Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C-:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=O)=[O:7])=[CH:4][CH:3]=1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].S(=O)(=O)(O)O.O>C(O)(=O)C>[C-:14]1([C:12]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: O=C(CCCCC(=O)[c-]1cccc1)c1ccc(Cl)cc1
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: c1cc[cH-]c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(C1=C([c-]2cccc2)CCC1)c1ccc(Cl)cc1

Procedure:
5-(4-Chlorobenzoyl)pentanoyl ferrocene (8.2g; 0.02 mole) and 5% (v/v) concentrated sulphuric acid in glacial acetic acid (200 ml) were stirred at room temperature for 1 hour, the mixture was poured into water and extracted with chloroform (3 × 100 mls.). The combined extracts were washed with saturated aqueous sodium bicarbonate, and water, dried (magnesium sulphate) and evaporated under vacuum to yield a red-brown oil which crystallized from pentane at 0°-5°. The solid was filtered off to yield pure 1-ferrocenyl-2-(4-chlorobenzoyl)cyclopent-1-ene; 2.5g (35%) mp 121°-123°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([O:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1F)[CH:8]=[CH2:9]>C(#N)C>[N:1]1([C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[C:11]([O:10][CH2:7][CH:8]=[CH2:9])=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C=CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Solvent: CC#N
Product: C=CCOC(=O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Yield: 99.2 %

Procedure:
Morpholine (7.78 mL, 88.9 mmol) was added to a solution of 2-fluoro-5-nitrobenzoic acid allyl ester (prepared as described in WO 9315078; 10 g, 44.4 mmol) in acetonitrile (100 mL) and the mixture was heated under reflux for 6 h. Volatile material was removed by evaporation and the residue was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were dried and concentrated by evaporation to give the title compound (12.87 g, 99%) as a viscous liquid; 1H NMR δ: 8.40(1H, s), 8.20 (1H, d), 7.10 (1H, d), 6.10-5.95 (1H, m), 5.40 (1H, d), 5.30 (1H, d), 4.80 (2H, s), 3.70-3.60 (4H, m), 3.20-3.10 (4H, m); MS m/e MH 293.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[O:22])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]>Cl.O1CCOCC1>[CH:36]1([CH2:35][C@H:24]([NH:23][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:15]([C@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:7][CH2:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH2:16]2)=[O:22])[CH2:25][NH:26][CH3:27])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCOCCCC[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCOCCCC[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CNC)CC2CCCCC2)C1
Yield: 98.2 %

Procedure:
tert-butyl (S)-2-((S)-3-((R)-5-ethoxy-1-phenylpentyl)piperidine-1-carboxamido)-3-cyclohexylpropylmethylcarbamate (40.7 mg, 0.071 mmol) was stirred in HCl/dioxane (4 N, 4 mL) at rt until no starting material remained. The solvent was removed to to give (3S)-N-((S)-3-cyclohexyl-1-(methylamino)propan-2-yl)-3-((R)-5-ethoxy-1-phenylpentyl)-piperidine-1-carboxamide (32.9 mg, 91%) as its HCl salt. 1H NMR (CD3OD) δ 0.9 (m, 3 H), 1.0 (m, 2 H), 1.11 (t, 3 H), 1.2-2.0 (20 H), 2.40 (m, 1 H), 2.65 (m, 1 H), 2.70 (s, 3 H), 3.93 (m, 1 H), 3.05 (m, 2 H), 3.31 (m, 1 H), 3.40 (q, 2 H), 3.91 (d, 1 H), 4.13 (m, 2 H), 7.13 (2 H), 7.19 (1 H), 7.28 (2 H). MS ESI +ve m/z 472 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[F:10][C:11]([F:21])([F:20])[C:12]1[N:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([O:19][CH2:18][C:15]2[CH:16]=[N:17][C:12]([C:11]([F:21])([F:10])[F:20])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1
Reactant: COc1cc(Br)ccn1
Reactant: OCc1ccc(C(F)(F)F)nc1
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc(OCc2ccc(C(F)(F)F)nc2)ccn1
Yield: 72.4 %

Procedure:
4-Bromo-2-methoxypyridine (3.06 g, 16.2 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74 mmol) and Cs2CO3 (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromography (silica gel, hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%) as a red oil: 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9, 2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).
Reaction SMILES: [BrH:1].C(O)(=O)C.N[C:7]1[N:15]=[CH:14][C:13]2[NH:12][C:11]3[N:16]=[CH:17][C:18]([Br:20])=[CH:19][C:10]=3[C:9]=2[CH:8]=1.BrBr.N([O-])=O.[Na+].O>[OH-].[NH4+].O.C(Cl)Cl>[Br:20][C:18]1[CH:17]=[N:16][C:11]2[NH:12][C:13]3[CH:14]=[N:15][C:7]([Br:1])=[CH:8][C:9]=3[C:10]=2[CH:19]=1
Reactant: Br
Reactant: Nc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: BrBr
Agent: O=N[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Brc1cnc2[nH]c3cnc(Br)cc3c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of hydrogen bromide (33%) in acetic acid (1.10 mL, 6.08 mmol) was added to 6-amino-3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (80.1 mg, 0.304 mmol) at 0° C. To the resulting suspension was added bromine (18 μL, 0.34 mmol), and then a 1N solution of sodium nitrite in water (0.43 mL, 0.43 mmol), and the mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was diluted with concentrated ammonium hydroxide-water (1:1) and DCM, filtered to remove the solid, and the filtrate layers separated. The aqueous phase was extracted into DCM and the combined organic phase was concentrated in vacuo. The residue was purified by flash chromatography (silica, 0-100% ethyl acetate in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@@H:13]3[CH2:14][NH:15][CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@@H:13]3[CH2:14][N:15]([C:23]([C:22]4[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=4)=[O:24])[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Clc1ccc(O[C@@H]2CCN3CCNC[C@@H]23)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCN2CC[C@@H](Oc3ccc(Cl)cn3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 100F (120 mg, 0.473 mmol) and 3-(trifluoromethyl)benzoyl chloride (118 mg, 0.568 mmol) in dichloromethane (1.5 mL) was added triethylamine (0.3 mL, 2.18 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=220 nm) to give the title compound 1H NMR (400 MHz, pyridine-4.90° C.) δ ppm 1.66-1.79 (m, 1 H), 2.18-2.44 (m, 4 H), 2.85-2.90 (m, 1 H), 2.92-3.13 (m, 3 H), 4.19 (br. s, 1 H), 4.58 (br. s, 1 H), 5.10-5.16 (m, 1 H), 6.64 (d, 1H, J=8 Hz), 7.40-7.50 (m, 2 H), 7.63-7.69 (m, 2 H), 7.87 (s, 1 H), 7.96 (s, 1 H); MS (DCI) m/z 426 (M+H)+.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:15]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:16]3[C:21]([N:22]=2)=[CH:20][N:19]=[CH:18][N:17]=3)[CH2:9][CH2:8]1>O1CCCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:15]2[C:14]([NH:13][CH:10]3[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][N:4]=[C:1]=[S:3])[CH2:8][CH2:9]3)=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][CH:20]=3)=[CH:29][CH:28]=1
Reactant: S=C=S
Reactant: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3cncnc32)cc1

Procedure:
To a stirred and cooled (-10° C.) mixture of 5.6 parts of N,N'-methanetetraylbis[cyclohexanamine], 13.9 parts of carbon disulfide and 90 parts of tetrahydrofuran were added portionwise 10 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine. Upon completion, the temperature was allowed to rise to room temperature and the reaction mixture was evaporated, yielding 16 parts of 9-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-9H-purin-8-amine (compound 181).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([C:30]2[O:31][C:32]([C:38]([F:41])([F:40])[F:39])=[C:33]([C:35](O)=[O:36])[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35]([C:33]3[N:34]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:31][C:32]=3[C:38]([F:40])([F:41])[F:39])=[O:36])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1

Procedure:
To a solution of 4-fluoronitrobenzene (1.41 g, 10 mmol) in THF (50 mL) was added N-Boc-4-hydroxypiperidine (2.01 g, 10 mmol) and sodium hydride (60% in mineral oil, 583 mg, 14.5 mmol). The mixture was stirred at room temperature for 14 hrs. After purification through flash column chromatography, 4-(4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.51 g, 78% yield) was obtained as a solid. This nitro compound was hydrogenated to the corresponding amine and coupled with 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid to give 4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester. LC-MS showed a single peak with a retention time of 4.08 min. LRMS calcd for C27H28F3N3O5 (M+1) 532.20, obsd 532.1
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].Cl[CH2:39][CH2:40][O:41][CH:42]=[CH2:43].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O.[I-].[K+]>[CH:40]([O:41][CH2:42][CH2:43][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11])=[CH2:39]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: C=COCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=COCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 60 °C
Reaction time: 15 h
Yield: 92.3 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (308 mg), (2-chloroethoxy)ethene (192 mg) and potassium iodide (5 mg) in N,N-dimethylacetamide (5 ml) was added cesium carbonate (586 mg), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (6:4) was concentrated under reduced pressure to give the object product (323 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[N+:11]([O-])=O.Cl>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[NH2:11]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Product: N#CSc1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 0.29 h

Procedure:
2 G. of 1-amino-2-nitro-4-thiocyanatobenzene is mixed with 6 ml. of concentrated hydrochloric acid and the mixture cooled to about -40°C. A solution of 12 g. stannous chloride in 6 ml. concentrated hydrochloric acid is added dropwise and the mixture allowed to warm slowly to room temperature. After 15-20 minutes at 15°-20°C, the product is filtered off and washed with 12 ml. 6N hydrochloric acid. Treatment with 25 ml. of saturated potassium bicarbonate solution and extraction with chloroform gives the free base. Recrystallization from benzene yields 1,2-diamino-4-thiocyanatobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:7][CH2:6]1)=[O:4].CN(C)C=O.C(Cl)(=O)C([Cl:24])=O>ClCCl>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([Cl:24])=[O:15])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCC(CCC(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)N1CCC(CCC(=O)Cl)CC1

Procedure:
To a solution of 49.5 gm (0.23 mol) of the compound of step c), in dichloromethane, was added 0.25 mL of dimethylformamide and 21 mL of oxalyl chloride (0.25 mol). After gas evolution subsided, formation of the title compound was complete. The resulting solution was used directly into the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]COC)[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[K+].Cl>C1(C)C=CC=CC=1.C(O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[N:12]1([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COCOc1cccc(Br)c1
Reactant: C1CCNC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Oc1cccc(N2CCCC2)c1
Temperature: 80 °C

Procedure:
7 g (30 mmol) of 1-Bromo-3-methoxymethoxy-benzene from step A and 2.5 g (35 mmol) of pyrrolidine were dissolved under argon in 60 mL of toluene. Then, 0.15 g (0.3 mmol) of bis(tri-t-butylphosphine)palladium(0), 2.5 g KOH und 0.6 g (0.15 mmol) cetyltrimethylammoniumbromid were added, and the reaction mixture was heated at 80° C. At the end of the reaction, the reaction mixture was poured into 200 mL of ethyl acetate, and the organic phase was extracted with 1N sodium hydroxide solution and then dried with magnesium sulfate. The solvent was distilled off in a rotary evaporator, and the residue was purified on silica gel using heptane/ethyl acetate (8/0.8). The product thus obtained was dissolved in 15 mL of ethanol and mixed with 10 mL of a 2.9 molar solution of ethanolic hydrochloric acid. The reaction mixture was then heated at 55° C. At the end of the reaction, the precipitate was filtered off, washed with ethanol, and then dried.
Reaction SMILES: [C:1]([CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)#[N:2].S(C)C.CO>C1COCC1>[NH2:2][CH2:1][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[CH3:26])[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1
Reactant: Cc1ccc(F)cc1[C@H](OCC#N)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: Cc1ccc(F)cc1[C@H](OCCN)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A solution of (R)-tert-butyl 3-((R)-(cyanomethoxy)(5-fluoro-2-methylphenyl)methyl)piperidine-1-carboxylate (1.8 g, 0.005 mol) in anhydrous THF (20 ml) was heated to reflux under nitrogen. A solution of BH3.Me2S in THF was added dropwise and stirring was continued under reflux overnight. When the resulting solution was cooled to rt, MeOH was added dropwise to quench the reaction. After evaporation of the solution, the crude product was purified by column chromatography to afford (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-fluoro-2-methylphenyl)methyl)piperidine-1-carboxylate (1.2 g, yield 66%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24][O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)Cc1ccc(C)c(O)c1
Reactant: Cc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(C)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxy-4-methylphenyl)acetate (Step C, 1.84 g, 9.5 mmol), K2CO3 (1.96 g, 14.2 mmol) in DMF (10 ml) was added 2,6-Dimethylbenzyl chloride (1.61 g, 10.4 mmol) at room temperature under argon. The reaction mixture was stirred for 16 hours at the room temperature, diluted with ethyl acetate and washed with water (2×), and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hexane:ethyl acetate, 4:1) to give the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][NH:12][C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:9]2[C:8](=[O:21])[N:7]([CH3:22])[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3].Br[CH2:25][C:26]#[C:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:25][C:26]#[C:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:13]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:9]2[C:8](=[O:21])[N:7]([CH3:22])[C:6]1=[O:23])[CH:2]([CH3:4])[CH3:3]
Reactant: BrCC#Cc1ccccc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)[nH]nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(CC#Cc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7-isobutyl-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (48.6 mg, 0.155 mmol), (3-bromoprop-1-ynyl)benzene (60.5 mg, 0.31 mmol) and potassium carbonate (42.8 mg, 0.31 mmol) in DMF (1.5 mL) is stirred at room temperature overnight. The mixture is filtered through a 0.45 μm microfilter and the filtrate is purified by a semi-preparative HPLC to give pure product as white solids. MS (ESI) m/z 428.2 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([OH:18])[C:14](=[O:19])[C:13]=2[CH:20]=1.O1CCC[CH2:22]1.[H-].[Na+].CI>O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([O:18][CH3:22])[C:14](=[O:19])[C:13]=2[CH:20]=1
Reactant: C1CCOC1
Reactant: O=c1c(O)coc2ccc(OCCCCCCCl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1coc2ccc(OCCCCCCCl)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5'-(6-chlorohexoxy)-2'-hydroxyacetophenone (32 g) and benzaldehyde (12 g) was dissolved in 250 mL of ethanol. A solution of 24 g of sodium hydroxide dissolved in 40 mL of water was added. This mixture was allowed to stand at room temperature for 6 hours. A solution of 8 g of sodium hydroxide dissolved in 40 mL of water was added, the solution was cooled to 15°-20° C., and then 20 mL of hydrogen peroxide (30% solution) was added and the solution was allowed to warm to room temperature and was stirred overnight. Then the solution's pH was adjusted to 3 using hydrochloric acid. The yellow precipitate was collected by vacuum filtration and washed with water, ethanol, and ether to give 16 g of 6-(6-chlorohexoxy)-3-hydroxy-4H- 1-benzopyran-4-one. Next, 10 g of 6-(6-chlorohexoxy)-3-hydroxy-4H-1-benzopyran-4-one was dissolved in100 mL of tetrahydrofuran. Then 800 mg of sodium hydride was added followed by 8.3 mL of methyl iodide and the resulting solution was stirred at room temperature for 48 hours. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and then with brine. After drying over sodium sulfate, the solvent was removed to give 8 g of 6-(6- chlorohexoxy)-3-methoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[CH:18](Br)Br.C([O-])(=[O:23])C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[CH:18]=[O:23]
Reactant: CC(=O)[O-]
Reactant: CCCCCOc1cc(C(Br)Br)c(Br)c2ccccc12
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCOc1cc(C=O)c(Br)c2ccccc12
Yield: 82.9 %

Procedure:
1-Bromo-2-dibromomethyl-4-pentyloxynaphthalene (1.13 g, 2.43 mmol), acetic acid (8 ml) and sodium acetate (0.8 g, 9.72 mmol) were mixed, and this solution was refluxed under heating for 4 hours. Acetic acid was evaporated under reduced pressure. Water (5 ml) was added, and the aqueous layer was extracted twice with ethyl acetate (20 ml). The organic layers were combined, washed with saturated brine (10 ml), a saturated aqueous sodium hydrogencarbonate solution (10 ml) and saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=25/1) to give 1-bromo4-pentyloxynaphthalene-2-carbaldehyde (0.647 g, 83%) as colorless crystals.