Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([NH:25][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:26]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Cc1ccc(F)cc1N
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)ccc1C
Reaction time: 96 h

Procedure:
The ester was prepared according to procedure A using diethyl 2-methylmalonate (6.18 mL, 36.0 mmol), pyridine (3.88 mL, 47.9 mmol) and 5-fluoro-2-methyl aniline (3.00 g, 23.97 mmol). Heating continued for 4 days. The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(5-fluoro-2-methylphenylamino)-2-methyl-3-oxopropanoate as a tan solid. Mass Spectrum (ESI) m/e=254.2, (M+1).
Reaction SMILES: O[C:2]1[CH:7]=C(O)[N:5]2[N:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+].[CH:27]([Cl:30])(Cl)Cl>>[Cl:19][C:2]1[CH:7]=[C:27]([Cl:30])[N:5]2[N:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=[C:4]2[N:3]=1
Reactant: ClC(Cl)Cl
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2nc(O)cc(O)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cc2nc(Cl)cc(Cl)n2n1
Temperature: 25 °C

Procedure:
A suspension of ethyl 5,7-dihydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (9.59 g, 43.0 mmol) and phosphorous oxychloride (20.0 mL, 215 mmol) was refluxed for 1 hr. After being cooled to ambient temperature, the reaction mixture was poured into saturated sodium bicarbonate and chloroform. The organic layer was separated and aqueous layer was extracted with chloroform. The organic layer was combined and concentrated in vacuo to give ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate. MS (APCI): m/z 260/262 (M+H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C:25]([F:28])([F:27])[F:26])[C@@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=1[CH3:24])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([NH:37][NH2:38])=[O:36])=[CH:33][CH:32]=1)#[N:30].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C@H:9]([C:25]([F:26])([F:28])[F:27])[C@@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=1[CH3:24])[C:11]([NH:38][NH:37][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([C:29]#[N:30])=[CH:40][CH:39]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
To a solution of (2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoic acid (280 mg) in THF (15 mL) were added 4-cyanobenzohydrazide (130 mg, 0.81 mmol), HOBt (109 mg, 0.81 mmol), EDC (232 mg, 1.21 mmol) and Et3N (0.25 mL, 1.79 mmol) at −20° C. sequentially. After addition, the mixture was stirred at −20° C. for 30 min., then room temperature overnight. The reaction was quenched by adding ice-water. After removal of the THF, the residue was extracted with EtOAc (200 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. The filtrate was concentrated and purified by flash chromatography to give the title compound N′-((2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoyl)-4-cyanobenzohydrazide (180 mg, 10%). 1H NMR (400 MHz, CDCl3, δ in ppm) 9.26 (b, 1H), 8.88 (b, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.36˜7.39 (m, 5H), 7.28 (d, J=8.7 Hz, 1H), 6.44 (d, J=8.7 Hz, 1H), 5.22 (d, J=6.6 Hz, 1H), 4.93 (d, J=11.1 Hz, 1H), 4.80 (d, J=11.1 Hz, 1H), 4.66 (m, 1H), 4.33 (d, J=6.6 Hz, 1H), 2.27 (s, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:2]1.C([Li])CCC.CCCCCC.O1CCCC1.O1CCCC1.O1CCCC1.[Cl-:44].[Cl-].[Cl-].[Cr+3:47]>O1CCCC1>[Cl-:44].[Cl-:44].[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[Cr+2:47]
Reactant: [Cr+3]
Reactant: C1=C(CCc2ccccn2)c2ccccc2C1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Cr+2]C1=Cc2ccccc2C1CCc1ccccn1
Temperature: -100 °C
Reaction time: 0.83 h

Procedure:
A solution of 22.1 g (0.1 mol) of 2-[2-(1H-inden-3-yl)ethyl]pyridine in 470 ml of tetrahydrofuran was cooled to −100° C. 62.5 ml of a 15% strength n-butyllithium solution in hexane (0.1 mol) were slowly added dropwise. After the addition was complete, the reaction mixture was stirred for a further 50 minutes at −100° C. The mixture was subsequently allowed to warm to room temperature. After stirring for another 2 hours, the solution was cooled to −60° C. and 38 g (0.1 mol) of chromium trichloride tris(tetrahydrofuran) were added while stirring. The mixture was allowed to warm slowly to room temperature and was subsequently stirred for another 10 hours at room temperature. The reaction mixture was then refluxed for 20 minutes and subsequently cooled to room temperature. The solid which had precipitated was filtered off and washed with hot tetrahydrofuran. The solid was subsequently washed with diethyl ether and dried under reduced pressure. This gave 28.1 g of (1-(2-pyridylethyl)indenyl)chromium dichloride (82%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[N:12]O)C(=O)[NH:8]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1CCN2C(=NCCC2)CC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[C:6]#[N:12]
Reactant: O=C1Nc2cc(Br)ccc2C1=NO
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: N#Cc1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a cold solution of oxime (10) (8 g, 33.33 mmol) in CH2Cl2 (200 mL) at 0° C. was added 2,6-lutidine (4.5 mL, 38.7 mmol), followed by the dropwise addition of trifluoromethanesulfonic anhydride (5.6 mL, 33.33 mmol). The cooling bath was removed, and the mixture was heated to reflux for 3 h. The reaction mixture was cooled to room temperature, and DBU (9.9 mL, 66.66 mmol) was added dropwise while maintaining the internal temperature of the reaction below 30° C. The mixture was further stirred at room temperature for 1 h and poured with vigorous stirring into excess dilute NaHCO3. This mixture was then stirred for several minutes, and the organic layer was separated. The aqueous layer was re-extracted with CH2Cl2 (100 mL×2). The combined extracts were dried with MgSO4 and concentrated to leave a dark brown solid, which was passed through a short silica column, eluting with CH2Cl2 (100%). The resulting fraction was dried under vacuum, triturated with CH2Cl2/hexanes, and the solid formed was filtered and dried under vacuum to afford 5.36 g (82%) of 11 as a light yellow solid. IR (KBr) νmax. cm−1: 3436, 3310 (NH2), 3032 (Ar—H), 2920 (Alph-H), 2246 (CN), 1610, 1512, 1418 (C═C). 1H NMR (500 MHz, CDCl3) δ=4.47 (br. s, 2H, NH2); 6.88 (dd, 1H, J=2.8, 8.2 Hz, H-5); 6.94 (br. s, 1H, H-3); 7.24 (d, 1H, J=8.2 Hz, H-6); 13C NMR (125.7 MHz, CDCl3) δ=95.17 (C-1), 117.16 (CN), 118.15 (C-3), 121.60 (C-5), 129.03 (C-4), 133.60 (C-6), 150.47 (C-2). Calculated (%) for C7H5BrN2 (195.96); C, 42.67; H, 2.56; N, 14.22. found (%); C, 42.60; H, 2.61; N, 14.17.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=1.[Cl:10][C:11]1[C:12]([O:34][CH3:35])=[CH:13][C:14]([O:32][CH3:33])=[C:15]([CH2:17][CH2:18][C:19]2([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]2)[CH:16]=1>>[Cl:10][C:11]1[C:12]([O:34][CH3:35])=[CH:13][C:14]([O:32][CH3:33])=[C:15]([CH2:17][CH2:18][C:19]2([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:24][C:23](=[O:25])[C:22]([CH2:2][C:3]3[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=3)=[C:21]([OH:26])[CH2:20]2)[CH:16]=1
Reactant: CCc1noc(CCl)n1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Product: CCc1noc(CC2=C(O)CC(CCc3cc(Cl)c(OC)cc3OC)(C3CCCC3)OC2=O)n1
Yield: 7 %

Procedure:
The title compound was prepared as described in Example B(53), using 5-(chloromethyl)-3-ethyl-1,2,4-oxadiazole (Step 1, below) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 7%. 1H NMR (300 MHz, DMSO-d6) δ 1.10 (t, J=7.8 Hz, 3H), 1.25-1.73 (m, 8H), 1.89 (m, 2H), 2.33 (m, 1H), 2.43-2.53 (m, 2H, overlap with DMSO-d5), 2.58 (q, m, overlap, 3H), 2.76 (d, J=18 Hz, 1H), 3.75 (ABQ pattern, J=16 Hz, 2H), 3.77 (s, 3H), 3.84 (s, 3H), 6.71 (s, 1H), 7.10 (s, 1H), 11.31 (br s, 1H). LC-MS (APCI) calcd for C25H31ClN2O6: 490.19; found (M+H+) 491.0 m/z.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:7]([O:20][CH:21]([CH3:23])[CH3:22])[CH:6]=2.C1C(=O)N([Br:41])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:41][CH2:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:7]([O:20][CH:21]([CH3:23])[CH3:22])[CH:6]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC(C)C)c(S(C)(=O)=O)cc12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC(C)C)c(S(C)(=O)=O)cc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-methyl-7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.97 g, 6.17 mmol), NBS (1.427 g, 8.02 mmol) and diphenylperoxyanhydride (0.149 g, 0.617 mmol) in carbon tetrachloride (30 mL) was heated to 100° C. and stirred overnight. The mixture was cooled to room temperature, and the solvent was removed under reduced pressure to give methyl 3-(bromomethyl)-7-[(1-methylethyl)oxy]-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 562.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][CH:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[O:14]C(=O)[NH:12]2)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[NH2:12][CH:11]([CH2:10][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:25][CH:24]=1)[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[OH:14]
Reactant: CC(C)(C)Oc1ccc(CC2NC(=O)OC2c2cccc(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)Oc1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of (4RS,5SR)-4-(4-tert-butoxybenzyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (3.80 g, 10.6 mmol) in ethanol (20 ml) was added 8N aqueous sodium hydroxide solution (3.96 ml, 31.7 mmol), and the mixture was stirred at 80° C. for 6 hrs. To the reaction solution was added water (20 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the objective substance (2.67 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14]>CN(C)C=O.[Pd]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)Nc1cnccn1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(N)cc1NC(=O)Nc1cnccn1
Temperature: 4 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
A solution of (2-methoxy-5-nitrophenyl)-3-pyrazin-2-yl-urea (Compound 159, Example 3) (16.9 g, 55 mmol) in dimethylformamide (DMF, 320 mL) was shaken under H2 in the presence of palladium on carbon (Pd/C) catalyst (1.6 g, 10% Pd) at 80° C. for 12 h. A second portion of catalyst was added (1.6 g) and shaking was continued for an additional 8 h at the same temperature. The solution was filtered through a pad of celite using an additional 200 mL of DMF. The filtrate was concentrated in vacuo and the residue was triturated with methanol (100 mL). The solid was collected, stirred in boiling methanol, and solids present (1.8 g) were filtered off and discarded. The filtrate was cooled at 4° C. overnight. Solids (1.4 g) were removed by filtration and the filtrate was concentrated in vacuo to a tan solid (2.6 g). The crude solid product was triturated with THF (200 mL), collected by filtration, and dried in vacuo to afford the product as a tan solid (1.85 g, 13%). 1H NMR (300 Mhz, d6 DMSO) δ: 10.10 (s, 1H), 9.94 (br s, 1H), 8.89 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.58 (s, 1H), 7.75 (d, 1H), 6.21 (d, 1 H), 4.70 (s, 2H), 3.76 (s, 3H). 13C NMR (75 Mhz, d6-DMSO) δ: 151.4, 149.4, 142.6, 140.9, 139.8, 137.2, 135.2, 128.7, 112.8, 107.7, 106.0, 56.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:21])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1
Reactant: Nc1cccc2cccnc12
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Yield: 44.9 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (1.4 g, 9.72 mmol), 4-methyl-2-nitro-benzenesulfonyl chloride (Intermediate 448) (2.97 g, 12.6 mmol), pyridine (7 ml) DMAP (cat.) and DCM (30 ml) gave the title compound (1.5 g, 45%), after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.C([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)(OC(C)(C)C)=O.Cl.O1CCOCC1>CC(O)C>[N:28]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(N3CCNCC3)ncnc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.6 %

Procedure:
To a solution of 4-chloroquinazoline (2.0 g, 12.2 mmol) (Tobe, Masanori, et al., Bioorg. Med. Chem. 2003, 11(3), 383) and DIEA (3.2 mL, 18.2 mmol) in 40 mL IPA was added Boc-piperazine (1.96 g, 12.81 mmol). The reaction mixture was heated to reflux and stirred for 20 hours, after which it was cooled to room temperature and concentrated by rotary evaporation. The residue was dissolved in dichloromethane (DCM) and washed with 1N NaOH. The organic layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was dissolved in 25 mL dioxane, and 4M HCl/dioxane (46 mL, 182 mmol) was added dropwise. The suspension was sonicated for 2 minutes and stirred 13 hours at room temperature, after which the reaction mixture was concentrated to dryness by rotary evaporation. The resulting amine HCl salt was dissolved in 2N NaOH and extracted with DCM. The organic layer was dried (Na2SO4), filtered, and concentrated by rotary evaporation. The resulting oil was purified on silica (9:1:0.02 DCM/MeOH/NR4OH) to give 4-piperazinylquinazoline as a yellow oil (2.5 g, 96%). 1H NMR (CDCl3, 400 MHz) δ 8.74 (s, 1H), 7.92-7.86 (m, 2H), 7.76-7.70 (m, 1H), 7.48-7.42 (m, 1H), 3.75 (t, J=4.9 Hz, 4H), 3.09 (t, J=4.9 Hz, 4H), 1.89 (br s, 1H). Rt 0.70. MS (ESI+) [M+H]+ 215.
Reaction SMILES: O[C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C:6](=[O:22])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2O)[CH2:3]1.[CH3:23][O:24][C:25](Cl)=[O:26]>N1C=CC=CC=1>[C:25]([C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C:6](=[O:22])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:25]([O:24][CH3:23])=[O:26])[CH2:3]1)([O:24][CH3:23])=[O:26]
Reactant: C[C@]12CC[C@H]3[C@@H](C(=O)C=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](C(=O)OC)[C@@]4(C)CC[C@@H]32)C1
Yield: 81 %

Procedure:
Prepared from 3β,17β-dihydroxyandrost-5-ene-7-one and methylchloroformate in pyridine at 0-5° C. Yield 81%, m.p. 167-9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13]O)=[CH:5][CH:4]=1.S(Cl)([Cl:17])=O>ClCCl.C(OCC)(=O)C>[Cl:17][CH2:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cccc(CO)c2c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2cccc(CCl)c2c1
Yield: 84 %

Procedure:
To a solution of the compound obtained in Step A (100 g) in dichloromethane (5 ml/g) there are added 2 equivalents of thionyl chloride (126.35 g). The mixture is heated to reflux and maintained at reflux for 2 hours. After returning to ambient temperature, the solvent is evaporated off under reduced pressure. The oil obtained is taken up in ethyl acetate and washed with water and then with saturated NaCl solution. The solvent is evaporated off under reduced pressure and the crude product is purified by passing over a pad of silica (eluant: heptane). The title compound is obtained in the form of a yellow solid in a yield of 84%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]=1[C:31]([F:34])([F:33])[F:32])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>CN(C)C=O>[CH2:24]([O:23][C:19]1[CH:20]=[CH:21][C:22]([Br:1])=[C:17]([O:16][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:18]=1[C:31]([F:33])([F:32])[F:34])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1c(OCc2ccccc2)cccc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1c(OCc2ccccc2)ccc(Br)c1OCc1ccccc1
Yield: 97.8 %

Procedure:
Add N-bromosuccinimide (4.67 g, 26.23 mmol) to a solution of 1,3-bis-benzyloxy-2-trifluoromethyl-benzene (9.40 g, 26.2 mmol) in dimethylformamide (100 mL) and stir. After 18 hours add water and extract with diethyl ether. Combine organic layers, dry with sodium sulfate, filter and concentrate under reduced pressure to yield the title compound as an orange oil (11.20 g, 98%): 1H NMR (CD3CN) δ 4.97 (2, 2H), 5.18 (s, 2H), 6.99 (d, 1H), 7.33-7.55 (m, 10H), 7.79 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.Cl.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:29]3[CH2:28][CH2:27][CH:26]([C:20]4[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=4[Cl:18])[CH2:31][CH2:30]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Reactant: Fc1ccc(Cl)c(C2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(F)ccc2Cl)CC1
Reaction time: 0.33 h
Yield: 42.3 %

Procedure:
To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (73 mg, 0.27 mmol) in THF (2.2 mL) was added a solution of LiOH monohydrate (13 mg, 0.30 mmol) in H2O (1.5 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (2.9 mL) under an atmosphere of N2. To this mixture was added 4-(2-chloro-5-fluorophenyl)piperidine hydrochloride (17, 68 mg, 0.27 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (240 mg, 0.54 mmol), and diisopropylethylamine (0.14 mL, 0.81 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(2-chloro-5-fluorophenyl) piperidin-1-yl)methanone as a white solid (50 mg, 42%): 1H NMR (500 MHz, DMSO-d6) δ 9.13-9.11 (m, 1H), 7.98 (dd, J=9.5, 1.0 Hz, 1H), 7.71 (dd, J=9.5, 1.5 Hz, 1H), 7.50 (dd, J=9.0, 5.5 Hz, 1H), 7.28 (dd, J=25, 3.0 Hz, 1H), 7.15-7.10 (m, 1H), 5.28-5.20 (m, 1H), 4.76-4.70 (m, 1H), 3.42-3.29 (m, 2H, overlaps with H2O), 3.07-2.98 (m, 1H), 1.96-1.65 (m, 4H).
Reaction SMILES: Cl.[CH:2]1([CH2:9][NH2:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:11]([N:18]1[CH:22]=[CH:21]N=C1)(N1C=CN=C1)=[O:12]>>[CH:2]1([CH2:9][NH:10][C:11]([NH:18][CH2:22][CH:21]2[CH2:5][CH2:4][CH2:3][CH2:2][CH2:8][CH2:7]2)=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCC1CCCCCC1
Agent: Cl
Product: O=C(NCC1CCCCCC1)NCC1CCCCCC1
Yield: 24 %

Procedure:
In the manner of step (a) of Example 6, cycloheptanemethylamine hydrochloride (R. B. Turner and R. H. Garner, J. Amer. Chem. Soc. 1958, 80:1424-1430; 22.00 g, 0.135 mole) was reacted with 1,1'-carbonyldiimidazole to give 1,3-bis(cycloheptylmethyl)urea as a white powder (4.45 g, 24%), m.p. 106°-108° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[C:4]1=[O:14].C(N(C(C)C)CC)(C)C.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>ClCCl>[Br:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:14])[CH:3]([NH:2][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:11]2
Reactant: CCCCCC(=O)Cl
Reactant: NC1CCc2cc(Br)ccc2C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCC(=O)NC1CCc2cc(Br)ccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To 2-amino-6-bromo-3,4-dihydronaphthalen-1(2H)-one hydrochloride (Preparation 82B, 1.1 g, 3.98 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (1.737 mL, 9.94 mmol) at 0° C. under a nitrogen atmosphere. To the homogenous solution was added hexanoyl chloride (0.602 mL, 4.38 mmol) dropwise over a period of 3 min. The reaction mixture was allowed to come to room temperature (˜5 min.) and was stirred at room temperature for 3 h. The reaction mixture was partitioned between dichloromethane (30 mL) and 1N HCl (10 mL). The dichloromethane layer was separated, washed with sat. aq. NaHCO3 (20 mL), dried over sodium sulfate and concentrated to yield N-(6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)hexanamide (1.2 g, 3.55 mmol, 89% yield) as an off-white solid. LC/MS M+1 339.