Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>C(#N)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)CCCCCCCBr
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: O=C(Cl)CCCCCCCBr
Temperature: 95 °C

Procedure:
A mixture of 8-bromooctanoic acid (26.4 g), thionyl chloride (40 ml) and acetonitrile (40 ml) was heated at 95° C. for 3 hours. The solvent was removed by distillation under vacuum and the residue purified by azeotropic distillation, using acetonitrile, to give 8-bromooctanoyl chloride.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)=O.Cl.[CH:20]1([NH:26][C:27]([C:29]2([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:20]1([NH:26][C:27]([C:29]2([F:35])[CH2:34][CH2:33][N:32]([CH2:1][C:3]3[CH:4]=[C:5]([NH:9][C:10](=[O:18])[C:11]4[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][CH:12]=4)[CH:6]=[CH:7][CH:8]=3)[CH2:31][CH2:30]2)=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: Cc1cncc(C(=O)Nc2cccc(C=O)c2)c1
Reactant: O=C(NC1CCCCC1)C1(F)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(C(=O)Nc2cccc(CN3CCC(F)(C(=O)NC4CCCCC4)CC3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(3-formyl-phenyl)-5-methyl-nicotinamide L-1 (60 mg, 0.25 mmol) and 4-fluoro-piperidine-4-carboxylic acid cyclohexylamide hydrochloride (66 mg, 0.25 mmol) in DCM (3 mL) is treated with DIPEA (0.128 mL, 0.75 mmol). Sodium triacetoxyborohydride (132 mg, 0.62 mmol) is added at once and the mixture is stirred at RT for 18 h. The mixture is diluted with DCM (5 mL) and washed twice with aq. sat. NaHCO3 (5 mL). The organic phase is dried over MgSO4 and evaporated. The residue is dissolved in acetonitrile and purified by prep HPLC E, delivering the title compound as a colorless powder, LC-MS A: tR=0.62 min; [M+H]+=453.4. 1H-NMR (CDCl3): δ 1-1.4 (m, 5H), 1.6-1.8 (m, 6H), 1.9-2.1 (m, 2H), 2.2-2.4 (m, 4H), 3.45 (s, 3H), 2.7-2.8 (m, 2H), 3.7-3.8 (m, 1H), 6.28 (t, J=6.5, 1H), 7.15 (d, J=8, 1H), 7.35 (t, J=8, 1H), 7.55 (s, 1H), 7.73 (d, J=8, 1H), 8.05 (s, 1H), 8.12 (s, 1H), 8.61 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]3[CH2:17][CH2:16]3)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1.[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Pd]>[C:19](=[N:32][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2([CH:15]3[CH2:17][CH2:16]3)[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:7]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=C1COCC(c2cc(Br)ccc2F)(C2CC2)N1
Agent: [Pd]
Product: O=C1COCC(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)(C2CC2)N1

Procedure:
In an analogous manner to that described for the preparation of Building block A [f)], the palladium-catalyzed amination of (RS)-5-(5-bromo-2-fluoro-phenyl)-5-cyclopropyl-morpholin-3-one with benzophenonimine yielded the (RS)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-cyclopropyl-morpholin-3-one as a yellow foam. Mass (calculated) C26H23FN2O2 [414.478]; (found) [M+H]+=415.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:25][CH2:26][CH:27]([NH:30][C:38](=[O:40])[CH3:39])[CH2:28][CH2:29]4)=[O:23])=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reaction time: 0.67 h
Yield: 45.8 %

Procedure:
Stirred 4-aminopiperidyl 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl ketone hydrochloride (300 mg, 0.582 mmol) in 10 mL THF with triethylamine (0.293 mg, 2.91 mmol). Acetic anhydride (89 mg, 0.873 mmol) was added and the reaction was stirred for 40 minutes. The solution was concentrated down and purified by preperative HPLC to give N-{1-[(4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl]-4-piperidyl}acetamide (0.120 g, 46% yield): HPLC Retention time; 6.92 min. (Method B) M+1; 450.4
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cccc(NCCCCOCc2ccccc2)c1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CCCCOCc1ccccc1)c1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
3-(4-Benzyloxybutylamino)benzonitrile (0.22 g) and potassium carbonate (0.21 g) were suspended in N,N-dimethylformamide (5 mL). To the reaction mixture was added methyl iodide (0.16 g), and the mixture was stirred at 50° C. for 16 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give the title compound (0.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([S:17][CH2:18][C:19]([OH:21])=O)[N:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:35]([CH2:37][NH2:38])[OH:36]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([S:17][CH2:18][C:19]([NH:38][CH2:37][CH2:35][OH:36])=[O:21])[N:3]=1
Reactant: Cc1cccc(Nc2cc(Cl)nc(SCC(=O)O)n2)c1C
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2cc(Cl)nc(SCC(=O)NCCO)n2)c1C

Procedure:
To the solution of [4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio]-acetic acid (85 g.), triethylamine (45 ml.), in anhydrous chloroform (750 ml.), cooled to -5° C., 35 ml. of ethyl chlorocarbonate and then 22 ml. of ethanolamine were added with stirring while the temperature was kept below +10° C. The reaction mixture was washed with water (350 ml.), and dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was washed with benzene (500 ml.) and crystallised several times from acetone. 55 g. of [4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio]-(N-β-hydroxyethyl)-acetamide were obtained, identical with the compound prepared as in Example 1.
Reaction SMILES: [CH:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:2][CH2:3][CH2:4][CH3:5].[Cl:17]CCl>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][C:14]([Cl:17])=[O:16])=[CH:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCC=Cc1ccccc1C=CC(=O)O
Reactant: ClCCl
Agent: CCC/C=C\c1ccccc1/C=C/C(=O)Cl
Agent: CCC/C=C\c1ccccc1/C=C/C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCCC=Cc1ccccc1C=CC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(E)-3-[2-((Z)-1-Pentenyl)phenyl]propenoic acid (1.08 g) was dissolved in a mixture of dichloromethane (10 ml), oxalyl chloride (0.5 ml) and N,N-dimethylformamide (0.05 ml). After stirring for 1 hour under nitrogen atmosphere at room temperature, the solvent was evaporated. The residue was dissolved in n-hexane and the mixture was filtered. Filtrate was evaporated to give (E)-3-[2-((Z)-1-pentenyl)phenyl]propenoyl chloride (1.15 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[S:13][C:7]2[N:8]=[CH:9][N:10]=[C:11]([OH:12])[C:6]=2[CH:5]=1.[C:14](Cl)(=[O:16])[CH3:15]>ClCCl>[OH:12][C:11]1[C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:14](=[O:16])[CH3:15])[S:13][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CC(=O)Cl
Reactant: NCCc1cc2c(O)ncnc2s1
Solvent: ClCCl
Product: CC(=O)NCCc1cc2c(O)ncnc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a 25-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen was added a solution of 6-(2-aminoethyl)thieno[2,3-d]pyrimidin-4-ol (570 mg, 2.92 mmol, 1.00 equiv) in 10 mL of dichloromethane. TEA (1.2 g, 11.86 mmol, 4.06 equiv) and acetyl chloride (460 mg, 5.86 mmol) were added at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give 400 mg (crude) of the desired N-(2-[4-hydroxythieno[2,3-d]pyrimidin-6-yl]ethyl)acetamide as a white solid. MS (ES): m/z 238 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([C:20]#[C:21][C:22]2[CH:27]=[CH:26]N=[CH:24][CH:23]=2)[CH:19]=1)=[O:13].O1CCC[CH2:35]1>[Pd].C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:35]=[CH:24][CH:23]=2)[CH:19]=1)=[O:13]
Reactant: C1CCOC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C#Cc3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(CCc3ccccc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
To a suspension of palladium on carbon (0.063 g, 0.059 mmol) in ethanol (1 mL) under nitrogen was added N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinylethynyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.13 g, 0.295 mmol) and then ethanol (5 mL) and tetrahydrofuran (THF) (1.5 mL). The suspension was stirred under an atmosphere of hydrogen (ca. 1 atm, balloon) overnight. The reaction mixture was then evacuated with nitrogen, and diluted with 10% MeOH/DCM. Celite was added and the contents stirred for 15 min., and then filtered through Celite (analytical grade) and washed with 10% MeOH/DCM. The filtrate was concentrated in vacuo and purified by silica gel chromatography (eluent: gradient of 5-95%. Dichloromethane/Chloroform containing 10% 2M ammonia (in methanol). The collected solid was dried in vacuum oven at 45° C. for 18 h. The final product was collected as 0.112 g (84%). LCMS E-S (M+H)=445.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, J=6.57 Hz, 6 H), 2.13 (s, 3 H), 2.21 (s, 3 H), 3.08-3.18 (m, 2 H), 3.22-3.29 (m, 2 H), 4.36 (d, J=5.05 Hz, 2 H), 5.18 (quin, J=6.69 Hz, 1 H), 5.90 (s, 1 H), 7.28 (d, J=6.06 Hz, 2 H), 7.53 (s, 1 H), 8.26 (s, 1 H), 8.38-8.47 (m, 2 H), 8.72 (t, J=5.05 Hz, 1 H), 11.56 (s, 1 H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(CCO)CC1
Temperature: 0 °C
Yield: 480.1 %

Procedure:
2-Piperazin-1-yl-ethanol (1.30 g, 1.0 mmol) and triethylamine (2.8 mL, 2 mmol) were dissolved in methylene chloride (20 mL). The solution was cooled to 0° C. and methanesulfonyl chloride (0.78 mL, 1 mmol) was added dropwise. The mixture was warmed to r.t., and the solvent was removed under reduced pressure. The residue was purified via silica gel chromatography (10% methanol in ethyl acetate) to afford the title compound (1.0 g, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:23])[C:9]([OH:22])([C:14]1[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=1)[C:10]([F:13])([F:12])[F:11].Cl.O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]#[N:32])=[CH:26][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:23])[C:9]([OH:22])([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=1)[C:10]([F:12])([F:11])[F:13]
Reactant: COc1ccc(C(O)(C(C)c2ccc(-c3ccc(CC#N)cc3)cc2Cl)C(F)(F)F)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(c1ccc(-c2ccc(CC#N)cc2)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 69.9 %

Procedure:
To a solution of {3′-chloro-4′-[3,3,3-trifluoro-2-hydroxy-2-(6-methoxy-pyridin-3-yl)-1-methyl-propyl]-biphenyl-4-yl}-acetonitrile (87 mg) in dioxane (2.8 ml) was added conc. aqueous HCl (0.31 ml). The mixture was stirred at 100° C. for 1.5 h. After cooling to room temperature, water was added and the mixture was extracted with EtOAc. The organic phase was concentrated to dryness and the product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>9:1) to give the title compound (59 mg) as a colorless solid. MS (m/e)=447.3 [M+H+].
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1.[Na].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Cl>CO>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1
Reactant: ClCc1cccc(Cl)c1
Reactant: OCc1ccc(O)cn1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: OCc1ccc(OCc2cccc(Cl)c2)cn1
Reaction time: 0.42 h

Procedure:
The solution of 16.2 g of 5-hydroxy-2-pyridinemethanol hydrochloride in 150 ml of methaol is added to a solution of 4.6 g of sodium in 250 ml of methanol, while stirring, over a period of 25 minutes. The solution is stirred for one hour and then a solution of 19.3 g of m-chlorobenzyl chloride in 50 ml of methanol is added. Then the mixture is refluxed for 19 hours, cooled, filtered and the filtrate evaporated to a residue. The residue is suspended in 100 ml of water, made basic with 20% aqueous sodium hydroxide solution and then extracted with chloroform. The chloroform extract is separated, dried over sodium sulfate, filtered and the filtrate evaporated, to yield 5-(m-chlorobenzyloxy)-2-pyridinemethanol melting at 78°-80°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:42]=[C:43]=[O:44])(=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[C:31]([NH:42][C:43](=[O:44])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CCCCCCCCCC(=O)N=C=O
Agent: NC(=O)[O-]
Product: CCCCCCCCCC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 42 %

Procedure:
The compound 89 (245 mg, 0.6 mmol) was converted to the carbamate with decanoyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 92 (152 mg, 42%) as crystals. Mp. 84-86° C. Rf 0.37 (EtOAc).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:4]([CH3:15])[N:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:4]([CH3:15])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CCCCCCc1c(C)nc(N)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCCCc1c(C)nc(N)nc1Cl
Yield: 18 %

Procedure:
By using ethyl 2-acetyloctanoate (6.43 g, 30 mmol) as a starting material and according to the method of Reference-example 2, there was obtained 2-amino-5-hexyl-6-methylpyrimidine-4-ol (4.70 g, 74%). By reacting the obtained 2-amino-5-hexyl-6-methylpyrimidine-4-ol (1 g, 4.78 mmol) and phosphorous oxychloride (12 ml), there was obtained the object compound (196 mg, 18%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][O:16][C:12]1[C:11]2[C:7]([C:34]3[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=3)=[N:8][N:9]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:10]=2[CH:15]=[CH:14][N:13]=1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCOCC1

Procedure:
A solution of 4-methoxy-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (167 mg), tetrakis(triphenylphosphine)palladium(0) (45.5 mg) and 2M aqueous sodium carbonate solution (1.0 mL) in DME (15 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (119 m).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15]([CH3:27])([CH3:26])[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:3].[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([CH:44]=1)[C:41](O)=[O:42])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([C:41]([N:22]2[CH2:23][CH2:24][CH:19]([N:17]3[C:16](=[O:25])[C:15]([CH3:27])([CH3:26])[C:14]([C:7]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH3:13])=[C:5]([O:4][CH2:2][CH3:3])[CH:6]=4)=[N:18]3)[CH2:20][CH2:21]2)=[O:42])[CH:44]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: CCOc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OCC
Agent: Cl
Product: CCOc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5ccccc5)ccc4C)CC3)C(=O)C2(C)C)cc1OCC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-diethoxyphenyl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B2) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclohexane/EA=6:4) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:28])=[CH:17]/[C:18]2[NH:19][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CI.[C:31]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:28])=[CH:17]/[C:18]2[N:19]([CH3:31])[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1cnc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1cnc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)n1C
Reaction time: 24 h
Yield: 53.8 %

Procedure:
Ethyl (E)-2-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-5-imidazolecarboxylate (Compound 5, 25 mg, 0.066 mmol) was dissolved in acetone (3 mL) at room temperature and treated with methyl iodide (0.025 mL) and K2CO3 (100 mg). The suspension was stirred for 24 hours, filtered through Celite and concentrated under reduced pressure. The residue was treated with water (5 mL) and the organic material was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate=5:1) to give the title compound as a light yellow solid (14 mg, 54%).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[O:21])[C:16]3([CH2:19][CH2:18][CH2:17]3)[N:15]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=O)=[CH:24][CH:23]=3)[C:14]2=[S:32])=[CH:9][C:8]=1[C:33]([F:36])([F:35])[F:34])#[N:6].[CH3:37][NH2:38]>C1COCC1>[CH3:37][NH:38][C:29](=[O:31])[CH2:28][C:25]1[CH:24]=[CH:23][C:22]([N:15]2[C:14](=[S:32])[N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:5]#[N:6])=[C:8]([C:33]([F:35])([F:36])[F:34])[CH:9]=3)[C:20](=[O:21])[C:16]32[CH2:19][CH2:18][CH2:17]3)=[CH:27][CH:26]=1
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CC(=O)O)cc3)C2=S)cc1C(F)(F)F
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CNC(=O)Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Thionyl chloride (0.238 g, 2 mmol) was added dropwise to a mixture of {4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}acetic acid (46c) (0.357 g, 0.777 mmol) in THF (5 ml) cooled to 0° C. The mixture was stirred for 1 hour at room temperature and then methylamine (0.5 ml) was added into the mixture. The mixture was stirred for an additional 2 hours. The medium was filtered and the filtrate was concentrated and chromatographed (dichloromethane:acetone, 80:20) to yield N-methyl-2-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}acetamide (46e) [RD149] (0.348 g, 0.738 mmol, 95%), the structure of which is illustrated in Formula 18, as an off-white powder.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[O:23].C1(C)C=CC=CC=1>O1CCCC1>[OH:23][CH:22]([C:13]1[S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:21]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: c1ccc(-c2csc3ccccc23)cc1
Reactant: CCOC(=O)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of butyllithium (1.6 M, 3.75 mL, 6 mmol) was added at −20° C. to a solution of 3-phenyl-1-benzothiophene (3a) (1.18 g, 5.61 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere. After 1 hour, a solution of ethyl glyoxylate in toluene (50%, 1.2 mL, 6 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 hours, quenched with water (5 mL) and concentrated in vacuo. The residue was partitioned between dichloromethane (40 mL) and water (15 mL). The organic layer was washed with water (2×15 mL), brine (15 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired alcohol (3b) as a white solid (340 mg, 1.09 mmol, 20%).