Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]([NH2:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:14]([N:16]1[C:20](=[O:21])[C:19]([O:22]C)=[C:18]([C:24](O)=[O:25])[CH2:17]1)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]([NH:13][C:24]([C:18]2[CH2:17][N:16]([CH2:14][CH3:15])[C:20](=[O:21])[C:19]=2[OH:22])=[O:25])[CH3:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN1CC(C(=O)O)=C(OC)C1=O
Reactant: CC(N)CCc1ccc(Cl)c(Cl)c1
Product: CCN1CC(C(=O)NC(C)CCc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 15 %

Procedure:
By appropriate application of method described in Example 180, 4-(3,4-dichlorophenyl)butan-2-amine (racemic) (50 mg, 0.23 mmol) and 1-ethyl-4-methoxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (85 mg, 0.46 mmol) were converted to Example 225 (racemate) (12 mg, 0.032 mmol, 15% yield for two steps).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2OS(C(F)(F)F)(=O)=O)[S:4][C:3]=1[C:19](=[O:21])[NH2:20].[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCOCC1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:32]2[CH2:33][CH2:34][N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:30][CH2:31]2)[S:4][C:3]=1[C:19]([NH2:20])=[O:21]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: NC(=O)c1sc2nccc(OS(=O)(=O)C(F)(F)F)c2c1N
Solvent: C1COCCO1
Product: NC(=O)c1sc2nccc(N3CCN(Cc4ccccc4)CC3)c2c1N
Reaction time: 8 h

Procedure:
A mixture of 20 mg trifluoromethanesulfonic acid 3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl ester and 50 microL of N-benzylpiperazine in 1 mL of dry dioxane was purged with N2 and capped and left at room temperature overnight. The reaction was diluted with EtOAc, washed four times with water, dried and concentrated to dryness in vacuo. The product was purified on a 2 mm silica gel prep plate, developing and eluting the band with MeOH—CH2Cl2 mixtures and then concentrating to dryness. The product was re-dissolved in 5-10% MeOH—CH2Cl2, filtered to remove silica gel, concentrated, and dried in vacuo at 60° C. overnight to provide 7.9 mg of the title compound as a beige solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][C:24]2=O)([O-:19])=[O:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C.O>[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][CH:24]2[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:9])[C:2]1=[O:1])([O-:19])=[O:18]
Reactant: O=C1CCc2c1cccc2[N+](=O)[O-]
Reactant: O=C(Nc1ccncc1)c1ccc[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccncc1)c1cccn(C2CCc3c2cccc3[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a mixture of 2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (8.0 g, 1.0 eq) in dry DMF (30 mL) was added 4-nitro-2,3-dihydro-1H-inden-1-one (1.2 eq) and PPh3 (3.0 eq), then added DIAD (3.0 eq) under N2 atmosphere. Then the mixture was stirred at room temperature overnight. At the end of reaction, water was added and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4, filtrated and evaporated to give the crude product, which was purified by Flash Column (PE:EtOAc=1:2), concentrated the crude product, and recrystallized by EtOAc to give 1-(4-nitro-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (3.5 g, 21%). MS (ESI) 377.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 12.22 (s, 1H), 8.62 (m, 1H), 8.53 (m, 2H), 8.24 (m, 1H), 7.67 (m, 2H), 7.49 (m, 2H), 6.75 (m, 1H), 6.50 (m, 1H), 3.71 (m, 1H), 3.57 (m, 1H), 2.97 (m, 1H), 2.21 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH2:22]([N:24]1[C:28]2=[N:29][C:30]([CH2:69][CH3:70])=[C:31]([CH2:40][NH:41][C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([NH:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[C:56](B5OC(C)(C)C(C)(C)O5)[CH:55]=4)=[O:51])[CH:45]=3)=[O:43])[C:32]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:27]2[CH:26]=[N:25]1)[CH3:23].C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O>O1CCOCC1.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.C(Cl)Cl>[CH2:22]([N:24]1[C:28]2=[N:29][C:30]([CH2:69][CH3:70])=[C:31]([CH2:40][NH:41][C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([NH:52][CH2:53][C:54]4[CH:59]=[C:58]([C:2]5[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]6[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]6)[CH:3]=5)[CH:57]=[CH:56][CH:55]=4)=[O:51])[CH:45]=3)=[O:43])[C:32]([NH:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:27]2[CH:26]=[N:25]1)[CH3:23]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Br)c2)CC1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(OC4CCNCC4)c3)c2)c1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3-bromophenyl)oxy]-1-piperidinecarboxylate (0.036 g, 0.100 mmol) in 1,4-dioxane (0.9 mL) and H2O (300 μL) was added N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1,3-benzenedicarboxamide (0.067 g, 0.1 mmol), Pd(Ph3P)4 (4.62 mg, 4.00 μmol), and K2CO3 (0.028 g, 0.200 mmol). This mixture was heated at 130° C. for 15 min. The reaction mixture was concentrated (Glas-Col) and purified with CombiFlash chromatograph. To the resultant material was added DCM (300 μL) and TFA (100 μL, 1.298 mmol) which was then stirred at room temperature for 30 min. The reaction mixture was concentrated (Glas-Col), purified using a Gilson HPLC (with 0.1% TFA), concentrated on a GeneVac EZ-2 and neutralized with an amine cartridge to afford 0.0237 g (33.1%) of the title compound. LC-MS m/z 716 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.39 (t, J=6.78 Hz, 3 H) 1.48 (t, J=6.90 Hz, 3 H) 1.80-1.97 (m, 2 H) 1.99-2.24 (m, 5 H) 3.09-3.28 (m, 4 H) 3.41 (t, J=9.29 Hz, 2 H) 3.66 (t, J=11.04 Hz, 2 H) 4.02 (d, J=8.78 Hz, 2 H) 4.33 (br. s., 1 H) 4.42-4.90 (m, 8 H) 6.61-6.85 (m, 1 H) 6.94-7.17 (m, 1 H) 7.21 (br. s, 2 H) 7.31-7.66 (m, 5 H) 8.04 (d, J=7.53 Hz, 2 H) 8.27 (br. s., 1 H) 8.35-8.44 (m, 1 H).
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.O.[NH3:12]>O1CCOCC1>[NH2:12][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1
Reactant: N#Cc1nc(F)cnc1F
Reactant: N
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1nc(F)cnc1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a mixture of 1.5 mL of 25% aqueous ammonia and 500 mL of dioxane was dissolved 1.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. The solution thus obtained was stirred at room temperature for 6 hours. Then, 20 mL of water was added to the reaction mixture and stirred for 20 minutes while cooling the mixture with ice. The deposited material was collected by filtration, washed successively with 5 mL of cold water and 5 mL of ethanol to obtain 0.84 g of 3-amino-6-fluoro-2-pyrazine-carbonitrile as a light yellow-colored solid product.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][C:8]=2[CH2:7][CH2:6]1.N>C(O)(=O)C.O>[CH2:5]1[CH:16]2[CH:8]([NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[CH2:7][CH2:6]1
Reactant: c1ccc2c3c([nH]c2c1)CCC3
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc2c(c1)NC1CCCC21
Temperature: 15 °C
Reaction time: 20 h
Yield: 85.6 %

Procedure:
1.9 g of sodium cyanoborohydride are added in portions to a solution of 1.5 g of 1,2,3,4-tetrahydrocyclopenta[b]indole in 40 ml of acetic acid cooled to 15° C. The reaction medium is stirred for 20 hours while allowing it to rise to ambient temperature and then the pH is brought to neutrality with a 28% aqueous ammonia solution. The reaction mixture is diluted with water and then extracted with dichloromethane, and the organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (95/05), so as to give 1.3 g of 1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole in the form of a colorless oil.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16]>>[OH:17][CH:13]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC=O
Reactant: COC(=O)c1ccc(I)c(C)c1
Product: CCCC(O)c1ccc(C(=O)OC)cc1C

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate (16), using methyl 4-iodo-3-methylbenzoate and butyraldehyde. 1H NMR (400 MHz, CDCl3, δ): 7.87 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 4.98 (q, J=4.4 Hz, 1H), 3.90 (s, 3H), 2.37 (s, 3H), 1.63-1.72 (m, 2H), 1.50-1.54 (m, 1H), 1.39-1.43 (m, 1H), 0.98 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)cc1

Procedure:
A mixture of 1-(4-methoxyphenyl)piperazine dihydrochloride (5.30 g, 20 mmole), 2-chloro-5-nitropyridine (3.2 g, 20 mmole) and potassium carbonate (4.14 g, 30 mmole) in DMF (20 ml) was heated at 120° for 66 hours. The reaction mixture was cooled, diluted with water and the resulting precipitate collected by filtration. To this solid was added methanol (200 ml) and the mixture was heated under reflux for 0.17 hour. After cooling, the solid was collected by filtration and dried to yield the desired product, m.p. 165°-6° (4.0 g, 64%), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O[CH2:10][C:11]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1(CO)CC1
Reactant: Oc1ccc(Br)cc1
Product: COC(=O)C1(COc2ccc(Br)cc2)CC1
Yield: 70.9 %

Procedure:
By using 4-bromophenol (1.33 g) and methyl 1-(hydroxymethyl)cyclopropane carboxylate (663 mg), the procedure was carried out in the same manner as in Reference example 2-1) to obtain methyl 1-[(4-bromophenoxy)methyl]cyclopropane carboxylate (1.03 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=O>>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][NH:1][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: NCCCO
Reactant: O=Cc1ccccn1
Product: OCCCNCc1ccccn1

Procedure:
prepared by reaction of 3-amino-propan-1-ol with pyridine-2-carbaldehyde
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>>[Cl:12][C:13]1[CH:20]=[C:19]([O:21][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1ccc(Oc2ccc(C=O)cc2C#N)cc1Cl

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-chloro-4-hydroxybenzonitrile.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][CH:7]([CH2:12][CH:13]=[CH2:14])[CH2:8][CH:9]1[CH2:11][CH2:10]1)C.Cl>O1CCCC1>[CH:9]1([CH2:8][CH:7]([O:6][CH2:5][CH:4]=[O:3])[CH2:12][CH:13]=[CH2:14])[CH2:10][CH2:11]1
Reactant: C=CCC(CC1CC1)OCC(OCC)OCC
Agent: Cl
Solvent: C1CCOC1
Product: C=CCC(CC1CC1)OCC=O
Temperature: 25 °C
Yield: 121.7 %

Procedure:
A mixture of [2-(2,2-diethoxyethoxyl)pent-4-en-1-yl]cyclopropane (C66) (20 g, 83 mmol), aqueous hydrochloric acid (2 M, 83 mL, 166 mmol) and tetrahydrofuran (250 mL) was stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated to remove tetrahydrofuran. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the product as a colorless oil (17 g). This material was taken directly into the following step.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].C([CH:16]1[C:29](=[O:30])[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[CH:23][CH:22]=[N:21]3)[N:18]=[CH:17]1)(O)=O>CN(C=O)C>[N:8]1([C:1]([CH:16]2[C:29](=[O:30])[C:28]3[C:19](=[C:20]4[C:25](=[CH:26][CH:27]=3)[CH:24]=[CH:23][CH:22]=[N:21]4)[N:18]=[CH:17]2)=[O:2])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1C=Nc2c(ccc3cccnc23)C1=O
Solvent: CN(C)C=O
Product: O=C1c2ccc3cccnc3c2N=CC1C(=O)n1ccnc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
1,1'-Carbonyldiimidazole (30.4 g) was added to a stirred mixture of 3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline (18 g) and DMF (400 ml). The mixture was stirred at 100° C. for 2.5 hours, and then cooled to ambient temperature. The resulting solid was filtered to give 3-(imidazol-1-ylcarbonyl)-4-oxo-3,4-dihydro-1,10-phenanthroline in 92% yield.
Reaction SMILES: [OH:1][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH:37](O)[CH2:38][CH2:39][CH3:40])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:4][CH2:3]1.[ClH:42].[O:43]1CCOCC1>CCOCC>[ClH:42].[OH:1][C:2]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:43])[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:11]([N:13]([CH3:14])[CH3:15])=[O:12])[CH2:6][CH2:7]1
Reactant: CCCC(O)CCOc1ccccc1C1(O)CCN(CCC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)CC1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOCC
Product: CN(C)C(=O)C(CCN1CCC(O)(c2ccccc2OCCCCCCO)CC1)(c1ccccc1)c1ccccc1
Yield: 86.3 %

Procedure:
In 50 mL of anhydrous ether was dissolved 500 mg (0.9 mmol) of 4-(4-hydroxy-4-(2-(3-hydroxyhexyloxy)phenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide (Compound No. 35). To the resulting solution was added 0.4 mL of a 4N solution of hydrochloric acid and dioxane under ice cooling and stirring. The white precipitate thus formed was collected by filtration, washed with ether and dried, whereby 460 mg (yield: 86.3%) of 4-(4-hydroxy-4-(2-(6-hydroxyhexyloxy)phenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide hydrochloride (Compound No. 37) was obtained.
Reaction SMILES: C1(OC)C(=CC=C(C=1)CC=C)O.C1CCN2C(=NCCC2)CC1.C(=O)(OC)OC.[CH3:30][O:31][C:32]1[C:33]([O:41][CH3:42])=[CH:34][C:35]([CH2:38][CH:39]=[CH2:40])=[CH:36][CH:37]=1>>[CH3:30][O:31][C:32]1[C:33]([O:41][CH3:42])=[CH:34][C:35]([CH:38]=[CH:39][CH3:40])=[CH:36][CH:37]=1
Reactant: C=CCc1ccc(OC)c(OC)c1
Agent: C=CCc1ccc(O)c(OC)c1
Solvent: COC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Product: CC=Cc1ccc(OC)c(OC)c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
15 mol of eugenol was charged into a pressure reactor, along with 0.2 mol of 1,8-diazabicyclo[5.4.0]-7-undecene and 16 mol of dimethyl carbonate. The reactor was sealed and was heated to 150° C. After 2 hr, complete conversion of the eugenol was shown to have occurred. After the distillation, 13 mol of eugenol methyl ether and 1 mol of isoeugenol methyl ether were obtained, corresponding to a yield of 86%, based on the starting amount of eugenol.
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:11][CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH:13]12[CH2:19][CH:16]([CH:17]=[CH:18]1)[CH2:15][CH:14]2[CH2:20][C:21](=[O:23])[CH3:22]>>[OH:23][C:21]([CH3:22])([CH2:20][CH:14]1[CH2:15][CH:16]2[CH2:19][CH:13]1[CH:18]=[CH:17]2)[CH2:2][C:1]([O:4][C:5]1([CH2:11][CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3]
Reactant: CC(=O)CC1CC2C=CC1C2
Reactant: CCC1(OC(C)=O)CCCCC1
Product: CCC1(OC(=O)CC(C)(O)CC2CC3C=CC2C3)CCCCC1
Yield: 92 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that 1-ethylcyclohexyl acetate was used instead of 1-ethylcyclopentyl acetate, and 3-(5-norbornen-2-yl)acetone was used instead of 5-norbornene-2-carbaldehyde. There was obtained 1-ethylcyclohexyl 3-hydroxy-3-methyl-4-(5-norbornen-2-yl)butyrate. Yield 92%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[C:21]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)[CH2:25]1)(=[O:23])[CH3:22]>>[C:21]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([NH:20][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([CH2:13][N:14]5[CH2:18][CH2:17][CH2:16][CH:15]5[CH3:19])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:35])=[CH:37][CH:38]=2)[CH2:25]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CCCC(c2ccc(C(=O)O)cc2)C1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: CC(=O)N1CCCC(c2ccc(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)cc2)C1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 4-(1-acetyl-piperidin-3-yl)-benzoic acid. MS: 503.3 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:17]1[N:25](S(C2C=CC(C)=CC=2)(=O)=O)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)C.[OH-].[K+]>CO>[CH3:16][N:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[CH:15][CH:14]=2)[C:10]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:11]1
Reactant: CCOC(=O)COc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(OCC(=O)O)ccc21
Yield: 53.3 %

Procedure:
A solution of {1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yloxy}-acetic acid ethyl ester [500 mg, Reference Example 15(b)] in methanol (25 mL) was treated with potassium hydroxide (5N, 3 mL) and then heated at reflux for 16 hours. The solvent was removed under reduced pressure and the residue was treated with water (10 mL). The pH of this mixture was adjusted to 7 by addition of acetic acid and the resulting colourless solid was collected by filtration then dried to give the title compound (170 mg) as a colourless solid, m.p.>300° C. MS: 322 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[C:21]2[CH:37]=[CH:38][CH:39]=[CH:40][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)[C:23]3[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=3[C:21]3[CH:37]=[CH:38][CH:39]=[CH:40][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NN1C(=O)C(C2CCCCC2)c2ccccc2-c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(C2CCCCC2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-N), the title compound was prepared. The reaction was monitored by tlc (Rf=0.35, 5% MeOH/CHCl3) and product was purified by chromatography (silica, 5% MeOH/CHCl3).
Reaction SMILES: C(OC([NH:8][C@H:9]([C@@H:41]([OH:54])[CH2:42][C@H:43]([C:47](=[O:53])[NH:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH:44]([CH3:46])[CH3:45])[CH2:10][C@@H:11]([CH:38]([CH3:40])[CH3:39])[CH2:12][NH:13][C:14](=[O:37])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:29])[NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][C:16]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=O)(C)(C)C.[ClH:55]>O1CCOCC1>[ClH:55].[NH2:8][C@H:9]([C@@H:41]([OH:54])[CH2:42][C@H:43]([C:47](=[O:53])[NH:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH:44]([CH3:45])[CH3:46])[CH2:10][C@@H:11]([CH:38]([CH3:40])[CH3:39])[CH2:12][NH:13][C:14](=[O:37])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:29])[NH:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][C:16]=1[O:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36]
Reactant: CCCCNC(=O)COc1ccc(C(=O)NC[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCCCC)C(C)C)C(C)C)c(OCCCCOC)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCNC(=O)COc1ccc(C(=O)NC[C@@H](C[C@H](N)[C@@H](O)C[C@H](C(=O)NCCCC)C(C)C)C(C)C)c(OCCCCOC)c1

Procedure:
In a manner analogous to that described in Example 21), reaction of (2S,4S,5S,7S)-N-[4-(tert-butoxycarbonyl)amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-8-methyl-nonyl]-4-butylcarbamoylmethoxy-2-(4-methoxybutoxy)-benzamide (80 mg) in 4N hydrochloric acid solution in dioxane at 0° C. for one hour, rapid concentration of the solvent under a high vacuum and lyophilisation yield (2S,4S,5S,7S)-N-(4-amino-7-butylcarbamoyl-5-hydroxy-2-isopropyl-8-methyl-nonyl)-4-butylcarbamoylmethoxy-2-(4-methoxybutoxy)-benzamide hydrochloride: Rf (W)=0.23. HPLC Rt =13.8 min. MS(FAB) m/e 665 (M+ +1).
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:22])=[C:11](B3OCC(C)(C)CO3)[CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[C:30]1[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([NH:38][CH3:39])=[O:37])=[CH:32][CH:31]=1>>[Cl:22][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH:3]=[O:4])=[CH:6][NH:7]2)=[CH:12][C:11]=1[C:30]1[CH:41]=[CH:40][C:33]([O:34][CH2:35][C:36]([NH:38][CH3:39])=[O:37])=[CH:32][CH:31]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: CNC(=O)COc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNC(=O)COc1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Temperature: 90 °C
Yield: 72.9 %

Procedure:
To the slurry of methyl-6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (240 mg, 1.0 mmol) was added 2 M potassium carbonate (2.5 mL, 5.0 mmol), 2-(4-bromophenoxy)-N-methylacetamide (240 mg, 1.00 mmol) and PddppfCl2 (50 mg, 0.061 mmol). The sealed vial was heated to 90° C. for 30 min. The reaction was cooled to room temperature and quenched with water (20 mL), and then washed three times with ethyl acetate (20 mL). The combined organics were dried and concentrated to give the title compound (250 mg, 55% yield) as a yellow solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.37 (d, 1H), 8.02 (s, 1H), 7.68 (s, 1H), 7.38 (d, 2H), 7.05 (d, 2H), 4.52 (s, 2H), 2.68 (d, 3H).