for 16 h. The solution was concentrated in vacuo and the residue was diluted with 50 mL of MeOH and concentrated in vacuo again. The resulting white solid was washed with 50% EtOAc/hexane to give the title compound. MS (ESI pos. ion) m/z: 300.4 (M+H). Calc'd Exact Mass for C17H14FNO3: 299.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Cl)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CCc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-(4-chlorophenyl)propionic acid (2.45 g, 13.27 mmol) in toluene (65 mL) and methanol (10 mL) was added trimethylsilyldiazomethane (2M solution in hexane, 7.63 mL, 15.26 mmol). The mixture was allowed to stir for 1 hour and gas evolution was observed initially. After 1 hour, the mixture became homogeneous and was quenched via addition of 3.5 mL of acetic acid. The mixture was concentrated in vacuo, and purified via column chromatography on a Biotage 65i column eluting with 0% ethyl acetate in hexanes (1 CV) followed by a gradient to 50% ethyl acetate in hexanes (over 7 CV) to furnish the desired product. 1H NMR (CDCl3, 500 MHz) δ 7.25 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 3.67 (s, 3H), 2.92 (t, J=7.7 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:39][CH2:38][O:37][CH2:36]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH:35]2[CH2:39][CH2:38][O:37][CH2:36]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: BrCCCC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
N2-Butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (150 mg, 0.428 mmol) was heated in dry DMF (2.5 ml) at 60° C. for 1 hour with potassium carbonate (237 mg, 1.713 mmol). The reaction mixture was cooled to room temperature and 3-(3-bromopropyl)tetrahydrofuran (99 mg, 0.514 mmol) was added. The mixture was then heated at 50° C. overnight. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers were separated and then dried by passage through a hydrophobic frit and evaporated to dryness. The residue was dissolved in 1:1 MeOH:DMSO (2.8 ml) and purified by mass directed autopreparation. Product containing fractions were evaporated under a stream of nitrogen in a blowdown apparatus to give the title compound as a clear gum (84 mg).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24](OC2C=CC=CC=2)=[N:25][C:26]#[N:27])=[CH:19][CH:18]=1>C(#N)C>[C:20]1([O:23][C:24]([N:10]2[CH2:9][CH2:8][CH:7]([N:6]3[C:5]4[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=4[NH:3][C:2]3=[O:1])[CH2:12][CH2:11]2)=[N:25][C:26]#[N:27])[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CC#N
Product: N#CN=C(Oc1ccccc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 60 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
To a solution of 4-(2-keto-1-benzimidazolinyl)piperidine (1.3 g; 5.98 mmol) in acetonitrile was added diphenyl N-cyanocarbonimidate (1.56 g; 6.55 mmol; 1.1 equiv). The reaction mixture was stirred at 60° C. for 48 h under nitrogen atmosphere and then concentrated under reduced pressure. The crude product was suspended in ethyl acetate (50 mL) and a saturated aqueous solution of sodium bicarbonate (50 mL) and stirred overnight at room temperature. The solid was collected by filtration and dried to give N-cyano-4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboximidic acid phenyl ester (1.85 g; 85%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.O>CN(C=O)C>[N:16]1[CH:17]=[CH:18][CH:19]=[N:20][C:15]=1[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Brc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ncccn1
Temperature: 100 °C
Yield: 49.5 %

Procedure:
To a solution of sodium hydride (4.4 g of a 60% dispersion in oil, 0.11 mol) in DMF (200 ml) was added diethyl malonate (16 ml, 0.11 mol) in DMF (50 ml) dropwise at room temperature. After 30 min 2-bromopyrimidine (8.0 g, 0.05 mol) was added portionwise and the solution heated at 100° C. for 3 h. The solution was cooled to room temperature, water (100 ml) was added and the mixture extracted with EtOAc (3×60 ml). The combined organic layers were dried (MgSO4) and evaporated. The residue was chromatographed on silica, using hexane:EtOAc (3:1) as the eluant, to afford the ester (5.9 g, 49%) as a pale yellow oil which solidified on standing at 0° C. 1H NMR (360 MHz, CDCl3) δ 1.29 (6H, t, J=7.1 Hz), 4.29 (4H, q, J=7.1 Hz), 5.10 (1H, s), 7.26 (1H, t, J=4.9 Hz), 8.74 (2H, d, J=4.9 Hz).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:20][C:21]([C:23]2[O:27][N:26]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=2)=O)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[CH:8][CH:9]=1)([O-])=O>C(O)(=O)C.[Fe]>[C:28]([C:25]1[CH:24]=[C:23]([C:21]2[NH:1][C:4]3[C:5]([N:20]=2)=[N:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[CH:8][CH:9]=3)[O:27][N:26]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)ccc2[N+](=O)[O-])on1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(-c2nc3nc(-c4ccccc4C(F)(F)F)ccc3[nH]2)on1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (78.0 mg, 0.180 mmol, prepared as described in the previous step) in acetic acid (5 mL) was treated with iron powder (50.1 mg, 0.898 mmol) and heated to 100° C. for 2 h. The volume of acetic acid was reduced to 2 mL by concentrating in vacuo, and saturated aqueous NaHCO3 (50 mL) was added. The resulting mixture was extracted twice with EtOAc (60 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 4-g SEPRA Si 50 SPE column (Isco system: Flow rate=10 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 5 min, then 1:99 to 1:9 v/v over 40 min) to yield 2-(3-tert-butyl-isoxazol-5-yl)-5-(2-trifluoromethyl-phenyl)-1H-imidazo[4,5-b]pyridine as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 10.06 (br. s., 1H), 8.16 (d, J=8.3 Hz, 1H), 7.81 (d, J 8.1 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.52-7.60 (m, 2H), 7.46 (d, J=8.3 Hz, 1H), 7.07 (s, 1H), 1.42 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C20H17F3N4O: 387.1 (M+H); Measured: 387.1.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:16]1N=CN(C(N2C=NC=C2)=O)C=1.CO>C1COCC1>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])[CH:9]=[CH:10][C:2]=1[OH:1]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Solvent: C1CCOC1
Solvent: CO
Product: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Temperature: 70 °C

Procedure:
To 77 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid in 300 ml THF was added 85 mmol CDI and the mixture heated at 70° C. for 1 h. 770 mmol methanol was then added and the mixture was heated at 70° C. for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane/dichloromethane 45:45:10) to afford the title compound. MS (m/e): 244.1 ([M−H]−, 100%)
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:40](=[O:41])[CH2:39][C:36]1[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Product: O=C(Cc1ccncc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4 with 98 mg (0.561 mmol) of 4-pyridylacetic acid hydrochloride, 143 mg (0.562 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 209 μl (1.50 mmol) of triethylaniine. The title compound is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.56, FD-MS: M+ =546.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8][C:9]([O:11]C)=[O:10].[N:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])=[N+:15]=[N-:16].CO.C[O-].[Na+].[OH-].[Na+]>CO>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:14]1[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[C:8]([C:9]([OH:11])=[O:10])[N:16]=[N:15]1
Reactant: [N-]=[N+]=Nc1ccccc1F
Reactant: COCCCCC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCc1c(C(=O)O)nnn1-c1ccccc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A solution of methyl 7-methoxy-3-oxoheptanoate (2.0 g) in methanol (70 ml) was cooled to 0° C.-5° C., 1-azido-2-fluorobenzene (960 mg) and 28% sodium methoxide methanol solution (2 g) were added and the mixture was stirred at 60° C. for 3 hr. Then, 1N sodium hydroxide (14 ml) was added, and the mixture was stirred at 60° C. for 1 hr. The solvent was evaporated under reduced pressure and water (20 ml) was added to the residue. 1N Hydrochloric acid was added for neutralization and the mixture was extracted with ethyl acetate (50 ml×2). The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (1.61 g) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:8]1.[C:25]1([CH:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.C(Cl)Cl>[C:35]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH:16]=[CH:17][CH:18]=3)[CH2:11][CH2:12]2)=[O:33])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN)CC2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3)) and Scheme AT using N-{3-[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 526.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10](O)[CH2:11][CH2:12][OH:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:13][CH2:12][CH2:11][CH2:10][O:5]1
Reactant: OCCCO
Reactant: O=Cc1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Brc1ccccc1C1OCCCO1

Procedure:
ortho-Bromobenzaldehyde (4a) (8 g, 43.24 mmol) was stirred with 1,3 propanediol (4.7 ml, 64.86 mmol) and p-toluenesulfonic acid monohydrate (164 mg, 0.86 mmol) in benzene (150 ml) in a flask equipped with a Dean-Stark trap and a condenser. The mixture was heated at reflux for 12 hrs, cooled, and extracted with 2 M NaOH (100 ml), and brine (100 ml×3). The solution was dried over MgSO4, and the solvent evaporated to the title compound in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:19])=[N:5]2
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 95 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 95%). 1H NMR (300 MHz, CDCl3): δ 3.25 (s, 4H), 3.78 (s, 3H), 4.13 (s, 4H), 6.86 (d, J=8.4 Hz, 2H), 7.22-7.26 (m, 3H), 7.44 (m, 1H), 7.70 (m, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[NH:32][C:33](=[O:35])[CH3:34]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[C:18]([NH:32][C:33](=[O:35])[CH3:34])[CH:19]=2)=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NC(C)=O
Product: COc1ccc(-c2nnc(N)nc2-c2ccccc2)cc1NC(C)=O
Yield: 25 %

Procedure:
N-[5-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide (0.170 g, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.5 g, 1.99 mmol) and N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide according to the general procedure of Example 1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([NH:17][CH2:18][CH3:19])([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:18]([NH:17][C:11]1([C:14]([NH2:16])=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH3:19]
Reactant: CCNC1(C(N)=O)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCNC1(C(N)=O)CCNCC1

Procedure:
To a solution of 1-benzyl-4-ethylaminopiperidine-4-carboxylic acid amide I-(7A-80)e (7.39 g, 28.3 mmol) in methanol (100 ml) was added 20% Pd(OH)2 on carbon (50% water; 1.48 g). The mixture was place on a Parr® shaker and was reduced (50 psi H2) at room temperature overnight. The mixture was filtered through a pad of Celite®, and then concentrated to a colorless solid (4.84 g, quantitative): +ACPI MS (M+1) 172.2; 1H NMR (400 MHz, CD2Cl2) δ 2.89 (ddd, J=12.9, 8.7, 3.3 Hz, 2H), 2.75 (ddd, J=12.9, 6.6, 3.7 Hz, 2H), 2.45 (q, J=7.2 Hz, 2H), 1.95 (ddd, J=13.7, 8.3, 3.7 Hz, 2H), 1.55 (ddd, J=13.7, 6.6, 3.3 Hz, 2h), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.C1C(=O)N([I:19])C(=O)C1>>[F:11][C:2]([F:1])([F:10])[C:3]1[C:8]([I:19])=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(C(F)(F)F)ccn1
Product: Nc1cc(C(F)(F)F)c(I)cn1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 20.0 g (123 mmol) 4-trifluoromethyl-pyridin-2-ylamine and 27.8 g (123 mmol) NIS. Yield after precipitation from the reaction mixture and isolation of additional product from the mother liquid by chromatography in silica gel: 20.3 g (57%).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[O:10]=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[CH:21]([CH3:34])[CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:34][CH:21]([N:12]2[C:13](=[O:20])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]2=[O:10])[CH3:22])=[C:4]([I:9])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(C)N2C(=O)c3ccccc3C2=O)cc1
Reactant: Oc1cnc(F)cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(COc1cnc(F)cc1I)N1C(=O)c2ccccc2C1=O
Yield: 42.8 %

Procedure:
Heat a mixture of 6-fluoro-4-iodo-pyridin-3-ol (150 mg, 0.63 mmol), toluene-4-sulfonic acid 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl ester (226 mg, 0.63 mmol), cesium carbonate (206 mg, 0.63 mmol) in DMF (2 mL) at 100° C. for 5 h. Cool the mixture and add water. Extract with ethyl acetate. Wash the organic layer with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo to a light yellow solid. Purify by column chromatography (hexane to 10% ethyl acetate in hexane) to afford the title compound as a white solid (115 mg, 43%). MS (ES) m/z 427 [M+1]+.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1>C(O)C>[CH:1]([C@H:14]1[CH2:20][C@H:19]([OH:18])[C@@H:17]([NH:30][CH2:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:16][O:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccc(F)cc1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Solvent: CCO
Product: O[C@H]1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCCc1ccc(F)cc1

Procedure:
(1R,4R,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28c (0.02 g, 0.075 mmol) was reacted with 2-(4-fluorophenyl)-ethylamine (0.21 g, 1.50 mmol) in ethanol (Procedure E) to yield (2R,4S,5S)-2-benzhydryl-5-[2-(4-fluorophenyl)-ethylamino]-tetrahydropyran-4-ol, (+)-29c, 0.030 g (98%, [α]D=(+)63.4, c=1, MeOH).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[CH:15]=[N:14]2)=[CH:9][CH:8]=1.[C:22]1(C)C=CC=C[CH:23]=1>>[CH2:22]([O:20][C:19]([C:16]1[CH:15]=[N:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:12][CH:11]=2)[C:17]=1[CH3:18])=[O:21])[CH3:23]
Reactant: Cc1ccccc1
Reactant: COc1ccc(-n2ncc(C(=O)O)c2C)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cnn(-c2ccc(OC)cc2)c1C
Temperature: 80 °C

Procedure:
Thionyl chloride (3.84 g) was added to a solution of 1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (5.0 g) described in Reference Example 5 in toluene (20 ml) at room temperature, stirred at 80° C. for an hour and the solvent and an excess amount of thionyl chloride were evaporated. Pyridine (10 ml) and ethanol (20 ml) were added to the resulting residue and stirred at 40° C. for 0.5 hour. After completion of the reaction, the solvent was evaporated and ethyl acetate and 1N aqueous solution of sodium hydroxide were added. The mixture was extracted with ethyl acetate three times and the organic layer was dried over anhydrous sodium sulfate and concentrated to give 1-(4-methoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (5.2 g).