Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]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.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/O)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[OH:1][C:2]1([C:5]2[O:7][N:62]=[C:61]([NH:60][C:55]3[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([C:44]4[C:43](=[O:65])[N:42]([CH3:41])[C:51]5[C:46]([CH:45]=4)=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=5)[CH:54]=3)[N:64]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)C1(O)CC1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
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: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4(O)CC4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-hydroxycyclopropanecarboxylic acid (6 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (31 μL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min, 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 3-(5-(5-(1-hydroxycyclopropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A57). MS m/z 404.4 (M+1).
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O-:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Amixtureofmethyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1N LiOH (15 mL), and methanol (50 mL) was stirred at 0° C. for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. 1H NMR (CDCl3): δ 0.87 (t, 3H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.25 (m, 1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
Reaction SMILES: [CH3:1][N:2]([C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[CH2:40][C:41](O)=[O:42].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[CH2:40][C:41]([N:13]1[CH2:14][CH2:15][CH:10]([C:7]2[S:8][CH:9]=[C:5]([C:3]([N:2]([CH3:1])[C@@H:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH3:18])=[O:4])[N:6]=2)[CH2:11][CH2:12]1)=[O:42]
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Reactant: O=C(O)Cc1cc(Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cc3cc(Cl)ccc3Cl)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[(1R)-1-phenylpropyl]-2-(4-piperidinyl)-4-thiazolecarboxamide (i.e. the product of Example 1, Step E) (171 mg, 0.5 mmol) was dissolved in 3 mL of dry dichloromethane. To this was added triethylamine (35 μL, 0.25 mmol), 2,5-dichlorobenzeneacetic acid (102 mg, 0.5 mmol) (i.e. the product of Example 3, Step A), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.56 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (˜1 mg). The mixture was shaken overnight at ambient temperature, diluted with dichloromethane, washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate to give 170 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:10][C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:31][CH:30]=3)[O:26][N:25]=2)=[CH:20][CH:19]=1)=O)(C)(C)C.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:35]1([C:32]2[CH:33]=[CH:34][C:29]([C:27]3[O:26][N:25]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([C@H:9]5[CH2:10][C@H:11]([CH2:13][C:14]([OH:16])=[O:15])[CH2:12][NH:8]5)=[CH:19][CH:20]=4)[N:28]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COC(=O)C[C@H]1C[C@H](c2ccc(-c3noc(-c4ccc(C5CCCC5)cc4)n3)cc2)N(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@@H]1CN[C@@H](c2ccc(-c3noc(-c4ccc(C5CCCC5)cc4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
A solution of methyl trans-N-tert-butyloxycarbonyl-2-(4-(5-(4-cyclopentylphenyl)-1,2,4-oxadiazol-3-yl)phenyl)-4-pyrrolidineacetate (4.4 mg, 8.3 μmol) in 2.5 mL of 20% TFA in CH2Cl2 was stirred at rt for 1 hr and then concentrated. The residue was redissolved in 5.0 mL of EtOH and sodium hydroxide (189 μL, 5.0 N, 0.95 mmol) was added. After stirring at rt for 1 hr, the reaction mixture was concentrated and the residue was purified on HPLC to give 3.5 mg (100%) of the title compound: 1H NMR (CD3OD) δ 1.60 (m, 214), 1.69 (m, 2H), 1.81 (m, 2H), 2.06 (m, 2H), 2.26 (m, 1H), 2.46 (m, 1H), 2.58 (m, 2H), 2.96 (m, 1H), 3.07 (m, 1H), 3.12 (dd, J=7.7, 11.9, 1H), 3.70 (dd, J=7.7, 11.8, 1H), 4.84 (t, J=8.6, 1H), 7.44 (d, J=8.2, 2H), 7.60 (d, J=8.4, 2H), 8.06 (d, J=8.4, 2H), 8.18 (d, J=8.2, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([N:16](CC)CC)C.CN>C1COCC1.[Cl-].[Na+].O>[CH3:14][NH:16][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold solution of 4-nitrobenzenesulfonyl chloride (2.7 g, 12 mmol) and triethylamine (27 mmol) in 60 mL of dry THF was added methylamine (8 mL of a 2 M solution in THF, 16 mmol). The mixture was stirred at room temperature overnight. Brine was added and the reaction solution was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to yield 4-nitrobenzenesulfonic acid methylamide as an oil. The crude material was used in the subsequent reaction without further purification.
Reaction SMILES: CC1OC(C=O)=CC=1.CC1OC=CC=1.[OH:15][CH2:16][C:17]1[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=1>>[OH:23][CH2:22][C:19]1[O:18][C:17]([CH:16]=[O:15])=[CH:21][CH:20]=1
Reactant: OCc1ccc(CO)o1
Agent: Cc1ccc(C=O)o1
Agent: Cc1ccco1
Product: O=Cc1ccc(CO)o1

Procedure:
N-undecane has a boiling point of 196° C. so it can be considered as kerosene or light diesel. The boiling point of the final mix can be increased by introducing a branch, thus increasing the number of carbon atoms. For example the use of butanal together with 2-methylfuran can produce 6-propylundecane with a boiling point of approximately 225-230° C., which due to this property can be used as kerosene and diesel. In this case n-butanal would be obtained by oxidation of n-butanol which can also be a product derived from biomass. The number of carbons may be increased to 16 using 5-methyl furfural with 2 moles of 2-methylfuran. 5-Methyl furfural can be obtained from biomass by hydrogenation of an intermediate product from biomass (see for example Angew. Chem. Int. Ed. 2008, 47, 7924-7926). Another isomer with 16 carbon atoms can be obtained by using in the alkylation step two moles of 2-methylfuran and one mole of 2,5-di(hydroxymethyl)furan. The latter can be produced by selective hydrogenation of 5-hydroxymethylfurfural (HMF) that also comes from biomass.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])=O)C.[Cl-].[Li+].[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CCO>[OH:3][CH2:4][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[C:9]([N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)=[O:10]
Reactant: CCOC(=O)c1cccc(C(=O)N2CCNCC2)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(c1cccc(CO)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-ethoxycarbonyl-benzoylpiperazine XLIX (200 mg, 0.76 mmol) in THF (5 ml), was added lithium chloride (36 mg, 0.84 mmol), NaBH4 (32 mg, 0.84 mmol) and EtOH (5 ml) sequentially. After stirring for 8 hours at room temperature, a saturated NaHCO3 solution was added and the aqueous phase was extracted with ethyl acetate (3×20 ml). The organic layers were combined, dried over MgSO4 and concentrated to give a crude mixture, which was used for the further reaction without purification.
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:34])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:26]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:25]=[N:24][CH:23]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.Cl>C(#N)C>[ClH:1].[C:29]([CH2:28][CH2:27][N:26]1[C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:4][CH2:3]3)=[O:34])[CH2:19][CH2:18][CH:17]\2[SH:20])=[CH:23][N:24]=[N:25]1)([OH:31])=[O:30]
Reactant: CCOC(=O)CCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Agent: Cl
Solvent: CC#N
Product: O=C(O)CCn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methylidene)-4-sulfanylpiperidine hydrochloride (500 mg) was added 3 N aqueous hydrochloric acid solution (20 ml) and the resulting mixture was stirred at 50° C. for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified using preparative HPLC [YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N aqueous hydrochloric acid solution (25:75, v/v)] to afford the title compound (410 mg, yield: 87%) as a pale colourless amorphous solid.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][C:9]([OH:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>CN(C)C=O>[C:3]([N:6]1[CH2:11][CH2:10][C:9]([O:18][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 76.2 %

Procedure:
A stirred suspension of sodium hydride (60% in oil, 1.00 g) in 50 ml of dimethylformamide was treated with a solution of 4.0 g of 1-acetyl-4-hydroxy-4-phenylpiperidine in 100 ml of dimethylformamide. The mixture was heated at 70° C. until evolution of gas had ceased. After cooled to ice bath temperature, a solution of 2.96 g of 1-fluoro-4-nitrobenzene in 40 ml of dimethylformamide was added, dropwise, and the reaction allowed to proceed for 20 hours. The reaction mixture was then poured into ice water and the aqueous suspension extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to an oil. High pressure liquid chromatography of the oil (silica gel; elution with 20% ethyl acetate/dichloromethane) afforded 4.73 g (77.29%) of 1-acetyl-4-(4-nitrophenoxy)-4-phenylpiperidine, m.p. 145°-150° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:29])=[C:11]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].C(O)C>[Fe].O>[CH2:1]([O:8][C:9]1[C:10]([F:29])=[C:11]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:23]=[CH:24][C:25]=1[NH2:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2F)cn1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2F)cn1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A mixture of 5-[3-(benzyloxy)-2-fluoro-4-nitrophenoxy]-2-(methylsulfonyl)pyridine (8.4 g), iron (powder, 5.5 g), calcium chloride (0.24 g), ethanol (200 mL) and water (40 mL) was refluxed for 4 h. The mixture was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated in vacuo to remove ethanol. The residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=20:80 to 40:60, volume ratio) to give the title compound (5.5 g, 70%) as a dark green oil. MS 389 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]1=[O:17].[CH:18](OCC)=[O:19]>C(COC)OC>[CH:18]([CH:11]([CH2:10][C:7]1[CH:8]=[CH:9][N:4]([CH3:3])[C:5](=[O:17])[CH:6]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:19]
Reactant: CCOC(=O)CCc1ccn(C)c(=O)c1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccn(C)c(=O)c1
Temperature: -5 °C
Reaction time: 72 h
Yield: 51.7 %

Procedure:
To a stirred suspension of 57% sodium hydride in oil (6.55 g) in dimethoxyethane (40 ml) at -5° C., was added dropwise over 40 minutes a mixture of ethyl β-(N-methyl-2-oxo-4-pyridyl)propionate (26.05 g) and ethyl formate (13.83 g) whilst maintaining the reaction temperature at -5° C. The temperature of the reaction mixture was slowly allowed to rise to ambient at which temperature it was stood for three days. The reaction mixture was poured on to ice, extracted with diethyl ether (3×100 ml) and the combined organic layers were washed with water (2×20 ml). The aqueous layer and washings were acidified to pH 4 with 2 N sulphuric acid whereupon a solid came out of solution. The mixture was kept at 0° C. for two hours, and the solid filtered off and dried in vacuo to afford ethyl α-formyl-β-(N-methyl-2-oxo-4-pyridyl)propionate (15.27 g) as a solid; recrystallisation from isopropanol afforded a solid, m.p. 164-5-165.5 ° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.NC(N)=[S:17]>C(O)C>[N+:8]([C:7]1[C:2]([SH:17])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: NC(N)=S
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1S
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 79.5 %

Procedure:
A mixture of 4.88 g of 2-chloro3-nitro-5-(trifluoromethyl)pyridine, 1.81 g of thiourea and 40 ml of ethanol was stirred at 50° C. for 5.5 hours. The reaction mixture was cooled down to room temperature, then, concentrated under reduced pressure. To the residue was added 24 ml of water and a mixture of 2.8 g of sodium hydroxide and 6 ml of water, and this was stirred at room temperature for 1.5 hours. The reaction mixture was washed with diethyl ether, then, acetic acid was added. This was cooled with ice, and the deposited solid was collected by filtration. This solid was dried under reduced pressure, to obtain 3.84 g of 3-nitro-5-(trifluoromethyl)pyridine-2-thiol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH3:48][C:49]1[CH:53]=[CH:52][O:51][C:50]=1[C:54](O)=[O:55]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:54]([C:50]2[O:51][CH:52]=[CH:53][C:49]=2[CH3:48])=[O:55])[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1ccoc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccoc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 51 %

Procedure:
The desired compound was prepared according to the procedure of Example A27, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and 3-methyl-2-furoic acid as starting materials in 51% yield. LCMS for C30H31ClN7O3 (M+H)+: m/z=572.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]=[CH:15][C:16]([C:18]2[S:19][C:20]([CH2:29][CH3:30])=[C:21]3[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][C:22]=23)=[O:17])=[CH:9][C:8]=1[CH2:31][CH3:32])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][CH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([C:18]2[S:19][C:20]([CH2:29][CH3:30])=[C:21]3[CH2:26][C:25]([CH3:27])([CH3:28])[CH2:24][CH2:23][C:22]=23)=[O:17])=[CH:9][C:8]=1[CH2:31][CH3:32])[CH3:2]
Reactant: CCOC(=O)CCc1c(C)cc(C=CC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc1CC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1c(C)cc(CCC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc1CC
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.8 %

Procedure:
To a solution of 3-{2-ethyl-4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propenyl]-6-methyl-phenyl}-propionic acid ethyl ester (153 mg, 0.328 mmol) in ethanol, Pd/C (80 mg, 10% Pd, moistened with 50% water) is added and the resulting slurry is stirred at rt for 72 h under 1 bar of H2. The reaction mixture is filtered and the filtrate is evaporated. The crude product is purified by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 μm, acetonitrile/water (0.5% HCOOH), 20% to 95% acetonitrile) to give 3-{2-ethyl-4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propyl]-6-methyl-phenyl}-propionic acid ethyl ester (95 mg) as an amorphous solid; LC-MS: tR=1.26 min, [M+1]=469.40.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=3)=[O:17])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].[NH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[CH3:31][C:28]([NH:27][C:22]([C:21]1[CH:25]=[CH:26][C:18]([C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:5]3[C:4]([NH:3][CH2:1][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:11][CH2:12]2)=[O:17])=[N:19][CH:20]=1)=[O:23])([CH3:32])[CH2:29][OH:30]
Reactant: CC(C)(N)CO
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(C)(C)CO)cn2)CC1
Yield: 70 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-amino-2-methyl-1-propanol. And then, the product was recrystallized to give a desired compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:17][NH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([N:18]([CH3:17])[C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: CNC1CCCCC1
Product: CN(c1ncnc2[nH]c(-c3ccccc3)cc12)C1CCCCC1
Yield: 10.5 %

Procedure:
The product from Method E (50 mg/0.218 mmol) was reacted with 0.12 mL of N-methylcyclohexylamine (0.920 mmol) as described in Method B. The reaction mixture was concentrate in vacuo, methanol was added, and the resulting precipitate filtered to provide 7 mg (10%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.18-1.25 (m, 1H), 1.47-1.66 (m, 4H), 1.75-1.90 (m, 5H), 3.30 (s, 3H), 4.74 (br, 1H), 6.79 (s, 1H), 7.32-7.36 (m, 1H), 7.47-7.51 (m, 2H), 7.77 (d, 2H, J=7.9 Hz), 8.33 (s, 1H). LRMS: 307 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[NH:31][N:30]=[N:29][N:28]=1.S(Cl)(Cl)=O.O>N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:26][C:27]2[NH:31][N:30]=[N:29][N:28]=2)=[O:15])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CC(C)(C)c1cc(OCc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(OCc2ccc(C(=O)Nc3nnn[nH]3)cc2)cc(C(C)(C)C)c1
Yield: 58.2 %

Procedure:
A solution of 2.00 g (5.9 mmole) of 4-(3,5-di-t-butylphenoxymethyl)benzoic acid and 0.61 g (5.9 mmole) of 5-aminotetrazole in 20 ml of pyridine was treated with a dropwise addition of 1.40 g (11.8 mmole) of thionyl chloride. The solution was stirred for one and a half hours before being poured into 150 ml of water. The resulting precipitate was collected, rinsed with water, air dried and recrystallized from aqueous dimethylformamide to give 1.4 g of white solid 4-(3,5-di-t-butylphenoxymethyl)-N-(tetrazol-5-yl)benzamide, m.p. >290° C. Analysis: Calculated for: C23H29N5O2 ; %C, 67.6; %H, 7.1; %N, 17.2; Found: %C, 67.8; %H, 7.3; %N, 17.6.
Reaction SMILES: N1(C([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:23](=[O:24])[NH:22][C:21]4[C:16]3=[N:17][C:18]([N:25]3[C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[N:27]=[CH:26]3)=[N:19][CH:20]=4)[CH2:11][CH2:10]2)=O)C=CN=C1.Cl>CS(C)=O.CCOC(C)=O>[N:25]1([C:18]2[N:17]=[C:16]3[C:21]([NH:22][C:23](=[O:24])[N:15]3[C@H:12]3[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]3)=[CH:20][N:19]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: O=C(O[C@H]1CC[C@H](n2c(=O)[nH]c3cnc(-n4cnc5ccccc54)nc32)CC1)n1ccnc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cnc(-n3cnc4ccccc43)nc2n1[C@H]1CC[C@H](O)CC1

Procedure:
trans-4-(2-(1H-benzo[d]imidazol-1-yl)-8-oxo-7,8-dihydropurin-9-yl)cyclohexyl 1H-imidazole-1-carboxylate (30 mg) was dissolved in DMSO (6 mL) and treated with 1N HCl (5 ml) at 50° C. for 3 hours. The mixture was diluted with EtOAc and washed with brine three times. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to obtain 16 mg of the title compound. 1H-NMR (300 MHz, CDCl3) δ 10.0 (s, 1H), 8.9 (dd, 1H), 8.2 (s, 1H), 7.9 (dd, 1H), 7.6 (dd, 2H), 4.4 (m, 1H), 4.1 (s, 1H), 2.9 (m, 2H), 2.0 (m, 2H), 1.6 (m, 4H).