Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+:4].C(O)(=O)/[C:6](=[C:8](\[CH:10]=[O:11])/Br)/Br.[OH2:14]>C(O)C>[CH:10](/[O-:11])=[C:8](\[N+:1]([O-:3])=[O:2])/[CH:6]=[O:14].[OH2:2].[Na+:4]
Reactant: O=N[O-]
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C/C(=C\[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium nitrite (714 g, 10.2 mol) in 700 ml of water at 50° C.±5° C. was added over a period of 3 hours a solution of mucobromic acid (48) (700 g, 2.7 mol) in 700 ml of warm ethanol. The reaction was stirred for 15 minutes, cooled to 0° C., and 700 ml of ethanol was added. The resulting orange precipitate was collected by vacuum filtration and dried in vacuo to yield sodium nitromalondialdehyde monohydrate (305 g, 1.9 mol) which was used in the next step without further purification. Glycine ethyl ester (300 g, 2.9 mol) and nitromalondialdehyde monohydrate (305 g, 1.9 mol) were placed in a 12 l round bottom flask and slurried with a mechanical stirrer in 560 ml of methanol and 280 ml of water. Sodium hydroxide (800 g, 20 mol) dissolved in 1.6 l water was added to the solution at a rate which maintained the temperature at 50° C. The reaction was cooled to 0° C. with an ice bath and neutralized to pH. 0 with 1.7 l HCl (conc.) while maintaining the temperature below 10° C. A black precipitate was removed by filtration through Celite and the product was extracted with 20 liters of ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide 4-nitropyrrole-2-carboxylic acid (140 g, 0.9 mol) as a brown solid which was used without further purification. To a solution of 4-nitropyrrole-2-carboxylic acid (140 g, 0.9 mol) dissolved in 180 ml of methanol was added 8 ml of concentrated sulfuric acid. The solution was refluxed for 15 hours, cooled to 0° C. and 90 ml of water was added. The solution was then allowed to stand at −20° C. for 2 days. The resulting light brown crystals were collected by vacuum filtration to yield pure methyl-4-nitropyrrole-2-carboxylate (49) (10 g, 0.62 mol) in 23% overall yield. 1H NMR (DMSO-d6) δ 14.2 (br s, 1H), 7.74 (d, 1H, J=1.6 Hz), 7.35 (d, 1H, J=1.7 Hz), 3.73 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:12]([N:32]=1)=[N:13][CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)[CH:16]=2.[C:33]([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CN(C=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH3:33])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:12]([N:32]=1)=[N:13][CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)[CH:16]=2
Reactant: CC(=O)[O-]
Reactant: Nc1ccc(F)c(-c2nc3ncc(-c4ccc(OCCN5CCOCC5)cc4)cc3o2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNc1ccc(F)c(-c2nc3ncc(-c4ccc(OCCN5CCOCC5)cc4)cc3o2)c1
Temperature: 80 °C

Procedure:
In a 40 ml vial 4-fluoro-3-(6-(4-(2-morpholinoethoxy)phenyl)oxazolo[4,5-b]pyridin-2-yl)aniline I-23 (15 mg, 0.032 mmol, 1.0 eq.) was dissolved in DCE. Paraformadelhyde (30 mg) followed by sodium acetate (2.62 mg, 0.032 mmol, 1.0 eq) was added and reaction was heated for one hour. Sodium triacetoxy borohydride (16 mg, 0.08 mmol, 2.5 eq) was added and the reaction was heated to 80° C. for 4 hours. LCMS indicated that the reaction was complete with a formation of new peak of desired mass 449.2 (M+1). The reaction was concentrated under reduced pressure. The crude reaction was dissolved in DMF and filtered through a frit funnel to remove the insoluble matter. The clear filtrate by purified by HPLC to get the desired product 4-fluoro-N-methyl-3-(6-(4-(2-morpholinoethoxy)phenyl)oxazolo[4,5-b]pyridin-2-yl)aniline (Example 421). The TFA salt was neutralized by passing a methanolic solution of the compound through a bicarbonate resin. MS M/Z=449.2 (M+1). RT=1.33: Method B.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][CH2:19][CH2:20][C:21]([CH3:24])(O)[CH3:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[CH2:10]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][CH2:19][CH2:20][C:21]([F:7])([CH3:24])[CH3:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)CCCN(Cc1ccccc1)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(F)CCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
Add diethylaminosulfur trifluoride (17.9 g, 111 mmol) drop-wise to a −78° C. solution of 5-(dibenzylamino)-2-methylpentan-2-ol (11 g, 37 mmol) in DCM (100 mL), under N2, warm to RT and stir overnight. Pour the mixture into ice-water, neutralize with satd. NaHCO3, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to afford the title compound (4.5 g, 41%). 1H NMR (400 MHz, DMSO-d6): δ 7.30-7.13 (m, 10H), 3.48 (s, 4H), 2.35 (m, 2H), 1.51-1.48 (m, 4H), 1.22 (d, J=21.2 Hz, 6H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](O)([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:27])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([F:27])([C:18]#[N:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CC1(F)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 5 h
Yield: 56.8 %

Procedure:
1-Benzhydryl-3-hydroxyazetidine-3-carbonitrile (10.5 g, 39.7 mmol) was dissolved in DCM and cooled to −78° C. DAST (12.80 g, 79.45 mmol) was slowly added and the reaction mixture was allowed to warm to rt where it was further stirred for 5 h. Reaction mixture was cooled to 0° C. and transferred into 500 mL NaHCO3 solution and extracted with (100 mL×3) DCM. Combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain 15.0 g of crude product, which was purified by chromatography to obtain 6.0 g of 1-benzhydryl-3-fluoroazetidine-3-carbonitrile. (57.14% yield). 1H NMR (400 MHz, CDCl3, ppm) δ=7.6-7.1 (m, 10H); 4.46 (s, 1H); 3.9-3.6 (m, 2H); 3.5-3.2 (m, 2H).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[N:11]=[C:12]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl>[Cl:9][C:10]1[N:11]=[C:12]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:23][CH:22]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Nc2nc(Cl)cc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Nc2nc(Cl)cc3ccccc23)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A mixture of ethyl 2-bromopropionate (1.33 g), 4-[N-(3-chloroisoquinolin-1-yl)amino]phenol (1.80 g), anhydrous potassium carbonate (1.01 g) and dimethyl formamide was heated, with stirring, at a temperature of 100° C. for a period of 1 hour. The mixture was cooled and poured into dichloromethane and the resulting mixture was repeatedly washed with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(3-chloroisoquinolin-1-yl)amino]phenoxy}propionate (1.74 g) as a yellow oil. The assigned structure was confirmed by proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ ppm); 1.20 (3H, t); 1.50 (3H, d); 4.12 (2H, q); 4.60 (1H, q); 6.60-8.20 (10H, m).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([CH3:24])=[N:19]2)(=O)=O>>[CH3:24][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[CH:23][C:14]=2[N:6]2[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]2)[N:19]=1
Reactant: C[C@H]1CNCCN1
Reactant: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cccc2n1
Product: Cc1ccc2c(N3CCN[C@@H](C)C3)cccc2n1
Yield: 27 %

Procedure:
The title compound was prepared in 27% yield using a similar procedure to Example 127 starting from (2S)-2-methylpiperazine and 2-methyl-5-quinolinyl trifluoromethanesulfonate (D1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:56]([C:57](O)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:48][CH:47]=1>CN(C=O)C>[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([C:52]2[C:56]([C:57]([N:10]3[CH2:11][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]([CH2:12][OH:13])[CH2:9]3)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:50][CH:51]=1
Reactant: OCC1CNCC1c1ccccc1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nocc2C(=O)N2CC(CO)[C@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A solution of (4-phenylpyrrolidin-3-yl)methanol (7 mg, 0.033 mmol), TBTU (13 mg, 0.039 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (11 μL, 0.066 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (7 mg, 0.033 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (5 mg). MS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1624.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][CH2:3][N:2]1[C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:37][C:34]2[NH:35][N:36]=[C:32]([O:31][CH2:30][C:24]3[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:33]=2)=[O:16])=[CH:18][CH:19]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCN3CCCC3C2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN5CCCC5C4)cc3)[nH]n2)cc(OC)c1
Yield: 27 %

Procedure:
4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)-N-[5-[(3,5-dimethoxyphenyl]methoxy]-2H-pyrazol-3-yl)benzamide was prepared following the procedure as for Example 159, but starting from methyl 4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c]pyrazin-2-yl)benzoate (0.25 g, 0.96 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.239 g, 0.96 mmol) and 2M trimethylaluminium in toluene (1.2 ml, 2.4 mmol). The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.124 g, 27%) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].Br[CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[O:10][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1c(I)cc(I)cc1I)C(=O)OCC
Temperature: 100 °C
Yield: 63.7 %

Procedure:
A stirred mixture of 70.8 g (0.15 mol) of 2,4,6-triiodophenol, 39.0 g (0.15 mol) of diethyl bromomalonate and 20.7 g (0.15 mol) of milled anhydrous potassium carbonate in 200 ml of dry dimethylformamide was heated at 100° C. under argon for 5 hours. The mixture was cooled and concentrated in vacuo. The resulting residue was combined with 300 ml of ice-cold water and the oily product was extracted with ethyl acetate (1×300 ml), 3×100 ml). The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to a dark oil. The oil was purified by chromatography (eluted by hexanes to 20% diethyl ether in hexanes) to yield 60.2 g (64%) of product as a light cream-colored solid.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: COc1ccccc1CN
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-methoxy-benzylamine and DIEA to give 2-(2-methoxy-benzylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 376 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].O1CC1C[O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[O:16]>>[C:5]([O:4][CH2:3][CH2:2][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH2:17])=[O:16])(=[O:7])[CH3:6]
Reactant: CC(=O)OCCBr
Reactant: NC(=O)c1cccc(OCC2CO2)c1
Product: CC(=O)OCCOc1cccc(C(N)=O)c1

Procedure:
In a manner analogous to that set forth in A of this example, but substituting 1-bromo-2,3-epoxypropane for 2-bromoethylacetate, 3-(2,3-epoxy-n-propoxy)benzamide was prepared.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[CH3:22]>>[CH3:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Cc1ccc(B(O)O)cc1C
Product: Cc1ccc(-c2nnc(N)nc2-c2ccccc2)cc1C
Yield: 66.6 %

Procedure:
6-(3,4-Dimethylphenyl)-5-phenyl-1,2,4-triazin-3-amine (55 mg, 67%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,4-dimethylphenylboronic acid (51.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][NH:24][CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C.Br[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[C:28]4[O:27][CH2:26][CH2:25][N:24]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3OCCNC4)no2)cc1Cl
Reactant: CCOC(=O)CCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN1CCOc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)C1
Temperature: 80 °C
Yield: 26.6 %

Procedure:
To a solution of 9-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (Example 31) (260 mg, 0.62 mmol) in acetonitrile (15 ml) was added N,N-diisopropylethylamine (0.214 ml, 1.23 mmol) followed by ethyl 3-bromopropanoate (0.158 ml, 1.231 mmol). The reaction mixture was heated at 80° C. overnight. A further 1 equiv. of N,N-diisopropylethylamine and ethyl 3-bromopropanoate were added and heating continued overnight. The reaction mixture was cooled and evaporated. Purification of the residue by column chromatography, eluting with 50-65% ethyl acetate in cyclohexane to give the title compound as a yellow oil (80 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][CH:21]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[CH3:22]>>[CH3:22][CH:21]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:30][CH:31]=1)[CH3:20]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)Oc1ccc(C=O)cc1
Product: CC(C)Oc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-propan-2-yloxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-propan-2-yloxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C[C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=CC=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[CH2:24](N1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O)CCC>>[CH2:17]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[SH:5]([CH3:24])[C:6]([C:7]([OH:9])=[O:8])=[CH:2][N:3]=2)[C:13]1=[O:23])[CH2:22][CH2:21][CH3:20]
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Reactant: CCCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Product: CCCCN1CCN(C2=NC=C(C(=O)O)[SH]2C)C1=O
Yield: 94 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-butyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 94% yield: MS (ES+) m/z 284.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.Br[C:16]1C2C(=CC=CC=2)C=CC=1.C(Cl)(=O)C>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:14])[CH3:16])=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Solvent: CC(=O)Cl
Product: CC(=O)c1ccc(Br)c2ccccc12

Procedure:
The 4-bromo-1-naphthoic acid required as starting material according to the process according to the invention has already been described in the literature. It can, for example, be prepared in a simple manner by reacting 1-bromonaphthalene with acetyl chloride in a Friedel-Crafts reaction to give 4-bromo-1-acetylnaphthalene (see K. Dziewouski and L. Sternback, Bull. acad. polonaise A, 1931, 59 to 68, or T. L. Jacobs, S. Winstein, J. W. Ralls and J. H. Robson Journ. org. chem. 11 (1946), 27-33) and by oxidation of the latter compound with hypochlorite [see T. L. Jacobs et. al, see above, or N. J. Leonard and A. M. Hyson, J. Am. chem. soc. 71 (1949), 1963].
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)(Cl)Cl>[CH3:21][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:37]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNc1ccccc1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (0.80 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.00 g) in chloroform (10 ml) and then palmitoyl chloride (1.58 ml) was added thereto while being cooled with ice. After being stirred for 2.5 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium bydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.3 ml) was added to a solution containing the residue (2.25 g) in ethanol (23 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.21 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=30:1), thereby yielding the entitled compound (1.44 g) as yellow syrup.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>C(OCC)C.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:21])[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)=[CH:15][CH:14]=1
Reactant: Oc1cccc2cc[nH]c12
Reactant: COc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(NC(=O)Oc2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 7-hydroxyindole (0.7 g.) in ethyl ether (25 ml) and triethylamine (1 ml) is added 0.8 g. 4-methoxyphenyl isocyanate (Aldrich 23860-0). The reaction is stirred for 3 days at room temperature. The solvent is removed in vacuo and the remaining oil is purified by HPLC on silica gel.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:9][NH:10][CH2:11][CH2:12][OH:13].N1C=CN=C1.O>ClCCl>[Si:5]([O:13][CH2:12][CH2:11][NH:10][CH3:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNCCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CNCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A solution of tert-butyldimethylchlorosilane (4.2 g, 27.9 mmol) in dichloromethane (10 mL) was added dropwise over 3 min to a stirred solution of 2-(methylamino)ethanol (2.0 g, 26.6 mmol) and imidazole in dichloromethane (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Water (20 mL) was added and the phases were separated. The aqueous phase was extracted with dichloromethane then the combined organic phases were passed through a phase separation cartridge and the solvent removed under reduced pressure to afford a colorless oil (5.10 g, 95%). This was taken through to the next step with no further purification.
Reaction SMILES: [CH2:1]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C(C)=CC=CC=1C>[Pd].O1CCCC1>[CH2:1]([C:11]1[CH:12]=[CH:13][C:14]([CH:15]=[O:16])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccc(C(=O)Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CCCCCCCCCCc1ccc(C=O)cc1
Yield: 77.1 %

Procedure:
Rosenmund Reduction--Hydrogenate a mixture of 4-(n-decyl)benzoyl chloride (28 g., 0.1 mol), 10% palladium on carbon (2 g.), 2,6-lutidine (10.9 g., dried over KOH and distilled), and tetrahydrofuran (THF) (300 ml., distilled from LiAlH4) in a Paar apparatus for 30 min. at 25° C. under an H2 atmosphere (62 psi). Filter the resulting mixture and collect the catalyst. Wash the catalyst with THF. Evaporate the filtrate and partition the residue between diethyl ether and H2O. Wash the combined organic solutions with aqueous HCl (0.1N) and NaHCO3 (0.1N) solutions. Evaporate the solvent from the dried organic solution to give a liquid. Distill the liquid to give 4-(n-decyl)benzaldehyde (19 g. 77% yield, b.p. 152°-156° C. at 0.3 mm).