Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][C@@H:33]([C:41]([OH:43])=[O:42])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C[O-].[Na+]>COCCO>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][C@H:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]1=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@H](Cc2ccccc2)C(=O)O)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.073 mmol), D-phenylalanine (241 mg, 1.46 mmol), and NaOMe (59 mg, 1.09 mmol) in 2-methoxyethanol (10 mL) was refluxed for 3 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-40% EtOAc/hexanes+2% AcOH) to give 40 mg of the title compound. MS: (+) m/z 545.06 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[C:16]([NH2:20])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:28](OCC)(=[O:30])C>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[C:16]([NH:20][CH:28]=[O:30])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc2c(c(C)c1N)C(c1ccc(C(C)C)cc1)CO2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Yield: 81 %

Procedure:
Using 3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 32, the title compound was synthesized in the same manner as in Reference Example 73. Yield: 81%. Melting point: 193-196° C. (hexane-ethyl acetate).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd]>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:24][CH:25]=1)([CH3:30])([CH3:31])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C(C)(C)C)cc1
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Yield: 99.8 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-(4-benzyloxyphenyl)-2-(4-t-butylphenoxy)propionate (3.00 g), which is the product of Reference example 36(a) and palladium on carbon (5%, 300 mg) and the reaction mixture was treated to afford the desired compound (2.37 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[C:11][Si](C)(C)C)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C(OCC)C>[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1cccc([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: O
Product: C#Cc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
A solution of 1-(3-nitrophenyl)-2-trimethylsilylacetylene (43 g, 0.197 mol) in diethylether (800 mL) is cooled to 0° C. under argon atmosphere. To this solution is added, dropwise over 30 min, a solution of TBAF (1M in THF, 217 mL, 0.217 mol) maintaining temperature below 10° C. The reaction mixture is stirred for 30 min at 0° C. The reaction mixture is poured into water and extracted with diethyl ether (×2). The organic layers are combined, washed with brine, and dried (Na2SO4). The solvents are removed under reduced pressure. The residue is purified by silica-gel chromatography with Hexane/EtOAc=20/1 to give orange oil (26 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[N:15]=2)=[O:13])[CH:9]=[CH:8][C:7]=1[O:24]C>Br>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[N:15]=2)=[O:13])[CH:9]=[CH:8][C:7]=1[OH:24]
Reactant: COC(=O)CCc1cc(C(=O)c2cccc(C(=O)OC)n2)ccc1OC
Agent: Br
Product: COC(=O)CCc1cc(C(=O)c2cccc(C(=O)OC)n2)ccc1O
Yield: 51.2 %

Procedure:
1.3g of 3-[5-(6-methoxycarbonyl-2-pyridylcarbonyl)-2-methoxyphenyl]-propionic acid methyl ester is refluxed in 12 ml of 62% hydrobromic acid for 12 hours. The reaction mixture is poured on ice/water, the precipitate is suctioned off and dried. The crude product (1.2g) is refluxed in 11 ml of methanol with 3 drops of concentrated sulfuric acid and concentrated by evaporation. The residue is taken up in ethyl acetate, shaken out with 10% sodium bicarbonate solution, washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate (0-40%). 640 mg of 3-[5-(6-methoxycarbonyl-2-pyridylcarbonyl)-2-hydroxyphenyl]-proPionic acid methyl ester of melting point 121°-122° C. is obtained.
Reaction SMILES: Cl.[CH3:2][C:3]([NH:6][NH2:7])([CH3:5])[CH3:4].CO[CH:10](OC)[CH2:11][CH:12](OC)OC.Cl>C(O)C.CO>[CH3:2][C:3]([N:6]1[CH:12]=[CH:11][CH:10]=[N:7]1)([CH3:5])[CH3:4]
Reactant: COC(CC(OC)OC)OC
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CC(C)(C)n1cccn1
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of (1,1-dimethylethyl)hydrazine hydrochloride (1.02 g, 8.19 mmol) (Aldrich), 1,1,3,3-tetrakis(methyloxy)propane (1.344 g, 8.19 mmol) (Aldrich) and hydrochloric acid (0.672 ml, 8.19 mmol) in ethanol (10 ml) was heated under reflux. A solution formed. After 16 h the reaction had gone to completion and so was concentrated in vacuo to yield the crude product. This was dissolved in methanol and passed through an aminopropyl cartridge (20 g), eluting with methanol. The combined filtrates were concentrated in vacuo to yield the title compound as a cream gum (210 mg)
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH:23]=[N:22][C:21]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:20]1.CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[CH3:12][O:11][C:5]1[CH:4]=[N:3][C:2]([N:19]2[CH:23]=[N:22][C:21]([NH:24][C:25](=[O:30])[C:26]([CH3:28])([CH3:27])[CH3:29])=[N:20]2)=[C:7]2[NH:8][CH:9]=[CH:10][C:6]=12
Reactant: COc1cnc(Br)c2[nH]ccc12
Reactant: CC(C)(C)C(=O)Nc1nc[nH]n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]ccc12
Temperature: 110 °C
Yield: 26 %

Procedure:
A mixture of 7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridine (250 mg, 1.101 mmol), potassium carbonate (457 mg, 3.30 mmol), copper(I) iodide (105 mg, 0.551 mmol), N-(1H-1,2,4-triazol-3-yl)pivalamide and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (78 mg, 0.551 mmol) in 1,4-dioxane (2 mL) were heated up at 110° C. for 13 h. The reaction mixture was filtered through a silica gel pad and concentrated under reduced pressure. The resulting crude was purified by prep HPLC to give N-(1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)pivalamide (90 mg, 26%) as pale yellow oil. LCMS: m/e 315.05 (M+H)+, ret time 1.55 min (method 8).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:11][C:7]=1[C:8](Cl)=[O:9])(=[O:4])[CH2:2][CH3:3].[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:11][C:7]=1[C:8]([O:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:9])(=[O:4])[CH2:2][CH3:3]
Reactant: OCc1ccccc1
Reactant: CCC(=O)Oc1ccc(OC(=O)CC)c(C(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC(=O)Oc1ccc(OC(=O)CC)c(C(=O)OCc2ccccc2)c1
Temperature: 26 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
To a solution of 2,5-dipropionoxybenzoyl chloride (10.3 gr., 0.036 mole) in 30 ml dry chloroform at 0° C. is added dropwise over a six hour period a solution of benzyl alcohol (3.45 gr., 0.032 mole) and pyridine (5.05 gr., 0.064 mole) in 6 ml of dry chloroform. The temperature is maintained at 0° C.-5° C. during the addition and the entire operation is performed under an argon atmosphere. The reaction is stirred at 26° C. for 16 hours and poured into 50 ml of cold water. The organic portion is extracted with 450 ml of ether and the organic layer is washed with 80 ml of 15% HCL (hydrochloric acid), 3×100 ml water, 100 ml of 1 N sodium hydroxide, 3×100 ml water, and dried over magnesium sulfate. Evaporation of the solvents affords 10.22 grams (90%) of benzyl 2,5-dipropionoxybenzoate as a colorless liquid. Distillation in a Hickman still affords 7.0 grams (60%) of benzyl 2,5-dipropionoxybenzoate as a colorless liquid of b.p. 227° C./0.14 mm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH2:16]([SH:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:28][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCS
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Product: CCCCCCCCCCCCSSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 85.6 %

Procedure:
As in Example 1, 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride is reacted with 40.5 g of dodecyl-mercaptan. There is obtained 81 g (86% of theory) of (4-nitro-2-trichloromethylphenyl)-dodecyl disulfide.
Reaction SMILES: [I:1][CH:2]1[CH2:10][CH:9]2[CH2:11][C:5]3([NH:13]C(=O)OC(C)(C)C)[CH2:6][CH:7]([CH2:12][CH:3]1[CH2:4]3)[CH2:8]2.[ClH:21]>O1CCOCC1>[ClH:21].[I:1][CH:2]1[CH2:10][CH:9]2[CH2:11][C:5]3([NH2:13])[CH2:6][CH:7]([CH2:12][CH:3]1[CH2:4]3)[CH2:8]2.[ClH:21]
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(C1)C(I)C3)C2
Agent: Cl
Solvent: C1COCCO1
Product: NC12CC3CC(CC(C1)C(I)C3)C2
Temperature: 25 °C

Procedure:
To a solution of carbamate 5A (0.10 mmol) in 1,4-dioxane (2 mL) was added a solution of 4 N HCl in dioxane (1.0 mL) and the mixture was maintained at rt for 16 h. The reaction mixture was concentrated and the residue was dissolved in water (2 mL). The aqueous layer was washed with EtOAc (3×5 mL) and concentrated to provide amine (5) in 64% yield as a hydrochloric acid salt. Data: LC/MS (ESR) m/z 292 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[C:27]1([CH:33]2[CH2:38][CH2:37][CH2:36][CH:35]([NH2:39])[CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:39][CH:35]3[CH2:36][CH2:37][CH2:38][CH:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:34]3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NC1CCCC(c2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCCC(c5ccccc5)C4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (83.9 mg, 0.223 mmol), N,N-dimethylpyridin-4-amine (2.72 mg, 0.0223 mmol), and 3-phenylcyclohexanamine (41 mg, 0.234 mmol) in DMF (1.2 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (47.0 mg, 0.245 mmol), and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified on a Biotage SP1 system to yield 58 mg of the title compound (48.7% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([F:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][NH2:29]>C(#N)C>[F:23][C:22]1[C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:29][CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CNCC1COc2c(F)cc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 1 mmol), methanamine (1 ml, 40% in water) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on flash column chromatography (EtOAc/MeOH) gave the title compound. Yield: 0.2 g, 69%. The amine was converted to the hydrochloric acid salt and crystallized from EtOH/Et2O. M.p. 243° C. MS m/z (rel. intensity, 70 eV) 275 (M+, 81), 97 (48), 70 (bp), 69 (73), 63 (58).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]1([NH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC(=O)Cl)cc1
Reactant: CCOC(=O)CCNc1ccccc1
Product: CCOC(=O)CCN(C(=O)Cc1ccc(C)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.115.1, starting from 4-methylphenylacetyl chloride and ethyl N-phenyl-3-aminopropionate, ethyl 3-[2-(4-methylphenyl)-N-phenylacetamido]propanoate was obtained as yellowish oil.
Reaction SMILES: [H-].[Na+].CS([C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1)(=O)=O.[CH3:25][O:26][CH2:27][CH2:28][OH:29].[Cl-].[Na+]>CN(C=O)C>[CH3:25][O:26][CH2:27][CH2:28][O:29][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1
Reactant: COCCO
Reactant: CS(=O)(=O)c1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Sodium hydride (60% content, oil dispersion, 1.20 g, 0.030 mol) was added to a mixture of 4'-methanesulfonyl-2,2':6',2"-terpyridine (3.11 g, 0.010 mol), 2-methoxyethanol (1.14 g, 0.015 mol) and DMF (0.1 liter) over a period of 10 minutes and then stirred for another 30 minutes. Thereafter, the reaction mixture was refluxed for 3 hours and then cooled to room temperature. The reaction mixture was then poured into an aqueous 4M sodium chloride solution and the crystal that precipitated was taken out by filtration under suction and then washed with water and hexane The crystal thus taken out was purified by passing the same into an alumina column using chloroform as an eluent, whereby 2.92 g of the above-entitled product (T-7) was obtained. Yield: 95%. m.p. 105.0 to 105.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10]>S(=O)(=O)(O)O>[C:9]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]=1[OH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)O
Reactant: Oc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(F)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.5 %

Procedure:
Concentrated sulfuric acid (30 mL) was added to 4-fluorophenol (50 g, 446 mmol) and tert-butanol (60 g, 810 mmol), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was partitioned between hexane and water, and the hexane layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane) to give the title compound (6.8 g, 7%) as a colorless oil.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[CH2:10][C:11]([O-:13])=[O:12].[Na+].Cl>O1CCCC1.O>[CH2:2]([CH:3]([O:6][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To a solution of 198 mg of 3-pentanol in tetrahydrofuran (4 ml), 180 mg of sodium hydride was added in nitrogen atmosphere at 0° C., and stirred for an hour at room temperature. To the solution 261 mg of sodium chloroacetate was added, followed by 2 hours' stirring at 100° C. The reaction solution was cooled to room temperature, diluted with water, acidified with 1N hydrochloric acid and extracted with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 103 mg of the title compound.
Reaction SMILES: [N:1]([C:4]1[C:11]([Br:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:5]=1[CH:6]=O)=[N+:2]=[N-].[CH:14]1(N)[CH2:16][CH2:15]1>C(Cl)Cl>[Br:12][C:11]1[C:4]2[C:5](=[CH:6][N:2]([CH:14]3[CH2:16][CH2:15]3)[N:1]=2)[CH:8]=[C:9]([Cl:13])[CH:10]=1
Reactant: NC1CC1
Reactant: [N-]=[N+]=Nc1c(Br)cc(Cl)cc1C=O
Solvent: ClCCl
Product: Clc1cc(Br)c2nn(C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Azido-3-bromo-5-chlorobenzaldehyde (1.38 g, 5.30 mmol) and cyclopropylamine (0.37 mL, 5.30 mmol) in methylene chloride (20 mL) were treated with molecular sieves (1.5 g). The reaction was stirred at room temperature for 2 h, filtered over celite and the resulting solution evaporated in vacuo. The resulting oil was suspended in toluene (15 mL) and heated at reflux for 2 h. After cooling to room temperature, the mixture was poured into ice water and extracted with diethyl ether (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (76%) as a light yellow solid. 1H-NMR (CDCl3, 500 MHz) δ 8.7 (s, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H), 3.05-3.09 (m, 1H), 0.95-0.99 (m, 4H). Mass spec.: 273.03 (MH)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:43]=[CH:44][CH:45]=1)[CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11]1)([CH3:3])[CH3:2].[CH3:46][O:47][CH2:48][CH2:49][C:50](Cl)=[O:51]>>[CH:1]([N:4]([C:50](=[O:51])[CH2:49][CH2:48][O:47][CH3:46])[C:5]1[CH:6]=[C:7]([CH:43]=[CH:44][CH:45]=1)[CH2:8][O:9][CH:10]1[CH:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:20][CH:21]=2)[CH2:14][CH2:13][N:12]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:11]1)([CH3:3])[CH3:2]
Reactant: COCCC(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(NC(C)C)c2)cc1
Product: COCCC(=O)N(c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1)C(C)C

Procedure:
Analogously to Example 116b, 0.400 g of tert-butyl 3-(3-isopropylaminobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.270 g of 3-methoxypropionyl chloride are reacted. The title compound is obtained as a colourless oil. Rf=0.27 (1:1 EtOAc-heptane); Rt=5.97.
Reaction SMILES: [N:1]1([C:10](OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][NH:8][CH2:9][CH:2]12.CC1C=CC(S(OC2C3CCC[C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[C:30]=3[N:31]=[CH:32][N:33]=2)(=O)=O)=CC=1.CC1C=CC(S(OC2C3CCCC4C=CC=CC=4C=3N=C(N)N=2)(=O)=O)=CC=1>>[N:31]1[C:30]2[C:34]3[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=3[CH2:7][CH2:3][CH2:4][C:5]=2[C:6]([N:1]2[CH2:2][CH:9]([NH2:8])[CH2:10]2)=[N:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ncnc3c2CCCc2ccccc2-3)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC2CNCC21
Agent: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Product: NC1CN(c2ncnc3c2CCCc2ccccc2-3)C1

Procedure:
The title compound was prepared using the procedure outlined in Example 59D substituting Example 2B for t-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate, and substituting the product from Example 118C for the product from Example 59C, followed by the procedure outlined in Example 59E. 1H NMR (CD3OD) δ 2.20-2.36 (m, 4H), 2.36-2.40 (m, 3H), 2.60 (t, 2H), 3.65-3.74 (m, 1H), 4.06 (dd, 2H), 4.47-4.55 (m, 2H), 7.26-7.34 (m, 1H), 7.36-7.43 (m, 2H), 7.62-7.67 (m, 1H), 8.41-8.44 (m, 1H). MS (M+H)+ m/z 281.
Reaction SMILES: O1CCOCC1.Br[C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13][C:12]=12.[CH3:18][O:19][C:20]([C:22]1[S:23][C:24]([CH3:36])=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>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.O>[CH3:18][O:19][C:20]([C:22]1[S:23][C:24]([CH3:36])=[C:25]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[N:13][C:12]=23)[CH:26]=1)=[O:21]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)s1
Reactant: Clc1cnc2c(Br)cnn2c1
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: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cnn3cc(Cl)cnc23)c(C)s1
Temperature: 100 °C
Yield: 67.7 %

Procedure:
To a flask containing 1,4-dioxane (58.1 mL) and water (19.4 mL) was added 3-bromo-6-chloropyrazolo[1,5-a]pyrimidine (3.60 g, 15.5 mmol), methyl-5-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-carboxylate (4.37 g, 15.5 mmol), palladium tetrakis (895 mg, 0.774 mmol), and sodium carbonate (4.92 g, 46.5 mmol). The reaction mixture was sealed and degassed with N2 for 15 min. The reaction mixture was then heated to 100° C. for 2 h. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (dichloromethane:hexane:ethyl acetate 20:75:5 to 20:60:20) to afford the title compound (3.23 g, 10.5 mmol). LRMS (APCI) calc'd for (C13H10ClN3O2S) [M+H]+, 308.0; found 308.0.