Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[Br:13][CH2:14][CH2:15][CH2:16][NH2:17]>C(Cl)Cl.[OH-].[Na+]>[Br:13][CH2:14][CH2:15][CH2:16][NH:17][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NCCCBr)OCc1ccccc1
Yield: 105.3 %

Procedure:
Benzylchloroformate (8.6 ml, 60 mmol) was added to a stirred mixture of 3-bromopropylamine hydrobromide (6.6 g, 30 mmol) in methylene chloride (100 ml) and 3N sodium hydroxide solution (100 ml) at 0° C. After stirring two phase reaction mixture at room temperature for overnight, organic layer was separated and washed with water twice (30 ml×2). After drying with MgSO4, the volatile solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc:Hx=1:4) to obtain desire compound (8.6 g, 98%) as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH2:13]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])[CH2:16][CH3:17])[CH3:14].ClCCl>O1CCOCC1>[CH2:13]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)[CH:23]=[CH:24][CH:25]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: CCN(CC)Cc1cccc(N)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCN(CC)Cc1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Temperature: 120 °C
Yield: 11.2 %

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in dioxane was added 3-((diethylamino)methyl)aniline (148 mg, 0.829 mmol). The mixture was heated in microwave for 140 minutes at 120° C. Dichloromethane was added, and washed with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The resulting solution was prepared by TLC (10% MeOH/DCM) to yield 10 mg 5-(3-((diethylamino)methyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (11% yield). LCMS (M+1=324)
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]2[CH2:12][C:7]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)([CH2:8]2)[C:6]1=[O:22])[CH:2]([CH3:4])[CH3:3]>C(O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]23[CH2:8][CH:9]([CH2:12]2)[C:10](=[O:11])[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:6]3=[O:22])=[CH:18][CH:17]=1
Reactant: CC(C)CN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1, 2.0 g of 3-isobutyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 100 ml of ethanol are hydrogenated in the presence of 0.1 g of palladium-on-carbon and worked up. Melting point 158°-160° (from ethyl acetate/petroleum ether).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.Cl.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[O:12])[CH2:23][CH2:22]2)=[O:20])=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indole-5-carboxylic acid (18 mg, 0.11 mmole) and 4-(4-chlorobenzoyl) piperidine hydrochloride (26 mg, 0.1 mmole) were dissolved in 5 ml dichloromethane. To this solution was added triethylamine (1 eq. to neutralize the HCl salt) catalytic DMAP and EDCI (33 mg, 0.11 mmole). The reaction mxture was stirred at room temperature overnight and then worked up by washing sequentially with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride. The compound was then purified by flash chromatography on silica gel (40:1 CHCl3/MeOH). 1H NMR (300 Mhz, CDCl3) δ 8.45 (s, 1H), 7.88 (d, 2H), 7.72 (s, 1H), 7.45 (d, 2H), 7.38 (d, 1H), 7.24 (s, 2H), 6.58 (s, 1H), 3.42 (m, 1H), 3.11 (m, 2H), 1.83 (m, 4H), 1.60 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]3[N:15]([CH3:19])[C:16](=[O:18])[O:17][C:13]=3[CH:12]=2)=[O:10])=[C:4]([Cl:22])[CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:25])[C:9]([C:11]2[CH:21]=[CH:20][C:14]3[N:15]([CH3:19])[C:16](=[O:18])[O:17][C:13]=3[CH:12]=2)=[O:10])=[C:4]([Cl:22])[CH:3]=1
Reactant: CI
Reactant: Cn1c(=O)oc2cc(C(=O)Cc3ccc(Br)cc3Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)c1ccc2c(c1)oc(=O)n2C)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
6-[2-(4-Bromo-2-chloro-phenyl)-acetyl]-3-methyl-3H-benzooxazol-2-one (747 mg) was dissolved in DMF (20 mL). The mixture was cooled to 0° C. To this solution was added sodium hydride (55% in mineral oil, 90 mg). The mixture was stirred for 10 minutes at 0° C. and then for 1 hour at r.t. The mixture was cooled to 0° C. and methyl iodide (292 mg) was added dropwise over a period of 10 minutes. Stirring was continued over night at r.t. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a brown foam (531 mg, 69%). MS (neg. ion, m/e)=394.2 [M−H)−].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]([CH3:15])[CH3:14])[N:7]=1)=O)C.[BH4-].[Na+].O>CO>[CH:13]([S:12][C:8]1[N:7]=[C:6]([CH2:4][OH:3])[CH:11]=[CH:10][N:9]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccnc(SC(C)C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)Sc1nccc(CO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
After 2-isopropylsulfanyl-pyrimidine-4-carboxylic acid ethyl ester (0.1 g, 0.44 mmol) obtained in Step B was dissolved in MeOH (4 mL), NaBH4(0.033 g, 0.9 mmol) was added to the solution, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was added with water, and then extracted with EtOAc. The separated organic layer was dried with MgSO4 and separated by column chromatography to obtain the title compound (0.063 g, 77%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].CO.[CH:21](=O)[CH2:22][CH3:23]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[CH:21][CH2:22][CH3:23])=[O:14])[CH3:2]
Reactant: CCC=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: O
Solvent: CO
Product: CCC=NN(C)C(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a test tube (outside diameter 21 mmφ×overall length 160 mm), 100 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39), 380 mg of methanol and 58 μl of propanal were added and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the resultant was extracted with chloroform three times. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 127 mg of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-propylidenehydrazine ((40-b)-(15)-3).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[H-].[Na+].[C:25](OCCBr)(=[O:27])[CH3:26]>CN(C)C=O>[OH:27][CH2:25][CH2:26][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4]1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Reactant: CC(=O)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
To a suspension of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (1.0 g) and sodium hydride (60% 0.15 g) in N,N-dimethylformamide (10 ml) was added acetoxyethyl bromide (0.58 g) at 5° C., and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice-water, and extracted twice with ethyl acetate. The extracts were combined, washed successively with 1N sodium hydroxide solution and sodium chloride aqueous solution, dried over magnesium sulfate, and then evaporated in vacuo. The residue was dissolved in 1,4-dioxane (12 ml) and a solution of sodium hydroxide (0.34 g) in water (1.5 ml) was added thereto. The reaction mixture was stirred at 60° C. for 3 hours, and evaporated in vacuo. The residue was treated with water and extracted with chloroform. The extract was washed with sodium chloride aqueous solution, dried over magnesium sulfate, and then evaporated in vacuo. The residue was crystallized from ethyl acetate to afford 3-[ 2-(2-hydroxyethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.84 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:38])[C:5]([CH3:37])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:33]C(=O)C)=[C:17]([CH:32]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:38])[C:5]([CH3:37])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:33])=[C:17]([CH:32]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(-n4ccnc4)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(-n4ccnc4)cc3)c2)=C(C)C1=O
Yield: 97.8 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-(imidazol-1-yl)aniline (0.070 g, 0.136 mmol) was dissolved in methanol (5 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.063 g, 0.133 mmol, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:38]4[CH2:39][CH2:40][N:35]([C:32](=[O:34])[CH3:33])[CH2:36][CH2:37]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-acetylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=557.97 (M+H+); retention time=0.68 minutes.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[Cl:57])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[C:51]=3[Cl:57])[N:48]=[CH:49][C:42]=12)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1cccc(Cl)c1Cl)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
Trimethylaluminium (2M in toluene) (0.638 mL, 1.28 mmol) was added to 5-chloropyridin-2-amine (164 mg, 1.28 mmol) in toluene (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 15 minutes. (2S)-Methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AR1) (425 mg, 0.64 mmol) in toluene (8 mL) was added sealed into a 20 mL microwave tube. The reaction was heated to 120° C. for 4 hours in the microwave reactor and cooled to RT. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organics were dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(1-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (460 mg, 95%). m/z (ES+) (M+H)+=763; HPLC tR=3.94 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:11]=3[C:12]=2[C:13]([O-:15])=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:11]=3[C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Temperature: 60 °C

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate (1 g, 3.5 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambient temperature was added 5 eq. of NaOH and heated to 60° C. for 3 h. The mixture was cooled to ambient temperature and to 0° C. in an ice-water bath, it was acidified slowly with 1.5 N HCl and then concentrated. The mixture with white precipitates was diluted with water and filtered to get the solid. It is further washed with water and dried in vacuum. Yield: 0.9 g (94.6%). 1H NMR (400 MHz, DMSO-d6): δ 6.82-6.85 (m, 1H), 7.35-7.40 (m, 3H), 7.46-7.49 (d, 1H, J=8.84 Hz), 8.02-8.05 (m, 2H), 9.4 (s, 1H), 13.05 (s, 1H). LCMS: (ES−) m/z=271.1
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Yield: 26 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (1.64 g, 4.20 mmol) and 4-chlorophenylboronic acid (620 mg, 3.9 mmol.) in toluene (20 mL) was added Pd(0) (97 mg) and Na2CO3 (5 mL of a 2 M solution), and the mixture was heated at reflux for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with Et2O. The solvent was removed under vacuum, and the residue was chromatographed (silica gel; EtOAc/hexane, 1:4) to afford the title compound (430 mg, 24% yield): 1H NMR (CDCl3, 300 MHz) δ 1.45 (s, 9H), 1.83-2.00 (m, 4H), 3.30-3.45 (m, 2H), 4.00 (m, 1H), 4.06-4.25 (m, 2H), 7.36-7.46 (m, 5H), 8.10 (s, 1H); MS (CI/NH3) m/z 423 (M+H)+.
Reaction SMILES: [CH:1]1(/[C:4](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5](/[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][CH:10]=2)\[C:6](O)=[O:7])[CH2:3][CH2:2]1.Cl.Cl.[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:27][N:28]([CH3:39])[CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:6](=[O:7])/[C:5](/[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:13][CH:14]=2)=[C:4](\[CH:1]2[CH2:3][CH2:2]2)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:34][CH:33]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: COCOc1ccc(/C(C(=O)O)=C(\c2ccccc2)C2CC2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(/C(C(=O)Nc2ccc(OCCN(C)C)cc2)=C(\c2ccccc2)C2CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 7 (65 mg, 0.200 mmol), 4-(2-(dimethylamino)ethoxy)benzenamine dihydrochloride (42.6 mg, 0.168 mmol), 4-Dimethylaminopyridine (1.2 mg, 0.00982 mmol) in CH2Cl2 (3 ml) was added O-Benzotriazoyl-N,N,N′,N′-tetramethyluronium Hexafluorophosphate (83.4 mg, 0.220 mmol) under ice cooling, and the mixture was stirred at 0° C. for 10 min. Then N,N-Diisopropylethylamine (90.4 mg, 0.701 mmol) was added under ice cooling. The mixture was stirred at 0° C. for 5 min, and at room temperature for 15 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with CHCl3, the organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by silica gel flash column chromatography (eluent: CH2Cl2 to CH2Cl2/MeOH, 6:1) gave the colorless solid (100%). The solid was triturated with hexane to give 8 (80%). 8: colorless powder; 1H-NMR (CDCl3) δ 0.45 (2H, m), 0.79 (2H, m), 2.36 (6H, s), 2.55 (1H, m), 2.76 (2H, t, J=5.5 Hz), 3.41 (3H, s), 4.07 (2H, t, J=5.5 Hz), 5.05 (2H, s), 6.74 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz), 6.95-6.99 (4H, m), 7.10-7.20 (4H, m), 7.44 (2H, d, J=8.8 Hz).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:23][C@@H:24]2[O:32][C@H:31]([CH2:33][OH:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]2[OH:26])=[N:10][N:11]([CH:20]([CH3:22])[CH3:21])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl>CN(C)C=O>[CH2:1]([C:8]1[C:9]([O:23][C@@H:24]2[O:32][C@H:31]([CH2:33][OH:34])[C@@H:29]([OH:30])[C@H:27]([OH:28])[C@H:25]2[OH:26])=[N:10][N:11]([CH:20]([CH3:22])[CH3:21])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)n1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2)c1-c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccccc2)c1-c1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-benzyl-3-(β-D-glucopyranosyloxy)-5-(4-hydroxyphenyl)-1-isopropyl-1H-pyrazole (0.02 g) and potassium carbonate (0.017 g) in N,N-dimethylformamide (20 mL) was added benzyl bromide at room temperature. The reaction mixture was stirred at 50° C. for 3 hours. After the reaction mixture was acidified by adding a hydrochloric acid aqueous solution (1 mol/L), the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give the title compound.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)[CH3:4].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1>>[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([Cl:15])=[CH:17][CH:18]=2)[CH2:9]1)[CH3:4]
Reactant: CCOC(=O)CN1CC[C@@H](N)C1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=O)CN1CC[C@@H](NC(=O)c2ccc(Cl)cc2)C1

Procedure:
5.1 Using general procedure D ((R)-3-amino-pyrrolidin-1-yl)-acetic acid ethyl ester dihydrochloride (example 1.2) was coupled with 4-chlorobenzoic acid to give [(R)-3-(4-chloro-benzoylamino)-pyrrolidin-1-yl]-acetic acid ethyl ester. Solid. MS 311.3 ([M+H]+)<
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14]([O:17][C@@H:18]([CH2:20][CH2:21][CH:22]=[CH2:23])[CH3:19])[CH2:15][CH3:16])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li+].[OH-].Cl>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14]([O:17][C@@H:18]([CH2:20][CH2:21][CH:22]=[CH2:23])[CH3:19])[CH2:15][CH3:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,3S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((R)-hex-5-en-2-yloxy)pentanoate (458 mg, 1.39 mmol), THF (5 mL) and MeOH (5 mL). To the stirred solution was added aq. LiOH (2.0 M, 2 mL). The mixture was stirred for 16 h, then was concentrated in vacuo to afford an aqueous solution. The solution was acidified with aq. HCl (1 M) and then transferred to a separatory funnel. The mixture was twice extracted with EtOAc. The combined organics were washed with brine; dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-((R)-hex-5-en-2-yloxy)pentanoic acid as a white foam (438 mg, 100%).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH2:4][CH3:5].Cl.[CH3:19][C:20](=[CH2:22])[CH3:21]>O1CCOCC1>[CH3:5][CH2:4][CH:3]([C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[CH2:9][C@@H:10]([C:12]([O:14][C:20]([CH3:22])([CH3:21])[CH3:19])=[O:13])[NH2:11])[CH2:2][CH3:1]
Reactant: CCC(CC)c1cccc(C[C@H](N)C(=O)O)c1
Reactant: C=C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CC)c1cccc(C[C@H](N)C(=O)OC(C)(C)C)c1
Yield: 74 %

Procedure:
According to example 54, 0.60 g of 3-(3-pentyl)-L-phenylalanine.HCl was treated with 30 mL of isobutylene in 35 mL of 1,4-dioxane in the presence of 0.5 mL of conc. H2S4. Work-up in the usual manner followed by acidification with 2 mL of 1N ethereal HCl afforded 0.53 g (74%) of tert-butyl 3(3-pentyl)-L-phenylalaninate.HCl as a light yellow glass.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:4]=1)=O.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][CH2:1][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[N:6]=[C:5]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH:4]=1)[CH3:28]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C=O)nc(C(F)(F)F)n2)CC1
Product: CCNCc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1

Procedure:
This compound was prepared according to the method of Example 41, Step 2 using tert-butyl 4-{[6-formyl-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate and ethylamine as starting materials. LCMS (M+H)+: 405.2.