Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.O=[C:14]1[CH2:19][CH2:18][N:17]([C@H:20]([CH3:24])[CH2:21][C:22]#[N:23])[CH2:16][CH2:15]1>>[NH2:23][CH2:22][CH2:21][C@H:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[CH2:15][CH2:16]1)[CH3:24]
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: C[C@H](CCN)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
Using general procedure A with 4-(trifluoromethoxy)-aniline (0.21 mL, 1.55 mmol) and (R)-3-(4-oxo-piperidin-1-yl]-butyronitrile (310 mg, 1.87 mmol) followed by general procedure J afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine as a white solid (277 mg, 55% over 2 steps).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:16]=[C:15]([NH2:17])[NH:14][N:13]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:18]1([C:21](=O)[CH2:22][C:23](OCC)=[O:24])[CH2:20][CH2:19]1.C[O-].[Na+].C(O)(=O)C>COCCO.O>[CH:18]1([C:21]2[CH:22]=[C:23]([OH:24])[N:14]3[N:13]=[C:12]([C:3]4[C:2]([CH3:1])=[N:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH:16]=[C:15]3[N:17]=2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: Cc1nc2ccccc2nc1-c1cc(N)[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCO
Solvent: CC(=O)O
Product: Cc1nc2ccccc2nc1-c1cc2nc(C3CC3)cc(O)n2n1
Temperature: 25 °C

Procedure:
A mixture of 3-(3-methylquinoxalin-2-yl)-1H-pyrazol-5-amine (Example 1.001 (c)) (200 mg, 0.888 mmol), ethyl 3-cyclopropyl-3-oxopropanoate (416 mg, 2.66 mmol), and sodium methoxide (28% in methanol, 1.03 g, 5.34 mmol) in 2-methoxyethanol (2.0 mL) was refluxed for 10 h. After being cooled to ambient temperature, the reaction mixture was acidified to pH 3-4 with acetic acid. The mixture was diluted with water and the resulting precipitate was collected and washed with diisopropyl ether to give 5-cyclopropyl-2-(3-methylquinoxalin-2-yl)pyrazolo[1,5-a]pyrimidin-7-ol. MS (APCI): m/z 318 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([N:64]2[C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=3[N:66]=[CH:65]2)[CH:59]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([N:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58]1[CH:63]=[CH:62][N:61]=[C:60]([N:64]2[C:68]3[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=3[N:66]=[CH:65]2)[CH:59]=1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc2c(c1)ncn2-c1cc([C@@H]2CCCN2)ccn1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(-n2cnc3ccccc32)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of (S)-tert-butoxycarbonylamino-cyclohexyl-acetic acid (51 mg, 0.21 mmol), HOBt (31 mg, 0.23 mmol) and HBTU (88 mg, 0.23 mmol) in DMF (5 mL) is stirred at room temperature for 30 min. Then a solution of —((S)-4-pyrrolidin-2-yl-pyridine-2-yl)-1H-benzoimidazole (10) in DMF (5 mL) is added, followed by diisopropylethylamine (135 mg, 1.05 mmol). After stirring at room temperature for 2 h, the reaction mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by flash chromatography on silica gel (EtOAc/Hexane: 5%˜40%) to give {(S)-2-[(S)-2-(2-benzoimidazol-1-yl-pyridin-4-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-carbamic acid tert-butyl ester (71 mg, 67%) as a white solid. M/Z=504.2 [M+1]
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@:19]([CH3:25])([CH:22]([CH3:24])[CH3:23])[CH2:20][OH:21]>>[OH:21][CH2:20][C@@:19]([NH:18][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:25])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)[C@@](C)(N)CO
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: CC(C)[C@](C)(CO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g; 100 mg, 0.42 mmol) and (2R)-2-amino-2,3-dimethyl-1-butanol (CAN 155158-75-1, 107.06 mg, 0.64 mmol) as starting materials, and isolated (20 mg, 14.04%) as off white sticky solid, LC-MS (UV peak area, ESI) 100%, 334.4 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[BH4-].[Na+].CC(C)=O>C(O)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19]([OH:20])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
Compound 1 (2.27 g, 6.14 mmol) was dissolved in ethanol (50 mL), and sodium borohydride (0.465 g, 12.3 mmol) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was added with acetone and stirred for 30 minutes, then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1), and obtained crystals were triturated with diethyl ether-hexane to obtain Compound 2 (2.10 g, yield 92%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:66](O)(=[O:70])[C@H:67]([CH3:69])[OH:68]>CN(C=O)C>[OH:68][C@@H:67]([CH3:69])[C:66]([N:21]1[CH2:20][CH2:19][C:17]2[N:18]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]4[O:1][CH:2]=[N:3][CH:4]=4)=[CH:7][CH:8]=3)[N:14]=[C:15]([N:23]([CH2:24][CH2:25][OH:26])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH2:22]1)=[O:70]
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](O)C(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (100 mg, 0.23 mmol, Example 1) was dissolved in DMF (5 mL). N-Ethyldiisopropylamine (0.081 mL, 0.47 mmol) was added followed by O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (115 mg, 0.30 mmol) and L-lactic acid (21.02 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, the crude dissolved in MeOH and acetonitrile, filtered and purified by preparative HPLC yielding (S)-2-hydroxy-1-(4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)propan-1-one (30.0 mg, 26%).
Reaction SMILES: [C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[C:20]3=[O:34])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[OH-].[Na+].O.Cl>C(O)C>[C@H:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][C:29]([OH:31])=[O:30])[C:20]3=[O:34])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: CCOC(=O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(=O)n(C2CCN([C@@H]3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
Ethyl (R)-2-{3-[1-(acenaphthen-1-yl)piperidin-4-yl]-2,3-dihydro-2-oxo-benzoimidazol-1-yl}acetate (2.6 g, 5.8 mmol) was dissolved in ethanol (10 ml), 2N-aqueous sodium hydroxide solution (10 ml) was added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, 1N-hydrochloric acid was added for neutralization, and the mixture was extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained solid was washed with ethyl acetate to give the title compound (2.4 g) as pale-yellow crystals.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N([O-])=O.[Na+].C(OCC)(=O)C.C(OCC)C.[H+].[B-](F)(F)(F)[F:29]>>[F:29][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1cccc2ncccc12
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Fc1cccc2ncccc12
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a suspension of 5-aminoquinoline (10.0 g, 0.069 mol) in 48% HBF4 (40 mL) at 0° C. was added portionwise sodium nitrite. This was stirred for 1 hour and then poured into 1:1 ethyl acetate/diethyl ether (50 mL). The resulting suspension was filtered and the solid dried. This solid was added portionwise to refluxing xylene (80 mL) and stirred for 2 hours then allowed to cool. The xylene was decanted off and the residue was dissolved in 1N aqueous hydrochloric acid (100 mL). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate (3×80 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel column chromatography, eluting with 2% ethyl acetate in petroleum ether to afford 5-fluoroquinoline as a colorless oil (2.5 g, 24.5%).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:32]1[S:41][CH2:40][C@H:39]2[C@:34]([C:44]3[CH:49]=[C:48](Br)[CH:47]=[CH:46][C:45]=3[F:51])([CH2:35][O:36][C@@H:37]([CH2:42][F:43])[CH2:38]2)[N:33]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>CN(C=O)C.O.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>[F:51][C:45]1[CH:46]=[CH:47][C:48]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:49][C:44]=1[C@@:34]12[N:33]=[C:32]([NH2:24])[S:41][CH2:40][C@@H:39]1[CH2:38][C@H:37]([CH2:42][F:43])[O:36][CH2:35]2
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](CF)C[C@H]2CS1
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: CN(C)C=O
Solvent: O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3F)CO[C@@H](CF)C[C@H]2CS1
Temperature: 85 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
2-Fluoropyridine-3-boronic acid (51.1 mg), tetrakis(triphenylphosphine)palladium (19.1 mg) and a 1 N sodium carbonate solution (363 μl ) were added to a solution of N,N-di(tert-butyloxycarbonyl)-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-fluoromethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (95 mg) in DMF (6.79 ml). After replacement with nitrogen, the mixture was stirred at 85° C. for two hours. After cooling to room temperature, the mixture was diluted with water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in dichloromethane (4.0 ml). TFA (1.0 ml) was added and the mixture was stirred at room temperature for three hours. Ice was added to the reaction mixture, followed by neutralization with a sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (59.0 mg).
Reaction SMILES: B(O)(O)[C@H]1N(C([C@@H](N)C(C)C)=O)CCC1.CS(O)(=O)=O.[C:21]([O:24][CH2:25][C:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])=O)(=[O:23])[CH3:22].CC(OC)(C)C.[C:39]([CH:44]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:41][CH2:42][CH3:43])=[O:40]>CCCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1.CCCCCCC>[CH2:42]([O:41][C:39](=[O:40])[CH:44]=[C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])[CH2:28][O:29][C:30](=[O:32])[CH3:31])[CH3:43]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Product: CCOC(=O)C=C(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A 3.5 L reactor equipped with a mechanical stirrer, a Pt-100 thermometer and a nitrogen inlet was charged with 127 g (731 mmol) 1,3-diacetoxyacetone, 1.95 L TBME and 309 g (877 mmol) carbethoxymethylene triphenylphosphorane. The solution was refluxed for 5 h, then allowed to cool to RT during 14 h. Then TBME was exchanged with 2.3 L heptane at 40° C./300 mbar and the mixture was stirred overnight at RT before 400 ml toluene was added. The suspension was stirred for 1 h at RT, then 2 h at 0-4° C., filtered, and the filter cake was washed portionwise with totally 600 ml pre-cooled toluene. The combined filtrates were concentrated on a rotatory evaporator at 45° C./10 mbar to give 193 g crude product as reddish oil. This material was dissolved in 200 ml of a heptane/ethyl acetate (3:1) mixture and was chromatographically filtered over a column containing 400 g silica gel 60 using heptane/ethyl acetate (3:1) as the eluent, to give 174 g 4-acetoxy-3-acetoxymethyl-but-2-enoic acid ethyl ester (98% yield; assay: 99.9%) as a colorless oil.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:3][CH:2]=1.O>C(OCC)C>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([CH:7]([OH:13])[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:5][CH:6]=1
Reactant: C=CCCCC(=O)c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Product: C=CCCCC(O)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
1-Biphenyl-4-yl-hex-5-en-1-one (1 g) was dissolved in diethyl ether (25 ml) NaBH4 (2.5 g) was added and the mixture stirred for 30 minutes. Water (50 ml) was added and most of the solvent evaporated under vacuo. The residue was poured into water and the product extracted with ethyl acetate. The organic layer was dried (Na2SO4) and the ethyl acetate evaporated under vacuum to give a white solid. δC (CDCl3, 62.9 MHz): 25.2, 33.6, 38.5, 74.3, 114.8, 126.4, 127.1, 127.2, 128.8, 138.6, 140.5, 140.9 and 143.9.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][NH:14][C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O.NN.[OH-].[Na+]>C(O)C>[NH2:3][CH2:12][CH2:13][NH:14][C@@H:15]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC[C@H](C)[C@H](NCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@H](C)[C@H](NCCN)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of the product of Example 3F (28.44 g, 78.9 mmol) in ethanol (400 mL) was treated with hydrazine hydrate (25 mL, 789 mmol), stirred at 70° C. for 2 hours, cooled to 25° C. The solid precipitate was dissolved by addition of aqueous NaOH solution (200 mL, 1 N). The reaction was partitioned between dichloromethane and water. The aqueous was extracted three times with dichloromethane. The combined organic extracts were dried over MgSO4, filtered and concentrated to give the title compound (15.4 g, 85% yield), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14]CC)=O)=[CH:8][C:7]([CH3:17])=[CH:6][CH:5]=2.[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[NH2:20][CH2:19][CH2:18][NH:21][C:12](=[O:14])[CH2:11][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:17])[CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: NCCN
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(C)cc12
Product: Cc1ccc2[nH]c(C)c(CC(=O)NCCN)c2c1
Temperature: 115 °C
Yield: 39 %

Procedure:
A mixture of 1.18 g (4.8 mmol) of ethyl (2,5-dimethylindol-3-yl)acetate and 7.5 mL of ethylenediamine was heated at 115° C. overnight. The excess ethylenediamine was removed under reduced pressure and the residue was chromatographed with 1:1 CH2Cl2-(EtOH+10% ethanolic NH3). The pure fraction of N-(2-aminoethyl)-(2,5-dimethylindol-3-yl)acetamide obtained (1.2 g) was treated with 15 mL of hexamethyldisilazine HDS) at gentle reflux (130° C.) overnight. The mixture was concentrated to dryness, dissolved in EtOH and treated with etheric HCl to acidic. Addition of ether in 3 portions induced light brown crystals. Yield: 39%; m.p. 245-7° C.; 1H NMR (DMSO-d6) d 11.02 (br. s, 1H), 9.94 (br. s, 2H), 7.23 (s, 1H ), 7.16 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 3.90 (s, 2H), 3.79 (s, 4H), 2.36 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].C([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[C:36][CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)=[CH:31][CH:30]=1)=[O:28])C.C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:38]2[CH2:39][CH2:40][CH2:41][CH:37]2[C:36]#[C:35][C:32]2[CH:33]=[CH:34][C:29]([C:27]([OH:28])=[O:26])=[CH:30][CH:31]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(CC(=O)N2CCCC2C#Cc2ccc(C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1F
Reaction time: 8 h

Procedure:
A mixture of 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetic acid (255 mg, 0.8 mmol), 2-[2-(4-ethoxycarbonylphenyl)ethynyl]pyrrolidine (195 mg, 0.8 mmol), EDC (230 mg, 1.2 mmol), DMAP (98 mg, 0.8 mmol) in DMF (20 mL) was stirred overnight. The reaction mixture was poured into 1 N HCl and the resulting precipitate was collected with suction and dissolve in CHCl3. The solution was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel with CHCl3—MeOH (100:1, v/v) as eluent to give the desired compound, which was dissolved in THF (8 mL). 0.25 N NaOH (8 mL) was added to this solution and the resulting mixture was stirred overnight. The mixture was poured into 1 N HCl and extracted with CHCl3. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was recrystallized from CHCl3-n-hexane to give 144 mg (37%) 33 as a pale yellow crystalline powder. mp 152-155 (d); 1H-NMR (DMSO-d6) δ1.92-2.27 (4 H, m), 2.50 (2 H, s), 3.33-3.78 (2 H, m), 3.80 and 3.82 (total 3 H, s, each), 4.88-5.12 (1 H, m), 6.77-7.24 and 7.99-8.20 (total 7 H, m,) 7.48 and 7.52 (2 H, d, J=8.3 Hz, each), 7.91 (2H, d, J=8.3 Hz), 8.72 (1H, s), 9.18 (1H, s), 13.11 (1H, br-s); MS (FAB) m/z 516 (M++1); Anal. Calcd. for C29H26N3O5F.2H2O: C, 63.15; H, 5.48; N, 7.63. Found: C, 63.58; H, 5.15; N, 7.22.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]1(=O)[CH2:38][CH2:37][C:36](=[O:39])[CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][CH:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][N:21]([C:34]4[CH2:38][CH2:37][C:36](=[O:39])[CH:35]=4)[CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C1CCC(=O)C1
Reactant: Cc1ccccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Product: Cc1ccccc1[C@@H]1C(O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]21

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(2-methylphenyl)octahydropyrano[3,4-c]pyrrole and cyclopentane-1,3-dione according to the procedures used for example 3. MS: (MH)+554.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][CH:18]=1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCBr)cc1
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCOc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
To a mixture of 292 mg 2-hydroxypyridine and 5 ml N,N-diemthylformamide, was added under ice cooling 150 mg of 60% sodium hydride in oil, and the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was again cooled in ice, 1.2 g ethyl 6-[p-(5-bromopentyloxy)phenoxy]-2,2-dimethylhexanoate was added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, the residue was extracted with chloroform, and the extract was washed with water and worked up as usual. The crude product thus obtained was purified by silica gel column chromatography (chloroform), affording 495 mg ethyl 6-[p-[5-(2-pyridyloxy)pentyloxy]phenoxy]-2,2-dimethylhexanoate as oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])=[O:8].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])=[O:8])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCCCCBr)Nc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCC(=O)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A mixture of 2 (28.4 g, 90 mmol) and sodium azide (12 g, 184 mmol) in DMF (200 mL) was stirred overnight at room temperature. The reaction mixture was poured into ice-water (500 mL) and extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water (4×100 mL) and brine (50 mL). After removal of the solvent the crude product was passed through a silica gel pad (100 g) and washed with 1:2 mixture of hexane and diethyl ether. Concentration of the appropriate fractions gave 22.5 g of 3 as a pale yellow oil. LC-MS (M++Na) 300