Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=2)[C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[N:6]=1.[CH:25]1([C:28]#[CH:29])[CH2:27][CH2:26]1.C1(CNCC2CCCCC2)CCCCC1>O1CCCC1.[Cu]I.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>[CH:25]1([C:28]#[C:29][C:2]2[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=3)[C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[N:6]=2)[CH2:27][CH2:26]1
Reactant: C#CC1CC1
Reactant: CSc1cccc(C(=NOCc2csc(Br)n2)c2nnnn2C)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: C1CCOC1
Product: CSc1cccc(C(=NOCc2csc(C#CC3CC3)n2)c2nnnn2C)c1
Yield: 80 %

Procedure:
A solution of N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-[3-(methylsulfanyl)phenyl]-1-(1-methyl-1H-tetrazol-5-yl)methanimine (150 mg, 0.35 mmol), cyclopropylacetylene (8.44 M in toluene, 84 μL, 0.70 mmol), copper(I) iodide (6.72 mg, 0.03 mmol), tetrakis(triphenylphosphine)palladium(0) (20.4 mg, 0.05 mmol), N,N-dicyclohexylmethylamine (0.30 mL, 1.41 mmol) in degassed tetrahydrofuran (3 mL) was stirred under an Argon atmosphere at room temperature for 24 h. After evaporation of the solvent in vacuo, purification on silica gel afforded N-{[2-(cyclopropylethynyl)-1,3-thiazol-4-yl]methoxy}-1-[3-(methyl-sulfanyl)phenyl]-1-(1-methyl-1H-tetrazol-5-yl)methanimine as a thick oil [116 mg, yield 80%; HPLC/MS: m/z=411 (M+H); logP(HCOOH)=3.99].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:18]=[N:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CC(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:8][C:6]1[CH:7]=[C:2]([C:17]2[CH:18]=[N:19][N:20]([C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:21]=2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Clc1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)ncn1
Temperature: 108 °C

Procedure:
In a microwave reaction tube were combined 4,6-dichloropyrimidine (480 mg, 3.22 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole (1.28 g, 2.93 mmol; JP 2005232071), bis(triphenylphosphine)-palladium(II) chloride (82 mg, 0.117 mmol), sodium carbonate (776 mg, 7.32 mmol), followed by the solvents 2-propanol (9.0 mL) and water (3.0 mL). The tube was sealed, and the reaction was heated to 108° C. for 30 minutes in the microwave reactor. After cooling to room temperature, the mixture was partitioned between ethyl acetate (2×100 mL) and water (200 mL). The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated under reduced pressure, and the resulting material was purified by silica gel flash column chromatography to afford the titled compound: 1H NMR (300 MHz, methanol-D4) δ ppm 7.11-7.22 (m, 6H), 7.28-7.41 (m, 9H), 7.81-7.83 (m, 1H), 8.23-8.26 (m, 1H), 8.30 (s, 1H), 8.75-8.78 (m, 1H). MS (DCI/NH3) m/z=423 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][C:20]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:19]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:40][NH2:41].C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:40]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][C:20]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:19]3)=[CH:14][CH:13]=1)=[N:7]2)[NH2:41]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CC2(C1)OCCO2
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CC2(C1)OCCO2
Temperature: 100 °C

Procedure:
To a solution of tert-butyl {2-[4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate (1-9) (5 g, 9.2 mmol) in dioxane (100 mL) was added hydrazine (3.0 g, 92 mmol) and the reaction mixture was heated to 100° C. for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate, extracted with chloroform, dried over sodium sulfate, filtered and concentrated to give tert-butyl {2-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate (1-10) as a yellow solid. MS (M+H)+: 540.
Reaction SMILES: [OH-].[Na+].I[C:4]1[C:9]([OH:10])=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:7]=[C:6]([I:17])[N:5]=1.[CH3:18]I.O>CN(C)C=O.C(OCC)(=O)C>[I:17][C:6]1[CH:7]=[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:9]([O:10][CH3:18])=[CH:4][N:5]=1
Reactant: CI
Reactant: COCCCCc1cc(I)nc(I)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCc1cc(I)ncc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 60 mmol NaOH in 50 ml N,N-dimethyl formamide is progressively added 50 mmol 2,6-diiodo-4-(4-methoxy-butyl)-pyridin-3-ol. The reaction mixture is stirred for 30 minutes and then cooled to 0° C. 60 mmol methyl iodide are added and the mixture is stirred for 15 minutes at room temperature. Water and ethyl acetate are added to the mixture, the layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60 F) and identified based on its Rf value.
Reaction SMILES: CN1CCCCC1.[O:8]([C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[F:33][C:34]1[CH:45]=[CH:44][C:37]([N:38]([CH2:40][CH:41]([NH2:43])[CH3:42])[CH3:39])=[CH:36][CH:35]=1>C(Cl)Cl.O>[F:33][C:34]1[CH:45]=[CH:44][C:37]([N:38]([CH2:40][CH:41]([NH:43][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:16])[CH3:42])[CH3:39])=[CH:36][CH:35]=1
Reactant: CC(N)CN(C)c1ccc(F)cc1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CC(CN(C)c1ccc(F)cc1)NC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
1.6 g of N-methylpiperidine was added to a solution containing 3.9 g of N-phenoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 2.2 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 3.0 g of 2-(4-fluoro-N-methylanilino)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous sodium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product in the form of a white crystal (yield: 19%).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7](=[O:20])[C:8]([C:17]([OH:19])=O)=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH:22]([CH3:46])[CH2:23][NH:24][C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>ClCCCl>[C:1]([C:5]1[NH:6][C:7](=[O:20])[C:8]([C:17]([N:24]([CH2:23][CH:22]([CH3:46])[CH3:21])[C@H:25]2[CH2:30][C@@H:29]([C:31]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[O:32])[CH2:28][NH:27][CH2:26]2)=[O:19])=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCNc1nc(C(C)(C)C)[nH]c(=O)c1C(=O)O
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNc1nc(C(C)(C)C)[nH]c(=O)c1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.4 %

Procedure:
2-tert-Butyl-4-[(3-methoxypropyl)amino]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (280 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (250 mg) and N,N-diisopropylethylamine (640 mg) were dissolved in 1,2-dichloroethane (10 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (420 mg) was added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and diluted with aqueous calcium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in TFA (1 ml), and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was concentrated and purified by HPLC to give the object compound (15.8 mg).
Reaction SMILES: C([CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)(O)=O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:10][C:8]1[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH:4]=1)(=[O:17])[CH3:16]
Reactant: O=C(O)COc1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1coc2ccccc12
Temperature: 135 °C
Yield: 76 %

Procedure:
To acetic anhydride (300 mL) was added 2-(carboxymethoxy)benzoic acid (7) (100 g, 0.510 mol) at ambient temperature and heated to 130-140° C. The reaction temperature was maintained for 14-20 h under stirring. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, the reaction mixture was cooled to 50-80° C., acetic anhydride was recovered at 50-80° C. at reduced pressure and the crude product was extracted with dichloromethane (500 mL). The dichloromethane layer was recovered completely to obtain the product meeting the desired specifications. Yield—76-85%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][C:56]1[C:61]([C:62](O)=[O:63])=[CH:60][CH:59]=[CH:58][N:57]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:55][C:56]1[C:61]([C:62]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:13][CH2:14]2)=[O:63])=[CH:60][CH:59]=[CH:58][N:57]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ncccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (100 mg, 0.340 mmol) in DMF (5 ml) was added HOBT.H2O (52.0 mg, 0.340 mmol), HBTU (129 mg, 0.340 mmol), 2-methyl-3-pyridinecarboxylic acid (46.6 mg, 0.340 mmol) and DIPEA (0.178 ml, 1.019 mmol). The reaction mixture was stirred for 2 hours at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([O:31]CC)=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:29]([OH:31])=[O:30])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(CCOc2nccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)c(CCCC3(C(=O)O)CCN(CCOc4nccs4)CC3)c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 0.68 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thiazol-2-yloxy)-ethyl]piperidine-4-carboxylate in 7 cm3 of dioxane, 9 cm3 of methanol and 2 cm3 of aqueous 5N sodium hydroxide solution was maintained at a temperature in the region of 60° C. for 20 hours. After cooling to about 20° C., the reaction mass was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was chromatographed under a pressure of 50 kPa of argon, on a column of silica gel (particle size 20-45μ; diameter 2.2 cm; mass 20 g), eluting with a mixture of dichloromethane/methanol (70/30 by volume). The fractions containing the expected product were combined and then concentrated to dryness under the above conditions. The residue obtained was taken up in 5 cm3 of ethyl acetate, stirred for 1 hour at room temperature and then filtered and rinsed with 3 times 3 cm3 of ethyl acetate and then 3 times 3 cm3 of pentane. 0.27 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thiazol-2-yloxy)-ethyl]piperidine-4-carboxylic acid was obtained in the form of a white solid melting at 188° C.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[NH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:6][CH:5]=1.O.CO.O.[OH-].[Li+]>O1CCCC1>[Cl:19][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([NH:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:14]=1)[NH:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][CH:6]=1)=[CH:18]2
Reactant: COC(=O)c1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 7 %

Procedure:
The compound obtained in Example 64 (300 mg, 0.81 mmol) was dissolved in 15 ml of tetrahydrofuran, 5 ml of water and 5 ml of methanol. 100 mg (2.44 mmol) of Lithium hydroxide monohydrate was added. The mixture was stirred at room temperature for 21 hours. At the end of reaction, tetrahydrofurane and methanol were removed by distillation under reduced pressure. To the distillate 1N HCl solution was added the mixture was extracted with ethylacetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to obtain the title compound 20 mg (Yield 7%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:20])=[CH:13][CH:14]=2)[C:9]1([CH2:23][CH3:24])[CH2:21][CH3:22])(C)(C)C.Cl.O1CCOCC1>ClCCl>[NH2:7][C@@H:8]1[C:9]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:10]2[CH:11]=[C:12]([OH:20])[CH:13]=[CH:14][C:15]=2[CH2:16][C@H:17]1[O:18][CH3:19]
Reactant: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.2 %

Procedure:
To a solution of trans-(1,1-diethyl-7-hydroxy-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (6.0 g, 17.2 mmol) in dichloromethane (60 mL) was added a solution of 4.0 N HCl in dioxane (21.5 mL, 86 mmol) over approximately 2 min. After stirring at room temperature overnight, the reaction mixture was concentrated at reduced pressure and dried under vacuum to give the hydrochloride salt of the title compound (5.5 g) (m/z): [M+H]+ calcd for C15H23NO2 250.36; found 250.2. 1H NMR (d6-DMSO, 400 mHz) δ (ppm) 9.26 (s, 1H), 8.09 (br s, 3H), 6.92 (d, J=8.0 Hz, 1H), 6.61 (m, 2H), 3.77 (m, 1H), 3.41 (s, 3H), 3.30 (dd, J=15.8 Hz, 5.9 Hz, 1H), 3.17 (m, 1H), 2.43 (dd, J=15.5 Hz, 9.6 Hz, 1H), 1.85 (m, 2H), 1.66-1.50 (m, 2H), 0.66 (t, J=7.4 Hz, 3H), 0.54 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[C:22]1([C:28]([NH2:31])([CH3:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:31][C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH3:30])[CH3:29])=[O:16])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: O=C(O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(NC(=O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2,4-difluorobenzyl)-1H-indole-5-carboxylic acid (50 mg, 0.17 mmol, 1 equiv) in DCM (2 mL) was added 2-phenylpropane-2-amine (27 μL, 0.18 mmol, 1.05 equiv), DIEA (30 μL, 0.17 mmol, 1 equiv) and HATU (68 mg, 0.18 mmol, 1.05 equiv). The reaction mixture was stirred 2 h at room temperature.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>C(#N)C>[NH2:14][CH2:13][CH2:12][NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: NCCN
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Solvent: CC#N
Product: Cc1cc(NCCN)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-4-methyl-5-nitropyridine (2.0 g, 11.5 mmol) in acetonitrile (10 ml) was added dropwise to ethylenediamine (2.5 ml) in acetonitrile (10 ml). The mixture was stirred overnight at room temperature. The solvent was removed by rotary evaporation and the residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide. The aqueous layer was further extracted 4 times with dichloromethane. The combined organic layers were washed with a saturated sodium chloride solution, dried and concentrated in vacuo to give (2-aminoethyl)(4-methyl-5-nitro(2-pyridyl))amine as an orange solid (1.74 g).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[C:21]([Cl:22])=[C:20]([Cl:23])[C:10]2[S:11][C:12]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+]>C(O)C>[Cl:22][C:21]1[C:7]([O:6][CH2:5][C:4]([OH:24])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[S:11][C:10]=2[C:20]=1[Cl:23]
Reactant: CCOC(=O)COc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc2cc(C3CCCCC3)sc2c(Cl)c1Cl
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of 11.8 g of ethyl[(6,7-dichloro-2-cyclohexylbenzo[b]thien-5-yl)oxy]acetate, 250 ml of 20% sodium hydroxide and 250 ml of 95% ethanol is refluxed for 2 hrs. and allowed to cool. The solvent is removed. The residue is stirred in 350 ml of 6N hydrochloric acid for 2 hrs. The mixture is filtered and the solid is air-dried, taken up in ether and redried over anhydrous magnesium sulfate and filtered. Recrystallization of the residue from acetone-hexane gives 9.0 g of [(6,7-dichloro-2-cyclohexylbenzo[b]thien-5-yl)oxy]acetic acid, mp 167°-167.5°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12](=[O:17])[C:11]=1[C:18]#[N:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:20]([O:17][C:12]1[C:11]([C:18]#[N:19])=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:15]=[C:14]([CH3:16])[N:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(=O)[nH]1
Solvent: Cc1ccccc1
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(OCc2ccccc2)n1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
A mixture of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (Cpd H, 6.6 g, 24 mmol), Ag2O (6.3 g, 27 mmol), and benzylchloride (4.1 g, 33 mmol) in toluene (79 mL) was heated at 100° C. for 21 hours. The reaction mixture was filtered through CELITE® then concentrated under vacuum. The residue was purified by column chromatography (0-30%, EtOAc/heptane) to give 2-(benzyloxy)-4-({[tert-butyl(dimethyl)-silyl]oxy}methyl)-6-methylpyridine-3-carbonitrile (Cpd I, 6.5 g, 74%) as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][C:30]([O:32]CC)=[O:31].O[Li].O>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:18]4[CH2:26][CH:22]5[CH2:21][CH:20]([CH2:25][CH:24]3[CH2:23]5)[CH2:19]4)[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: O=C(O)CC1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate, isomer 2 (1.57 g, 3 mmol) in ethanol (15 mL) was added 2 M aq LiOH.H2O (15 mL, 30 mmol) at 0° C. and the mixture was stirred overnight at rt. The reaction mixture was washed with 1 aq N HCl until pH=5-6. The combined organic layers were dried over Na2SO4, filtered and concentrated to obtain 2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid isomer 2 (1.33 g, 90%). LC-MS Method 5 tR=1.44 min, m/z=503.1; 1H NMR (CD3OD): δ=1.19-1.48 (m, 2H), 1.48-1.62 (m, 4H), 1.65-1.95 (m, 12H), 2.20-2.66 (m, 3H), 2.70-3.12 (m, 4H), 3.50 (m, 1H), 3.70-4.08 (m, 3H), 4.89 (m, 1H), 6.90-7.15 (m, 2H), 7.40 (m, 1H).
Reaction SMILES: [C:1]([O:18][CH2:19][CH:20]([CH2:22][OH:23])[OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:48](O)(=O)[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]>ClCCl>[CH2:48]([O:23][CH2:22][CH:20]([CH2:19][O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:21])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]/[CH:56]=[CH:57]\[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOCC(O)COC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
Glycerol palmitate (example 2b) (5.516 g, 0.017 mol) was dissolved in dichloromethane (500 ml) and dicyclohexylcarbodiimide (5.165 g, 0.025 mol), dimethylaminopyridine (3.058 g, 0.025 mol) and oleic acid (4.714 g, 0.017 mol) were then added. The reaction mixture was stirred at room temperature for 24 hours. The dicyclohexylurea precipitate was filtered, washed with dichloromethane and the filtrate was evaporated under vacuum. The residue obtained was purified by silica gel chromatography (eluent:CH2Cl2) to give the desired compound as a white solid (yield: 23%).