Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12].[C:37]([O-:40])(=[O:39])[CH3:38].[Na+].[I-].[Na+]>C(O)(=O)C>[C:37]([O:40][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1)=[O:12])(=[O:39])[CH3:38]
Reactant: O=C(Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1)c1ccccc1OCCCCCCBr
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCCCCCCOc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Yield: 55.6 %

Procedure:
A mixture of 1-{4-[2-(6-bromohexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (2.00 g), sodium acetate (0.36 g), sodium iodide (0.55 g) and acetic acid (20 ml) is refluxed for 1 day. The solvent is distilled off and the resulting residue is extracted with ethyl acetate. The organic layer is washed successively with 2N aqueous sodium hydroxide solution and saturated saline solution, and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; chloroform: methanol=500:1), and recrystallized from ethanol to give 1-{4-[2-(6-acetyloxyhexyloxy)benzoylamino]benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (1.07 g) as white powder, m.p. 145°-146° C.
Reaction SMILES: [N:1]1([C:6]2[CH2:11][CH2:10][N:9]([C:12](=[O:14])[CH3:13])[CH2:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:15]/[N:16]=[C:17](\Cl)/[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[N:21]1[CH:22]=[CH:23][C:18]([C:17]2[CH:7]3[CH2:8][N:9]([C:12](=[O:14])[CH3:13])[CH2:10][CH2:11][C:6]3([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[O:15][N:16]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)N1CC=C(N2CCCC2)CC1
Reactant: O/N=C(\Cl)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC2(N3CCCC3)ON=C(c3ccncc3)C2C1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1-(4-(Pyrrolidin-1-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (1.2 g, 6.176 mmol) (synthesis: see below) was dissolved in methylene chloride (10 ml) and the solution was cooled to 0° C. under an inert gas. (Z)-N-Hydroxyisonicotinimidoyl chloride (1.45 g, 9.264 mmol), dissolved in methylene chloride (5 ml), and triethyl-amine (2.1 ml, 14.82 mmol), dissolved in methylene chloride (5 ml), were added, stir for 15 h, during this allow to warm to room temperature. The mixture was diluted with methylene chloride (30 ml) and washed water (20 ml) and citric acid (10%, 20 ml). The aqueous phase was neutralized with sodium bicarbonate and extracted with methylene chloride and the combined organic phases were washed with saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with ethyl acetate/methanol/ammonia (25% eq.) 100/10/1. The yield was 0.64 g (33%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:24])[N:15]3[CH2:18][C:17]4([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[CH2:16]3)[C:9]2=[O:25])=[CH:4][CH:3]=1.Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C>ClCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](=[O:24])[N:15]3[CH2:18][C:17]4([CH2:19][CH2:20][N:21]([CH2:34][C:35]5[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=5)[CH2:22][CH2:23]4)[CH2:16]3)[C:9]2=[O:25])=[CH:31][CH:30]=1
Reactant: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCNCC2)C1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccc(C(F)(F)F)cc3)CC2)C1
Temperature: 40 °C

Procedure:
To 3,3-bis(4-fluorophenyl)-1-(2-oxo-2-(2,7-diazaspiro[3.5]nonan-2-yl)ethyl)pyrrolidin-2-one (0.050 g, 0.114 mmol; Example 153A) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.030 g, 0.125 mmol) in dichloromethane (0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.030 mL, 0.171 mmol), and the reaction was heated to 40° C. for 1 hour. The reaction was cooled, loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences), and the title compound eluted with a gradient of 0.8% methanol/dichloromethane containing 0.2 N NH3 to 5.6% methanol/dichloromethane containing 0.2 N NH3(Flow=25 mL/minute) over 30 minutes. 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.1, 2H), 7.42 (d, J=8.0, 2H), 7.34-7.27 (m, 4H), 7.04-6.94 (m, 4H), 3.97 (s, 2H), 3.72 (d, J=19.3, 4H), 3.52 (dd, J=5.5, 12.0, 4H), 2.75 (t, J=6.5, 2H), 2.31 (s, 4H), 1.74 (d, J=4.9, 4H); MS (ESI+) m/z 598.2 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:16][CH:15]2[N:17]([C:18]3[C:19]4[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[C:25]([C:33](=[O:38])[NH:34][CH:35]([CH3:37])[CH3:36])[S:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)(=O)=O.[N-:39]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN1C(=O)CCC1.C(Cl)Cl>[NH2:39][CH2:6][CH2:7][O:8][CH2:9][CH:10]1[CH2:11][C@H:12]2[N:17]([C:18]3[C:19]4[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[C:25]([C:33]([NH:34][CH:35]([CH3:37])[CH3:36])=[O:38])[S:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C@H:15]([CH2:14][CH2:13]2)[CH2:16]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)NC(=O)c1sc2ncnc(N3C4CCC3CC(COCCOS(C)(=O)=O)C4)c2c1-c1ccccc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)NC(=O)c1sc2ncnc(N3[C@@H]4CC[C@H]3CC(COCCN)C4)c2c1-c1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
2-[[8-[6-(isopropylcarbamoyl)-5-phenyl-thieno[2,3-d]pyrimidin-4-yl]-8-azabicyclo[3.2.1]octan-3-yl]methoxy]ethyl methanesulfonate (0.3 g, 0.5 mmol) was dissolved in NMP (2 mL). Sodium azide (0.2 g, 3 mmol) was added and the reaction heated to 150° C. in the microwave for 30 minutes. The reaction mixture was diluted with DCM (20 mL), washed with water (2×20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in THF (5 mL). Triphenylphosphine (0.2 g, 0.8 mmol) was added and the reaction stirred overnight at room temperature. It was heated to reflux for 5 hours. The solvent was removed at reduced pressure. The resulting residue was taken up in DCM, washed with water, dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient of DCM to 90/10/1 DCM/MeOH/NH4OH to afford 4-[(1R,5S)-3-(2-aminoethoxymethyl)-8-azabicyclo[3.2.1]octan-8-yl]-N-isopropyl-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide (100 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1>C1(C)C=C(C)C=C(C)C=1>[OH:1][CH2:6][CH2:5][O:4][CH2:3][C:2]1[NH:15][C:14]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[N:8]=1
Reactant: Nc1cccnc1N
Reactant: O=C1COCCO1
Solvent: Cc1cc(C)cc(C)c1
Product: OCCOCc1nc2ncccc2[nH]1

Procedure:
1,4-Dioxan-2-one (6.13 g, 60 mmol) and 2,3-diaminopyridine (5.46 g, 50 mmol) in mesitylene (100 ml) were heated at reflux in a Dean-Stark separator for 10 h. After cooling, mesitylene was decanted off and the residue was purified by silica gel chromatography (dichloromethane:methanol 9:1) (yield: 8.47 g, 87% of theory).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH2:15])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:29][C:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=2)[NH:32][CH:31]=1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH:15][C:39]([C:35]2[CH:34]=[C:33]3[C:38]([C:30]([Br:29])=[CH:31][NH:32]3)=[CH:37][CH:36]=2)=[O:40])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2N)cc1
Reactant: O=C(O)c1ccc2c(Br)c[nH]c2c1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc3c(Br)c[nH]c3c2)cc1
Yield: 78.9 %

Procedure:
Using the procedure described in Example 9, Part C, 4-t-butyldimethylsilyloxy-N2-(4-t-butylbenzoyl)-1,2-benzenediamine (750 mg, 1.9 mmol) and 3-bromoindole-6-carboxylic acid (456 mg, 1.9 mmol) yielded 930 mg (79%) of the title compound.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:17]=1N)=[O:12])[CH3:9].C(OC(C1C(N)=NN(C2CCC2)C=1)=O)C.[ClH:38]>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[C:17]=1[Cl:38])=[O:12])[CH3:9]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(C2CCC2)c1N
Agent: CC(C)(C)ON=O
Agent: CCOC(=O)c1cn(C2CCC2)nc1N
Solvent: CC#N
Product: CCOC(=O)c1cnn(C2CCC2)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl nitrite (5.1 mL, 38.7 mmol), cuprous chloride (3.8 g, 38.7 mmol), and anhydrous acetonitrile (100 mL) was added a mixture of 5-amino-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester and 3-amino-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester (from last step without further purification) in anhydrous acetonitrile (50 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then at 60° C. for 2 h. The mixture was cooled to room temperature and then poured into 6N HCl (50 mL) and extracted with dichloromethane. The aqueous layer was extracted three times with dichloromethane. After the combined organic layers were concentrated in vacuo, the crude residue was purified by flash chromatography eluting with a gradient of 10-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes. The desired fractions were concentrated in vacuo and dried under vacuum to give 5-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester (eluted first, 610 mg, 10.3%) and 3-chloro-1-cyclobutyl-1H-pyrazole-4-carboxylic acid ethyl ester (eluted later, 147 mg, 2.5%). LRMS m/z calcd for C10H13ClN2O2 (M+H) 229.1, found 229.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[O:10])=[CH:5][CH:4]=1.[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:19]([OH:24])(=[O:25])[CH2:20][CH2:21][C:22]([OH:2])=[O:23].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[O:10])=[CH:7][CH:8]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[O:10])=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)O1
Agent: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)O
Temperature: 135 °C

Procedure:
A mixture of 4-methoxybenzoin (20 g, 0.083 mole) and succinic anhydride (9.1 g, 0.091 mole) in toluene (6 mL) is heated for 7 hours under nitrogen at 135° C. (internal temp.). The solution is poured into 0.5N-NaHCO3, the organic layer was separated and reextracted with 0.5N-NaHCO3. The combined extracts are washed with ether and then acidified in the cold with concentrated HCl. The liberated oil is extracted with ethyl acetate (3×), the extracts washed with water and dried (MgSO4). Removal of the solvent yields a yellow solid (20.89 g, 73.8%), m.p. 104°-108° C. It is used in the next step without further purification.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=1.I[CH3:15]>CO>[CH3:15][S:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=1
Reactant: CCCc1cc(O)nc(S)n1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCc1cc(O)nc(SC)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 1N solution of potassium hydroxide in methanol (110 mL) was added dropwise at 0° C. to a suspension of 2-mercapto-6-propyl-pyrimidin-4-ol (17.0 g) in methanol (220 mL). The mixture was stirred at room temperature for 15 minutes. After cooling at 0° C., iodomethane (6.8 mL) was added dropwise over 15 minutes. The mixture was stirred at room temperature for 6 hours, then filtered. The first precipitate was successively washed with methanol, water, isopropanol, then dried under reduced pressure. The filtrate was concentrated under reduced pressure, triturated with water, filtered. The second precipitate was successively washed with methanol, water, isopropanol, then dried under reduced pressure. Both precipitates were combined to afford 2-methylsulfanyl-6-propyl-pyrimidin-4-ol (15.5 g) as white crystals (mp=158° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2].Cl.[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH:17]([C:36]([CH:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:37])[C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2]
Reactant: CCOC(=O)CCc1ccc(C#N)cc1OC[C@H]1CCCN1
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(C#N)cc1OC(C(=O)C1CCN(c2ccncc2)CC1)[C@H]1CCCN1
Reaction time: 8 h

Procedure:
570 mg (1.89 mmol) of ethyl 3-[4-cyano-(2R)-2-(pyrrolidine-2-ylmethoxy)phenyl]propionate was dissolved in 10 ml of DMF. 504 mg (2.1 mmol) of 1-(4-pyridyl)-4-piperidinecarboxylic acid hydrochloride, 479 mg (2.8 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.78 ml (5.7 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24](=[O:34])[C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C=O)C.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:24](=[O:34])[C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNC(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Prepared using General Procedure 4: To a stirring solution of 4-((4-nitrobenzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-2 (857 mg, 1.75 mmol) in DMF (7 mL) was added sodium hydride (77.0 mg, 1.92 mmol). After 5 min, tert-butyl 2-bromoacetate (0.30 mL, 2.01 mmol) was added. After stirring at room temperature for 1 h, additional tert-butyl 2-bromoacetate (0.297 mL, 2.01 mmol) and sodium hydride (77.0 mg, 1.92 mmol) were added and the reaction stirred for another 1 h. The reaction mixture was diluted with EA (100 mL) and washed with brine (200 mL). The organic layer was concentrated and purified by chromatography (EA/hexanes) to provide 888 mg (84%) of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-nitrobenzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-3. LCMS-ESI (m/z) calculated for C34H40N2O8: 604; no m/z observed, tR=3.62 min (Method 5).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O.[NH:28]1[CH2:41][CH2:40][CH2:39][C@@H:29]1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>C1COCC1>[N:13]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([N:28]1[CH2:41][CH2:40][CH2:39][C@@H:29]1[C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(Nc1ccccc1)[C@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.5 %

Procedure:
201 mg (1.05 mmol) of EDCl was added to 5 ml of THF solution of 100 mg (0.526 mmol) of Boc-Pro-OH (manufactured by Tokyo Chemical Industry Co., Ltd), and 113 mg (0.526 mmol) of H-D-Pro-NHPh (manufactured by Tokyo Chemical Industry Co., Ltd), followed by stirring for 6 hours at room temperature. After a reaction mixture was concentrated under reduced pressure, the concentrate was extracted by adding water and ethyl acetate. After an organic layer was washed sequentially with a diluted hydrochloric acid, an aqueous solution of sodium hydrogen carbonate and water (one time for each), it was concentrated under reduced pressure, thereby obtaining crude amide. The obtained amide compound was purified by a silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/1 (volume ratio)), thereby obtaining 160 mg of the product with a yield of 73.6%.
Reaction SMILES: [CH3:1][N:2]([N:6]=O)[C:3](N)=[O:4].[N+:8](=[CH2:10])=[N-:9].[CH3:11][CH2:12][O:13][CH2:14][CH3:15].[CH2:16](Cl)[CH2:17][CH2:18]C>>[N+:2](=[CH2:1])=[N-:6].[CH3:11][CH2:12][O:13][CH2:14][CH3:15].[N+:8](=[CH:10][C:3](=[O:4])[CH2:16][CH2:17][CH3:18])=[N-:9]
Reactant: CCCCCl
Reactant: CN(N=O)C(N)=O
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCC(=O)C=[N+]=[N-]
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
A 100 ml quantity of diazomethane ether solution (containing 2.8 g of diazomethane) is prepared from 10 g of N-methyl-N-nitrosourea. To the diazomethane ether solution is added dropwise 1.7 g of n-butyl chloride with ice-cooling, and the mixture is thereafter stirred for 30 minutes. Nitrogen gas is passed through the reaction mixture at room temperature to remove the excess of diazomethane therefrom. The ethereal solution is distilled in a vacuum, and the residue is purified by column chromatography (silica gel, developed with chloroform) to give 1.75 g of light yellow oily 1-diazo-2-pentanone (yield 97.8%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[CH3:50][C:51]([CH3:66])([CH3:65])[C@H:52]([NH:56][C:57]([O:59][CH2:60][CH2:61][CH2:62][CH:63]=[CH2:64])=[O:58])[C:53](O)=[O:54].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:50][C:51]([CH3:66])([CH3:65])[C@H:52]([NH:56][C:57]([O:59][CH2:60][CH2:61][CH2:62][CH:63]=[CH2:64])=[O:58])[C:53]([N:30]1[CH2:31][C@:27]([O:26][CH3:25])([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:54]
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Yield: 75.2 %

Procedure:
HATU (248 mg, 0.652 mmol) was added to a solution of (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (200 mg, 0.593 mmol), (S)-3,3-dimethyl-2-((pent-4-enyloxy)carbonylamino)butanoic acid (180 mg, 0.741 mmol) and DIEA (0.311 mL, 1.778 mmol) in DCM (8 mL) and stirred at r.t. 60 hours. The reaction was evaporated and purified on the Biotage (10-40% EtOAc:Hex) to give the product (2S,4R)-methyl 1-((S)-3,3-dimethyl-2-((pent-4-enyloxy)carbonylamino)butanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (251 mg, 0.446 mmol, 75% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96-1.00 (m, 1H) 1.04-1.10 (m, 1H) 1.11-1.21 (m, 7H) 1.64-1.79 (m, 2H) 2.06-2.20 (m, 2H) 2.52 (dd, J=13.30, 8.78 Hz, 1H) 2.83-3.04 (m, 4H) 3.72-3.82 (m, 3H) 3.96-4.12 (m, 3H) 4.15-4.21 (m, 1H) 4.31-4.41 (m, 1H) 4.86-5.10 (m, 3H) 5.19-5.30 (m, 1H) 5.41 (d, J=9.79 Hz, 1H) 5.67-5.87 (m, 2H) 6.61-6.76 (m, 1H) 7.28-7.44 (m, 7H) 7.61-7.71 (m, 1H). LCMS: r.t.=2.18 min., [M+H]+=563 Phenomenex Luna S10 (3×50 mm); Solvent A=95% water—5% methanol—10 mM ammonium acetate, Solvent B=5% water—95% methanol—10 mM ammonium acetate; gradient=0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 ml/min; inj. vol.=10 ul; wavelength=220 nm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C[O:10][C:11](=[O:26])[CH:12]([O:24][CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22]Br)[CH:15]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:22][CH2:21][O:20][C:16]1[CH:15]=[C:14]([CH2:13][CH:12]([O:24][CH3:25])[C:11]([OH:26])=[O:10])[CH:19]=[CH:18][CH:17]=1
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)C(Cc1cccc(OCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCOc2cccc(F)c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-fluoro-phenol and 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 351, Step 1) via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example-285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C18H19FO5 [M−H]−: 333.1.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([NH:26][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: NN1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCOCC2)n(C)n1
Yield: 87 %

Procedure:
As described for example 48c, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using 4-aminomorpholine instead of N,N-dimethylhydrazine, to the title compound (104 mg, 87%) which was obtained as a colorless oil. MS: m/e=416.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:15](Cl)=[O:16])[CH3:2].[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:15]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:2]
Reactant: Nc1nccs1
Reactant: CCOc1nc2c(cnn2CC)nc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOc1nc2c(cnn2CC)nc1C(=O)Nc1nccs1

Procedure:
A mixture of 15.3 g. of 6-ethoxy-1-ethyl-1H-pyrazolo-[3,4-b]pyrazine-5-carbonyl chloride (0.06 mol.), 6.6 g. of 2-amino-thiazole (0.66 mol.) and 9.1 ml. of triethylamine (0.66 mol.) in 400 ml. of dry benzene are refluxed for 21/2 hours. After cooling the reaction mixture, the precipitated triethylamine hydrochloride is filtered off and the filtrate is evaporated to dryness. The crude 6-ethoxy-1-ethyl -N-2-thiazolyl-1H-pyrazolo-[3,4-b]pyrazine-5-carboxamide is recrystallized from ethyl acetate, m.p. 151°-152°, yield 9.9 g. (52 %).