Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([C:7]1CC[CH2:10][C:9](=[O:13])[CH:8]=1)C(N)=O)#N.C[N:15]([CH3:18])C=O.C(O[CH:22]([O:26][CH2:27][CH3:28])N(C)C)C>O>[CH3:22][O:26][C:27]1[CH:28]=[C:8]([C:9]([CH2:10][C:18]#[N:15])=[O:13])[CH:7]=[CH:3][CH:1]=1
Reactant: CN(C)C=O
Reactant: CCOC(OCC)N(C)C
Reactant: N#CC(C(N)=O)C1=CC(=O)CCC1
Solvent: O
Product: COc1cccc(C(=O)CC#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution consisting of 40 parts of α-cyano-3-oxo-1-cyclohexen-1-acetamide in 125 parts by volume of dimethylformamide, in an atmosphere of nitrogen, is added dropwise, over a period of 10-15 minutes, 40 parts of dimethylformamide diethyl acetal. After the reaction mixture is stirred at room temperature for about 18 hours, 10 parts of water is added and the organic solvents are removed by distillation under reduced pressure. The residual oily product is extracted with dilute aqueous sodium hydroxide and the extract is washed several times with chloroform, then filtered to remove he small amount of insoluble material. Neutralization of the alkaline solution by the addition of dilute hydrochloric acid results in precipitation of the product, which is purified by recrystallization from aqueous acetone to afford 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarboni=trile, melting above 290°. It is further characterized by ultraviolet absorption maxima at about 227, 232, 279 and 324 mμ with molecular extinction coefficients of 17,900, 16,000, 13,000 and 6,800, respectively, and by infrared absorption peaks, in potassium bromide, at about 2.87, 2.97, 4.48, 5.92, 6.03, 6.07, 6.23 and 6.45 μ and also by nuclear magnetic resonance peaks, in deutero=pyridine, at approximately 1.92, 2.58, 2.97, and 8.72 parts per million.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.S(Cl)([Cl:17])=O>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([Cl:17])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C(Cl)c1cc2ccccc2cc1O
Reaction time: 3 h
Yield: 585.5 %

Procedure:
494.0 g (2.63 mol) of 3-hydroxy-2-naphthoic acid and 2470.0 g=2872 ml of xylene are initially introduced into a 2 l four-necked flask having an internal thermometer, gas removal tube and stirrer, 6.0 g of N,N'-dimethylformamide are added, 328.0 g=201.1 ml (2.76 mol) of thionyl chloride are metered in at 47°-50°0C. over the course of 1 h and the mixture is subsequently stirred for 3 h until evolution of gas has ended. 3181.8 g of 3-hydroxy-2-naphthoyl chloride are obtained as a clear solution in xylene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([NH:13][C:14](=[O:39])[N:15]([CH2:24][CH2:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:27]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:24][N:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:14]([NH:13][C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:46](=[O:48])[CH3:47])=[CH:7][CH:6]=3)[S:12][N:11]=2)=[O:39])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1ccc(-c2nc(NC(=O)N(CCc3ccccn3)CCC(c3ccccc3)c3ccccc3)ns2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nc(NC(=O)N(CCc3ccccn3)CCC(c3ccccc3)c3ccccc3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(5-(4-aminophenyl)-1,2,4-thiadiazol-3-yl)-1-(3,3-diphenylpropyl)-1-(2-(pyridin-2-yl)ethyl)urea (0.042 g, 0.079 mmol), prepared in the previous step, in DCM (1.5 mL) at 0° C. was added pyridine (50 μL, 49 mg, 0.62 mmol) and acetic anhydride (9.0 μL, 9.0 mg, 0.088 mmol). The reaction mixture was warmed to room temperature. After 1 h, additional acetic anhydride (10 μL) and a small amount of DMAP were added. Stirring was continued at room temperature. After 3 h, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The crude reaction mixture was dissolved in DCM (˜2 mL) and diluted with ˜5 mL of hexanes. The precipitate was collected by filtration and dried under high vacuum to give N-(4-(3-(((3,3-diphenylpropyl)(2-(2-pyridinyl)ethyl)carbamoyl)amino)-1,2,4-thiadiazol-5-yl)phenyl)acetamide 158. Mass spectrum, calculated for C33H32N6O2S 576.2; found 577.2 (M++1).
Reaction SMILES: C(C1C=CC(C2ON=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:25])=[CH:18][CH:17]=4)=CC=1C(F)(F)F)C(C)C.[CH2:30]([C:35]1[S:36]C2C3C(=CC(C=C)=CC=3)CCC=2[N:39]=1)[CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:30]([C:35]1[S:36][C:13]2[C:16]3[C:21](=[CH:20][C:19]([CH:24]=[O:25])=[CH:18][CH:17]=3)[CH2:22][CH2:23][C:12]=2[N:39]=1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CC(C)Cc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Reactant: C=Cc1ccc2c(c1)CCc1nc(CCCCC)sc1-2
Product: CCCCCc1nc2c(s1)-c1ccc(C=O)cc1CC2

Procedure:
This compound was prepared according to the procedure described for Preparation 23D, employing 192 mgs of 2-pentyl-7-vinyl-4,5-dihydronaphtho[2,1-d]thiazole (86C). Yield: (190 mgs, 98%). LC/MS M+1=286.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:45])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33](OC3C=CC([N+]([O-])=O)=CC=3)=[O:34])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:47]1[C:51]2([CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48]1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:24]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]([N:54]3[CH2:55][CH2:56][C:51]4([CH2:50][CH2:49][CH2:48][CH2:47]4)[CH2:52][CH2:53]3)=[O:34])=[O:45])[CH2:21][CH2:22]2)=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCC2(C1)CCNCC2
Reactant: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCOC(=O)N1CCC2(CCCC2)CC1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Yield: 93 %

Procedure:
A solution of the carbonate (2.0 g, 3.2 mmol) produced in Example 5, 8-aza-spiro [4,5]-decane hydrochloride (680 mg, 3.9 mmol) and triethylamine (2.7 ml, 19 mmol) in 30 ml of anhydrous dimethylformamide was stirred under nitrogen at room temperature for 5 hours. The reaction was diluted with methylene chloride, extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4), and the solvent removed under reduced pressure to give 1.85 g of a white solid. Recrystallization of this solid from methylene chloride-diisopropyl ether gave 1.0 g (50%) of the title compound as a white crystalline solid, mp 83-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:20])[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([N+:21]([O-:23])=[O:22])=[CH:6][C:5]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=2)=[C:4]([F:20])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2ccc(Cl)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)ccc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c1=O
Reaction time: 1 h
Yield: 95.1 %

Procedure:
1.0 g (3.3 mmol) of 3-(4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 10 ml of concentrated sulfuric acid, and 0.25 g (4.0 mmol) of fuming nitric acid was dropwise added thereto under cooling with ice, followed by stirring for 1 hour. This reaction solution was poured into.ice water and extracted with ethyl acetate. After washing with water and a saturated sodium hydrogencarbonate aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 1.1 g (yield: 96%) of the desired product. Melting point: 139-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.[N:21]([CH2:24][CH3:25])=[C:22]=[S:23]>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:22]([NH:21][CH2:24][CH3:25])=[S:23])=[CH:16][CH:15]=1
Reactant: CCN=C=S
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Solvent: C1CCOC1
Product: CCNC(=S)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Product: Cl
Reaction time: 2 h
Yield: 94.1 %

Procedure:
4-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenylamine (50 mg, example 17, intermediate 1) was dissolved in tetrahydrofurane (4 ml) and isothiocyanato-ethane (14 mg) was added to the stirred solution. After 2 h at reflux temperature the solution was concentrated and the residue kept for 2 h at 85° C. The crude product was purified by preparative HPLC. The product containing fractions were combined and the acetonitrile was removed in vaccuo. After addition of potassium carbonate the aqueous phase was extracted with ethyl acetate. The organic layer was separated, dried (magnesium sulphate), filtered and concentrated in vaccuo. The residue was dissolved in water/2N hydrochloric acid and freeze dried to give 33 mg of the title compound.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=[N:21][CH:22]=1>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=1
Reactant: C#Cc1ccccc1
Reactant: O=S(=O)(Oc1cncc(F)c1)C(F)(F)F
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1cncc(C#Cc2ccccc2)c1
Temperature: 60 °C
Yield: 65 %

Procedure:
Add phenylacetylene (0.180 mL, 1.6 mmol), copper (I) iodide (0.015 g, 0.08 mmol) bis(triphenylphosphine)palladium (II) dichloride (0.027 g. 0.04 mmol) and triethylamine (0.85 mL, 6 mmol) to a solution of trifluoromethanesulfonic acid 5-fluoro-pyridin-3-yl ester, (prepared essentially as described in PREPARATION 6), (0.367 g, 1.5 mmol) in degassed ethyl acetate (1.5 mL) and heat at 60° C. for 16 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with dichloromethane, to give the title compound (0.192 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:19]OC)=[N:4][NH:5][C:6]=1[C:7]1[C:8]([CH3:18])=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13].[BrH:22].CC(O)=O>>[Br:22][CH2:19][C:3]1[C:2]([Cl:1])=[C:6]([C:7]2[C:8]([CH3:18])=[CH:9][C:10]([CH3:17])=[C:11]([CH:16]=2)[C:12]([OH:14])=[O:13])[NH:5][N:4]=1
Reactant: Br
Reactant: COCc1n[nH]c(-c2cc(C(=O)OC)c(C)cc2C)c1Cl
Solvent: CC(=O)O
Product: Cc1cc(C)c(-c2[nH]nc(CBr)c2Cl)cc1C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of methyl 5-(4-chloro-3-(methoxymethyl)-1H-pyrazol-5-yl)-2,4-dimethylbenzoate (compound 281.3, 20 mg, 0.06 mmol) and HBr-HOAc (5 mL) was stirred overnight at 80° C., then concentrated under reduced pressure to yield 20 mg (90%) of the title compound as a yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:50][C:51]([F:64])([F:63])[C:52]1[CH:53]=[C:54]([CH:60]=[CH:61][CH:62]=1)[O:55][CH:56]1[CH2:59][NH:58][CH2:57]1>CN(C=O)C.O>[O:27]=[C:25]([N:58]1[CH2:59][CH:56]([O:55][C:54]2[CH:60]=[CH:61][CH:62]=[C:52]([C:51]([F:50])([F:64])[F:63])[CH:53]=2)[CH2:57]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 51.8 %

Procedure:
DIPEA (158.2 mg, 1.22 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (75 mg, 0.30 mmol) in DMF (2 mL) followed by HOBt (43.4 mg, 0.32 mmol) and EDCI (61.6 mg, 0.32 mmol). After 2 minutes of stirring, 3-(3-trifluoromethyl-phenoxy)-azetidine hydrochloride (77.5 mg, 0.3 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added followed by extraction with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (using silica gel 60- and 100% ethyl acetate as eluent) to afford 69 mg (51.1% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[3-(3-trifluoromethyl-phenoxy)-azetidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 445.14, 90.72%. 1H NMR (300 MHz, DMSO-d6): δ 14.8 (s, 1H), 8.2 (t, 1H), 7.78 (t, 2H), 7.5 (t, 1H), 7.3 (m, 5H), 7.16 (d, 2H), 7.1 (d, 1H), 5.18 (m, 1H), 4.64 (q, 1H), 4.36 (m, 1H), 4.18 (m, 1H), 3.84 (m, 3H).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C:7](O)=O)=[O:3].FC(F)(F)C(O)=O.N[C@@H:30]([CH2:44][C:45]1[CH:50]=[C:49](F)[CH:48]=[C:47](F)[CH:46]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1.[CH3:53][N:54](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:44]([C@H:30]([NH:1][C:2](=[O:3])[C:4]1[CH:5]=[C:6]([CH2:7][C:53]#[N:54])[CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)c1cc(CC#N)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(OC)c2)c1
Temperature: 40 °C

Procedure:
A mixture of 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoic acid (IX, 0.13 g), (2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol (VIII, 0.14 g), HATU (0.17 g), and dichloromethane (10 mL) is stirred at 40 degrees C. overnight. After cooling, the mixture is washed with water and the organic phase is separated and dried over magnesium sulfate and taken to dryness under reduced pressure. Chromatography (silica gel) gives the title compound, M+H=571.2.
Reaction SMILES: Br.C(O)(=O)C.[OH:6][B:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25]C)[N:18]=3)=[CH:15][C:10]=2[CH2:9][O:8]1>O>[OH:25][C:19]1[N:18]=[C:17]([O:16][C:14]2[CH:13]=[CH:12][C:11]3[B:7]([OH:6])[O:8][CH2:9][C:10]=3[CH:15]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: COc1nc(Oc2ccc3c(c2)COB3O)ccc1C#N
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1O
Temperature: 50 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
To a solution of 48% HBr (2 mL) and acetic acid (4 mL) was added 6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)-2-methoxynicotinonitrile (D46) (0.300 mg, 1.06 mmol). The reaction was stirred for 24 hours at 50° C. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and then filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column (7:3 to 9:1 ethyl acetate/hexane). The material was further purified by reverse phase HPLC to give 2-hydroxy-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinonitrile (0.027 g, 10% yield). ES(−) MS m/z=267 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ ppm 4.97 (s, 2H), 6.4 (br s, 1H), 7.15 (d, J=7.9 Hz, 1H), 7.25 (s, 1H), 7.77 (d, J=7.9 Hz, 1H), 8.09 (d, J=7.9 Hz, 1H), 9.24 (s, 1H), 12.7 (br s, 1H).
Reaction SMILES: [CH2:1]([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:12]([C:14]1[CH:15]=[C:16]([N+:20]([O-])=O)[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>[Pd].C(OCC)(=O)C.C1COCC1>[CH2:23]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]([C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCN(CCCCCCCCCC)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCN(CCCCCCCCCC)C(=O)c1cccc(N)c1
Yield: 107.2 %

Procedure:
To an ice bath cooled solution of 0.80 g (2.69 mmol) of di-decylamine and 0.75 mL (5.4 mmol) of triethylamine in 10 mL of anhydrous methylene chloride was added dropwise a solution of 0.50 g (2.69 mmol) of 3-nitrobenzoyl chloride in 5 mL of methylene chloride with stirring. The mixture was stirred at room temperature for 4 hours. Water was added, the organic layer was separated and dried. The solvent was removed at reduced pressure and the residual oil was purified by chromatography on 30 g of silica gel using 12.5% ethyl acetate-hexane to give 1.0 g of 3-(di-decylaminocarbonyl)-1-nitrobenzene as an oil. The nmr and mass spectra were consistent with the structure. A mixture of 1.0 g of 3-(di-decylaminocarbonyl)-1-nitrobenzene and 0.2 g of 10% palladium on carbon in 20 mL of ethyl acetate and 20 mL of THF was stirred under a hydrogen atmosphere at room temperature for 2 hours when hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated to give 1.0 g of 3-(di-decylaminocarbonyl)benzenamine as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:29])[CH:27]=[CH2:28].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:29])[CH:27]=[CH2:28]
Reactant: C=CC(=O)O
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a 2-liter four-necked flask equipped with a thermometer, stirring apparatus, condenser and dropping funnel were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 72.06 g (1.0 mole) of acrylic acid, 500 g of toluene and 209.47 g (2.07 moles) of triethylamine. After replacing the air in the container with nitrogen, 105.8 g (0.69 mole) of phosphorus oxychloride was added dropwise with stirring. After completion of the dropwise addition, the reaction solution was kept at 80° C. for 1 hour. Thereafter, the organic layer was washed with water until it became neutral, and toluene was removed under reduced pressure. The residue was then recrystallized from n-hexane to obtain 374.8 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate having a melting point of 132° to 134° C. Yield, 95%.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[S:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[S:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCNCC4)cs3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCN(CCCCO)CC4)cs3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.28 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-4-yl]piperidine hydrochloride (preparation already described above) and 61 μl (0.42 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14](F)[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][O-:21].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14]([O:21][CH3:20])[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: C[O-]
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(Nc3cccc(Br)c3)ncnc2cn1

Procedure:
Treatment of 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (see a previous experimental) at 100° C. in a pressure vessel with sodium methoxide in methanol gives 4-(3-bromoanilino)-6-methoxypyrido[3,4-d]pyrimidine. 1H NMR (DMSO) δ 9.93 (1H, s), 8.94 (1H, s), 8.61 (1H, s), 8.26 (1H, brs), 7.94 (1H, brd, J=7.6 Hz), 7.88 (1H, s), 7.43-7.32 (2H, m), 4.01 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:14][N:15]=[N+]=[N-])[CH2:9][C@@H:10]([CH3:13])[CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH3:19]O>[Pd]>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:14][NH2:15])[CH2:9][C@@H:10]([CH3:13])[CH2:11][CH2:12][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Reactant: CO
Agent: [Pd]
Product: CCC[C@H](C)C[C@H](CN)CC(=O)OC(C)(C)C
Reaction time: 96 h

Procedure:
A mixture of 125 (2.8 g, 10.4 mmol) and 10% Pd/C (1.0 g) in methanol (50.0 mL) was hydrogenated at 41 PSI for 96 hours. The solution was filtered to give 1.7 g of crude 126 which was used in the next step without further purification. MS, m/z (relative intensity): 244 [M+1H, 100%], 285 [M+1H+CH3CN, 25%].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C@@H:6]1[C@H:13]([OH:14])[C@H:12]([CH3:15])[O:11][C@@H:8]([O:9][CH3:10])[CH2:7]1)=[O:4].B(F)(F)F.[CH3:22]COCC.[N+](=C)=[N-]>C(Cl)Cl>[F:17][C:2]([F:1])([F:16])[C:3]([NH:5][C@@H:6]1[C@H:13]([O:14][CH3:22])[C@H:12]([CH3:15])[O:11][C@@H:8]([O:9][CH3:10])[CH2:7]1)=[O:4]
Reactant: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Agent: FB(F)F
Solvent: ClCCl
Product: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](OC)[C@H](C)O1
Reaction time: 1.5 h
Yield: 85 %

Procedure:
A solution of 2.57 g.; 10 mmoles of methyl 2,3,6-trideoxy-3-trifluoroacetamido-α-L-lyxo-hexopyranoside (II-A) in 45 ml. of dry methylene dichloride was treated at 0° C. with 0.1 ml. of boron trifluoride etherate. While maintaining the temperature at 0°, an excess of diazomethane dissolved in methylene dichloride was added until a faint yellow color persisted. After 90 minutes at 0°, a white solid (polymethylene) was removed by filtration, and the filtrate was washed successively with 10% sodium bicarbonate solution and with water, after which it was dried with anhydrous magnesium sulfate. The residue which was obtained by evaporation was crystallized from ethyl ether-hexane to give pure methyl 2,3,6-trideoxy-3-trifluoroacetamido-4-O-methyl-α-L-lyxo-hexopyranoside (II-B, 2.3 g., 85%): m.p. 137°-138°; [α]D =-150° (c=1, in CHCl3); mass spectrum m/e 271 (M+). The pmr spectrum (CDCl3) showed absorptions at 1.23 (d, CH3 --C-- 5), 3.23 and 3.40 (two s, --OCH3) and 4.70δ (broad s, C--1--H).