Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:11])=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[S-:12][C:13]#[N:14].[K+]>C(O)C>[Cl:2][C:3]1[C:4]([CH3:11])=[C:5]([NH:9][NH:10][C:13]([NH2:14])=[S:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(Cl)cccc1NN
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1c(Cl)cccc1NNC(N)=S

Procedure:
19.3 g (0.1 mole) of 3-chloro-2-methylphenylhydrazinehydrochloride were dissolved in 200 ml of absolute ethanol. 11.64 g (0.12 mole) of potassium thiocyanate were added to the solution, and the mixture was heated during reflux for 16 hours. The mixture was then cooled, whereby the product was partially precipitated, and the mixture was subsequently evaporated to dryness by means of a rotating evaporator. The product was recrystallized from 200 ml water and 250 ml methanol, separated by filtration and washed thoroughly with water.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CS(O[CH2:20][CH2:21][CH2:22][C:23]#[CH:24])(=O)=O>O1CCCC1>[CH3:1][C:2]([CH2:24][CH2:23][CH2:22][C:21]#[CH:20])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: C#CCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCC(C)(C(=O)OCC)C(=O)OCC

Procedure:
A solution of diethyl methylmalonate (Aldrich Chemical Company, 35.6 ml) in dry tetrahydrofuran (200 ml) was added, dropwise, to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 9.1 g) in tetrahydrofuran (50 ml) under nitrogen. After the addition was complete, the mixture was heated to gentle reflux for 1 hour and then allowed to cool before a solution of pent-4-ynyl methanesulphonate (35.2 g) in tetrahydrofuran (50 ml) was added. The resulting mixture was heated to gentle reflux for a further 2 hours. The bulk of the solvent was then removed in vacuo and the residue was partitioned between diethyl ether and water. The organic phase was separated and washed with water and brine before drying over anhydrous magnesium sulphate and evaporation under reduced pressure. Distillation gave diethyl 2-methyl-2-(pent-4-ynyl)malonate (45.8 g) as a colourless oil (b.p. 92°-97°, 0.5 mm Hg)
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])[O:11][CH3:12])=[O:9])[C:4](=[O:22])O1.C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:32][N:33](C)[C:34](C1CN(C)C(=O)C=1O)=O>CO>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:13]([N:10]([O:11][CH3:12])[C:8]([C:7]2[CH2:32][N:33]([CH3:34])[C:4](=[O:22])[C:5]=2[OH:6])=[O:9])[CH3:14])=[CH:20][CH:19]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CON(C(=O)C=C1OC(C)(C)OC1=O)C(C)c1ccc(F)cc1
Agent: C=O
Agent: CN
Solvent: CO
Product: CON(C(=O)C1=C(O)C(=O)N(C)C1)C(C)c1ccc(F)cc1
Yield: 47 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[1-(4-fluorophenyl)-ethyl]-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation Compound 12 to give the title compound as a white solid (47% yield); mp 136–138° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.68 (3H, d, J=7.1 Hz, CH3), 3.1 (3H, s, NCH3), 3.49 (3H, s, OCH3), 4.13 (2H, AB system, JAB=18.2 Hz, Δv=45.7 Hz, NCH2), 5.75 (1H, q, J=7.1 Hz, CH), 7.06 (2H, m, aromatics), 7.42 (2H, m, aromatics). Anal. calcd for C15H17FN2O4: C, 58.43; H, 5.55; N, 9.08. Found: C, 58.40; H, 5.38; N, 9.01.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11](=[O:14])[CH2:12][Cl:13])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:15]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:15])[CH:9]=[C:10]([C:11](=[O:14])[CH2:12][Cl:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(C(=O)CCl)ccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1ncnn2c(C(=O)CCl)cc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of 1-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-chloroethanone (500 mg, 2.37 mmol) in DMF (40 mL) at −40° C., was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (339 mg, 1.19 mmol). The reaction was allowed to stir for 1 hr while warming to rt. A precipitate had formed and the reaction was filtered and the precipitate was washed With Et2O to afford 360 mg (52%) of the desired product as a white powder. 1H NMR (300 MHz, DMSO-d6) 8.12 (s, 1 H), 7.53 (s, 1 H), 5.10 (s, 2H); LC-MS (m+H]+=291, RT=2.51 min.
Reaction SMILES: O.[CH3:2][O:3][C:4]([CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1)=[O:5].[CH2:12](O)[CH2:13][OH:14].C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>[O:14]1[C:10]2([CH2:9][CH2:8][CH2:7][CH:6]2[C:4]([O:3][CH3:2])=[O:5])[O:11][CH2:12][CH2:13]1
Reactant: COC(=O)C1CCCC1=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCC12OCCO2
Yield: 70.3 %

Procedure:
A reflux condenser equipped with a Dean-Stark water separator was attached to a round bottom flask containing methyl 2-cyclopentanonecarboxylate (2 ml, 16.2 mmol), ethylene glycol (994 μl, 17.8 mmol), p-toluenesulfonic acid monohydrate (139 mg, 0.73 mmol), and benzene (30 ml). The mixture was heated under reflux for 2 hours. To the reaction mixture, triethylamine (0.22 ml) was added and the mixture was concentrated and purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane=1/9, 1/1) to obtain the title compound (2.12 g, yield 70.3%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]([CH3:14])[C:3]1=[O:15].O[N:17]=[C:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.N>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:13][N:25]=[C:18]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[N:17]=3)=[CH:10][C:5]=2[N:4]([CH3:14])[C:3]1=[O:15]
Reactant: NC(=NO)c1cccnc1
Reactant: Cn1c(=O)n(C)c2cc(C(=O)O)ccc21
Agent: N
Product: Cn1c(=O)n(C)c2cc(-c3nc(-c4cccnc4)no3)ccc21

Procedure:
The title compound was prepared according to Method C using 1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid (Matrix) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, CD3OD) δ 3.49 (s, 3 H), 3.53 (s, 3H), 7.36 (d, J=8.3 Hz, 1 H), 7.64 (ddd, J=8.0, 5.1, 0.8 Hz, 1 H), 7.98 (d, J=1.6 Hz, 1 H), 8.08 (dd, J=8.3, 1.6 Hz, 1 H), 8.55 (dt, J=8.0, 1.9 Hz, 1 H), 8.73 (dd, J=4.8, 1.6 Hz, 1 H) 9.29 (d, J=1.2 Hz, 1 H). MS (DCI/NH3) m/z 308 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:19]3[O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:18]=3[CH:17]=[CH:16][CH:15]=2)[C@@H:10]([O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[CH2:9]1)=O)(C)(C)C.[ClH:39]>>[ClH:39].[CH:17]1[C:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][C:19]=2[C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc3c2oc2ccccc23)[C@@H](OCc2ccc3ccccc3c2)C1
Agent: Cl
Product: c1ccc2cc(CO[C@H]3CNCC[C@@H]3c3cccc4c3oc3ccccc34)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (3R*,4R*)-4-dibenzofuran-4-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid t-butyl ester (prepared analogously as described in Example 1; 191 mg, 0.38 mmol) and HCl (5 M in 2-propanol, 2 mL, 10 mmol) is stirred for 1 h at RT. The solvent is removed in vacuo and the residue purified by preparative HPLC (CH3CN/H2O). A saturated aqueous NaHCO3 solution is added to the combined pure fractions, CH3CN is evaporated in vacuo, and the remaining aqueous layer extracted twice with DCM. The combined organic phases are dried (Na2SO4) and evaporated. The resulting gum is treated with HCl (4M in 1,4-dioxane, 1 mL) and stirred for 30 min at RT. Evaporation of the solvent in vacuo yields (3R*,4R*)-4-dibenzofuran-4-yl-3-(naphthalen-2-ylmethoxy)-piperidine hydrochloride as a white solid: MS 408.6 [M+H]+; Rf 0.20 (DCM/MeOH 9:1).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[S-:12][C:13]#[N:14].[Na+].[Br-].[Na+].BrBr>C(#N)C.[Cl-].[Na+].O>[S:12]([C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]([OH:11])=[CH:2][CH:3]=1)[C:13]#[N:14]
Reactant: Oc1cccc2c1CCCC2
Reactant: N#C[S-]
Agent: BrBr
Agent: [Br-]
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: N#CSc1ccc(O)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5,6,7,8-Tetrahydro-naphthalen-1-ol (1 g, 6.8 mmol) was dissolved in 25 ml acetonitrile. Sodium thiocyanate (1.76 g, 22 mmol) and sodium bromide (0.7 g, 6.8 mmol) were added and stirred for 5 minutes at ambient temperature. Bromine (1.2 g, 7.48 mmol) was added drop wise over 5 minutes. The orange solution was allowed to stir two hours. Brine was added and the crude product was extracted twice into ethyl acetate. The combined organic extracts were washed once with brine, dried over anhydrous sodium sulfate, decanted and concentrated. Normal phase chromatography afforded the title product, 1.28 g, 92%. 400 MHz 1H MR (DMSO-d6) δ 11.1 (s, 1H), 7.40 (d, 1H, J=8.8 Hz), 6.61 (d, 1H, 8.8 Hz), 2.78 (m, 2H), 2.59 (m, 2H), 1.70 (m, 4H). MS m/z 278 (m+1) Preparation of (4-Thiocyanato-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid methyl ester (compound YYB) The title compound was prepared in the manner analogous to example 1C utilizing compound YYA. 400 MHz 1H NMR (DMSO-d6) δ 7.4 (d, 1H, J=8.8 Hz), 6.80 (d, 1H, 8.8 Hz), 4.84 (s, 2H), 3.64 (s, 3H), 2.78 (m, 2H), 2.59 (m, 2H), 1.70 (m, 4H). MS m/z 278 (m+1). Preparation of (4-Mercapto-5,6,7,8tetrahydro-naphthalen-1-yloxy)-acetic acid methyl ester (compound YY) The title compound was prepared in the manner analogous to example 1D utilizing compound YYB. 400 MHz 1H NMR (DMSO-d6) δ 7.08 (d, 1H, J=8.8 Hz), 6.55 (d, 1H, 8.8 Hz), 4.71 (s, 1H), 4.70 (s, 2H), 3.63 (s, 3H), 2.45 (m, 2H), 2.44 (m, 2H), 1.65 (m, 4H). MS m/z 253 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH:25]=[O:26])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1([Mg]Br)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.[Mg].C1(Br)CCCCC1>O1CCCC1.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[OH:26])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: Br[Mg]C1CCCCC1
Agent: [Mg]
Solvent: CCOCC
Solvent: BrC1CCCCC1
Solvent: C1CCOC1
Product: OC(CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C1CCCCC1
Reaction time: 0.25 h

Procedure:
A solution of 0.4 g of 3-(3,4-dibenzyloxyphenyl)propionaldehyde in 5 ml of anhydrous tetrahydrofuran was cooled to 0° to 5° C. and then 5 ml of an ether solution of cyclohexyl magnesium bromide prepared from 0.12 g of metallic magnesium and 0.82 g of cyclohexyl bromide was added dropwise to the solvent. Thereafter, the reaction mixture was stirred for 15 minutes and after adding thereto 50 ml of an aqueous 5% hydrochloric acid solution, the product was extracted with 30 ml of toluene. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to provide an oily product. The product was applied to silica gel column chromatography and eluted with toluene to provide 0.2 g of 3-(3,4-dibenzyloxyphenyl)-1-cyclohexyl-1-propanol.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH3:24])[CH:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:8]1[CH3:23])[CH3:6].Br[CH2:26][CH2:27][O:28][CH3:29]>[Cl-].[Na+].O>[C:19]([O:18][C:16]([C:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]([CH:5]([CH:4]([O:3][CH2:26][CH2:27][O:28][CH3:29])[CH3:24])[CH3:6])[C:8]=1[CH3:23])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C(C)O
Reactant: COCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCOC(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 40 °C

Procedure:
Sodium hydride (0.026 g, 0.657 mmol) and (±)-tert-butyl 1-(3-hydroxybutan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (0.1 g, 0.329 mmol) were added to a 25 mL rbf and the atmosphere was purged with N2. DMF (5 mL) was added and the reaction was heated at 40° C. for 1 h. The reaction was cooled to ambient temperature and 1-bromo-2-methoxyethane (0.062 ml, 0.657 mmol) was added. The reaction was heated at 90° C. for 3 d. LCMS showed ˜60% conversion. The reaction was poured into half-saturated brine, extracted with EtOAc, the org layer was washed with half-saturated brine, brine, filtered, concentrated and loaded onto a column with aid of DCM. 2×12 g column, the column was then treated with 2 CV of Hex then 20% EtAOc in Hex to elute (±)-tert-butyl 1-(3-(2-methoxyethoxy)butan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (44.4 mg, 37.3%). LRMS (M+H+) m/z: calcd 363.46. found 363.1.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1([C:17]([O:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)=[O:18])[CH2:16][CH:15]=[CH:14][CH2:13]1>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:14]12[O:9][CH:15]1[CH2:16][N:12]([C:17]([O:19][CH2:20][C:21]1[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=1)=[O:18])[CH2:13]2
Reactant: O=C(OCc1ccc2ccccc2c1)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccc2ccccc2c1)N1CC2OC2C1
Reaction time: 96 h
Yield: 43.6 %

Procedure:
mCPBA (4.203 g, 17.04 mmol) was added to a solution of naphthalen-2-ylmethyl 2,5-dihydro-1H-pyrrole-1-carboxylate (2.15 g, 8.52 mmol) in chloroform (35 mL), and the reaction was stirred for 4 days. The reaction mixture was diluted with saturated NaHCO3 and chloroform, and the organic layer was washed with CHCl3, dried over sodium sulfate and condensed. The residue was purified by silica gel chromatography, eluting with a gradient from 1% EtOAc/DCM to 15% EtOAc/DCM, to provide the desired product as a solid (1.0 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)[C:13]=2[CH3:14])=[O:17])[CH:22]=[CH:23][C:24]=1[N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[CH2:31][CH2:30]1)#[N:27]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 8.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (0.7 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.6 g), the title compound (0.1 g) was obtained, melting point: 257° C. (decomposition).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1>>[F:25][C:26]([F:40])([F:41])[C:27]1[CH:28]=[C:29]([C:7]2[N:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)nc23)CC1
Yield: 90.7 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (160 mg, 0.441 mmol) and 3,5-di(trifluoromethyl)phenylboronic acid (183 mg, 0.71 mmol) were converted to 171 mg of the title compound by the procedure of Example 3. (91%). MS(FD) m/e 427.6 (M+). EA calculated for C21H19F6N3: C, 59.02; H, 4.45; N, 9.84. Found: C, 59.31; H, 4.69; N, 9.83.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:29]3[CH2:28][CH2:27][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH3:18])[CH2:31][CH2:30]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: NC(=O)c1cc2ccc(OCC3CO3)cc2o1
Product: COc1ccccc1N1CCN(CC(O)COc2ccc3cc(C(N)=O)oc3c2)CC1

Procedure:
The procedures of Example 8a were repeated except that 1.2 g (0.005 mole) of 2-carbamoyl-6-(2,3-epoxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine were employed to give the desired compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5]1.[CH:12](OCC)=[O:13].O>O1CCCC1.C(OCC)(=O)C>[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][CH:7]([CH:12]=[O:13])[C:6](=[O:10])[CH2:5]1
Reactant: CC1(C)CCCC(=O)C1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C=O)C(=O)C1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a suspension of sodium hydride (28 g, 697 mmol) in tetrahydrofuran (500 ml) was added dropwise a solution of 3,3-dimethylcyclohexanone (80 g, 634 mmol) in tetrahydrofuran (250 ml) under ice-cooling over about 1 hr, and the mixture was stirred for 1 hr. Then, a solution of ethyl formate (99 g, 1.3 mol) in tetrahydrofuran (250 ml) was added dropwise over about 1 hr, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated and extracted with 2 N aqueous sodium hydroxide solution. The aqueous layer was acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 4,4-dimethyl-2-oxocyclohexanecarbaldehyde. To a solution of the obtained 4,4-dimethyl-2-oxocyclohexanecarbaldehyde in methanol (376 ml) was added dropwise a solution of hydrazine monohydrate (31 ml, 640 mmol) in methanol (31 ml) with heating under reflux over about 1 hr, and the mixture was stirred for 15 min. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the organic layer was separated. Then, the organic layer was washed with saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole. To a solution of the obtained 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole in N,N-dimethylformamide (1.4 L) were added iodine (232 g, 915 mmol) and potassium hydroxide (121 g, 1.8 mol) at room temperature, and the mixture was stirred for about 4 hr. Then, under ice-cooling, an aqueous solution (800 ml) of sodium hydrogensulfite (80 g) was added dropwise. Water (2 L) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Then, hexane (350 ml) was added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were collected by filtration, washed with hexane, and dried under reduced pressure to give 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (41 g, yield 23%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].C(Cl)Cl.[C:10]([OH:16])([C:12]([F:15])([F:14])[F:13])=[O:11]>>[OH:16][C:10]([C:12]([F:15])([F:14])[F:13])=[O:11].[CH2:1]([NH:3][C:4](=[O:5])[OH:6])[CH3:2]
Reactant: CCNC(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)O
Reaction time: 0.5 h

Procedure:
The 2-((R)—((R)-1-((S)-2-(Boc-amino)-3-(R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)ethylcarbamate (5 mg, 0.008 mmol) was dissolved in DCM/TFA (3/1 mL). The solution was stirred for 30 min and concentrated. The crude mixture was purified on preparative HPLC to afford 2-((R)—((R)-1-(S)-2-amino-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)(3-chlorophenyl)methoxy)ethylcarbamate TFA salt 2.8 mg, yield 54%. 1H NMR (CD3OD) δ 7.36-7.32 (m, 3H), 7.23 (d, J=7.6 Hz, 1H), 4.20 (br d, J=13.6 Hz, 1H), 4.04 (d, J=8.8 Hz, 1H), 3.89-3.78 (m, 3H), 3.64 (s, 3H), 3.48-3.42 (m, 2H), 3.37 (m, 1H), 3.28-3.24 (m, 5H), 3.15 (dd, J=10.8, 9.2 Hz, 1H), 2.92 (m, 2H), 1.97 (m, 1H), 1.78 (m, 2H), 1.68-1.54 (m, 4H), 1.45-1.07 (m, 5H). MS ESI+ve m/z 511 (M+H).
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([C:36](F)(F)F)[C:29]3[N:33]=[C:32]([CH3:34])[NH:31][C:30]=3[CH:35]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:32]1[NH:31][C:30]2[CH:35]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:36])[C:29]=2[N:33]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1nc2c(C(F)(F)F)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1

Procedure:
128 mg (0.500 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 167 mg (0.500 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2-methyl-4-trifluoromethyl-1H-benzimidazole and 0.261 mL (1.50 mmol) DIPEA in 1.5 mL DMF were stirred for 10 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:3]=1.[CH2:21]([NH2:24])[CH2:22][NH2:23]>C(OCC)(=O)C>[NH2:23][CH2:22][CH2:21][NH:24][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:3]=1
Reactant: CCn1cnc2c(Nc3cccc(Cl)c3)nc(Cl)nc21
Reactant: NCCN
Solvent: CCOC(C)=O
Product: CCn1cnc2c(Nc3cccc(Cl)c3)nc(NCCN)nc21
Temperature: 150 °C

Procedure:
250 mg (0.81 mmol) of 2-chloro-6-(3-chloro-phenyl-amino)-9-ethyl-9H-purine are dissolved in 5.8 ml (97 mmol) of ethylenediamine and the solution is heated under reflux for 3 hours (oil bath temperature of 150° C.). After cooling to room temperature, the reaction mixture is taken up in ethyl acetate (250 ml) and extracted with water (150 ml). The aqueous phase is extracted twice with ethyl acetate and the combined organic extracts are washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure at 35° C. and the residue is dried under an HV. The crude product is recrystallized from diethyl ether. 2-(2-Amino-ethyl-amino)-6-(3-chloro-phenylamino)-9-ethyl-9H-purine is obtained; Rf=0.22 (methylene chloride:methanol:concentrated aqueous ammonium hydroxide solution=900:100:1); FAB-MS: (M+H)+=322; m.p. 79–80° C.