Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)O1.Br[C:21]1[N:25]=[CH:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[CH:28][CH:27]=2)[N:22]=1.C([O-])(O)=O.[Na+].O1CCOCC1>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.O>[F:39][C:33]([F:38])([O:32][C:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH:24]=[N:25][C:21]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)=[N:22]2)=[CH:27][CH:28]=1)[C:34]([F:37])([F:36])[F:35]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A microwave vial was charged with methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (147 mg, 0.561 mmol), 3-bromo-1-(4-(pentafluoroethoxy)phenyl)-1H-1,2,4-triazole (200 mg, 0.559 mmol), NaHCO3 (94 mg, 1.2 mmol), and Pd(PPh3)4 (39 mg, 0.034 mmol). Dioxane (3.8 mL) and water (1.2 mL) were added, the reaction vial was capped, and the reaction was heated at 140° C. for 30 min in a Biotage Initiator® microwave reactor with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to RT, and allowed to stand overnight. A white solid formed, which was filtered and air-dried to give the title compound as a white solid (146 mg, 62%): mp 192-195° C., 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.28 (d, J=9.0 Hz, 2H), 8.19-8.12 (d, J=9.0 Hz, 2H), 7.82 (d, J=9.0 Hz, 2H), 7.45-7.38 (m, 2H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −85.90, −87.86; ESIMS m/z 414 ([M+H])+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[C:19]3\[C:20](=[O:25])[NH:21][C:22](=[O:24])[S:23]\3)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]>C(Cl)Cl.CO.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc(/C=C3/SC(=O)NC3=O)cc2)nc1
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CCc1ccc(CCOc2ccc(C[C@H]3SC(=O)NC3=O)cc2)nc1
Reaction time: 18 h

Procedure:
A stock solution of the Rh(COD)2BF4 (10.6 mg, 26.1 μmol) in DCM (9.5 mL) was made in a glove box. Ligand SL-W003-2 ((S)-1-[(S)-2-(2i-diphenylphosphinophenyl)ferrocenyl]ethyl-dicyclohexyl phosphine) (8.4 mg, 12.5 μmol), was weighed into a vial and 500 μL of the Rh(COD)2BF4 stock solution was added. A solution of 5-[1-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl}-meth-(E)-ylidene]-thiazolidine-2,4-dione (4.5 mL of a stock solution containing 78.2 mg in 35 mL MeOH) was added to the reaction vial containing the catalyst solution. The vial was purged with N2 (5×) and H2 (5×) and finally charged with 25 bar of H2. After 18 h the H2 was released and the reaction vial was purged with N2 (3×). A sample of the reaction vial was taken and diluted with an equal volume of EtOH containing 1% formic acid. e.e. (Method 4) 75%, Rt 36.11 min, conversion 50%.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][NH:8]C(OC(C)(C)C)=O)=[O:4].[C:16]([OH:22])([C:18]([F:21])([F:20])[F:19])=[O:17]>ClCCl>[Br:1][CH2:2][C:3]([NH:5][CH2:6][CH2:7][NH2:8])=[O:4].[F:19][C:18]([F:21])([F:20])[C:16]([O-:22])=[O:17]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCNC(=O)CBr
Solvent: ClCCl
Product: NCCNC(=O)CBr
Product: O=C([O-])C(F)(F)F
Reaction time: 0.5 h

Procedure:
N-bromoacetyl-N′-BOC-ethylenediamine (2 is dissolved in 50% TFA in dichloromethane (5 ml of the solution per mmol of 3) at 20° C. The deprotection is allowed to proceed for 30 min, then the reaction mixture is concentrated on a rotary evaporator and solidifies upon addition of dry ethyl ether. The solid material is filtered off, washed with ether/petroleum ether on filter and dried. The desired N-bromoacetyl-ethylenediamine is obtained in the form of triflouroacetate salt.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][CH2:12][CH:13]=[O:14]>ClCCl>[Br:1][CH:12]([CH2:11][C:5]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3])[CH:13]=[O:14]
Reactant: BrBr
Reactant: O=CCCc1c(F)cccc1Cl
Solvent: ClCCl
Product: O=CC(Br)Cc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of bromine (11 g, 0.081 mol) in dichloromethane (50 mL) was slowly added to a solution of 3-(2-chloro-6-fluoro-phenyl)-propionaldehyde (15 g, 0.081 mol) in dichloromethane (250 mL) at 0° C. The mixture was stirred overnight at room temperature and then the solvent was removed to give the crude product which was used directly in the next step.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)/[CH:3]=[O:4].[CH:13](OC)(OC)OC>ClCCl.C(OCC)C>[CH3:13][O:4][CH:3]1[C:7]2[C:6](=[CH:11][CH:10]=[C:9]([CH3:12])[CH:8]=2)[CH:5]=[C:2]1[CH3:1]
Reactant: COC(OC)OC
Reactant: C/C(C=O)=C\c1ccc(C)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC1C(C)=Cc2ccc(C)cc21
Reaction time: 1 h
Yield: 59 %

Procedure:
Anhydrous FeCl3 (2.0 g, 12.3 mmol.) was added to a solution of (2E)-2-methyl-3-(4-methylphenyl) -2-propenal (5.0 g, 31.3 mmol.) and trimethyl orthoformate (36.4 g, 34.3 mmol.) in dichloromethane (35 ml). The dark red solution was stirred for one hour, then diluted with 100 ml of diethyl ether and washed with water (3×75 ml). The organic phase was dried (MgSO4), filtered and concentrated. Kugelrohr distillation (65-80° C., 20 mTorr) yielded 3.2 g (18.4 mmol., 59% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].CCN(C(C)C)C(C)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH:4][C:21](=[O:23])[CH3:22]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Bromo-5-nitroaniline (10 g) was dissolved in 500 mL of CH2Cl2, DIEA (6.6 g) was added to the mixture, followed by DMAP (100 mg). The mixture was cooled to 0° C. in ice bath. Acetyl chloride (4 g in 50 mL CH2Cl2) was added dropwise to the reaction mixture. After the mixture was stirred at RT over 3 h, extracted once with saturated NaHCO3 solution and once with brine, the resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 1:1 EtOAc:Hexane to 100% EtOAc to afford N-(2-bromo-5-nitrophenyl)acetamide as a white solid. MS: 258 (M−1). Calc'd. for C8H7BrN2O3-259.06.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:17][CH2:16][C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
A mixture of 4-(4-nitrophenyl)-1H-imidazole (for a preparation see Intermediate 120) (3.5 g, 18.5 mmol), 1,1-dimethylethyl 2-propenoate (2.37 g, 2.71 mL, 18.5 mmol) and DBU (2.82 g, 2.79 mL, 18.5 mmol) in DMF (50 mL) was stirred at 50° C. for 16 h then was cooled to room temperature and partitioned between AcOEt (100 mL) and water (100 mL). The layers were separated and the organic phase was washed with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 25 to 50% AcOEt in hexanes) gave 1,1-dimethylethyl 3-[4-(4-nitrophenyl)-1H-imidazol-1-yl]propanoate (2.6 g, 8.19 mmol, 44%) as an orange solid. LCMS (method G): Retention time 0.90 min, [M+H]+=318.0
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=[S:18])[NH2:17])[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.Br[CH2:24][C:25]([C:27]1[CH2:31][C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][N:28]=1)=O>C(O)C.O>[C:32]1([C@@H:30]2[O:29][N:28]=[C:27]([C:25]3[N:17]=[C:16]([CH:13]4[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH2:7][N:6]5[C:2]([CH3:1])=[CH:3][C:4]([C:19]([F:22])([F:20])[F:21])=[N:5]5)[CH2:11][CH2:12]4)[S:18][CH:24]=3)[CH2:31]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(CBr)C1=NO[C@@H](c2ccccc2)C1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(C(N)=S)CC1
Solvent: O
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NO[C@@H](c4ccccc4)C3)cs2)CC1
Temperature: 50 °C

Procedure:
A mixture of 1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidine-carbothioamide (i.e. the product of Example 8, Step C) (1.7 g, 5.0 mmol) and 2-bromo-1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazolyl]ethanone (i.e. the product of Example 12, Step E or E1) (1.35 g, 5 mmol) in ethanol (15 mL) was heated at 50° C. for 30 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to give the title product, a compound of the present invention, as a pale-yellow gum. High performance liquid chromatography (HPLC) analysis showed that the title product was about 95% pure and contained the (R)-enantiomer in about 98% enantiomeric excess.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([F:17])[CH:3]=1.[Cu](C#N)[C:19]#[N:20].C(N)CN>CN(C=O)C>[C:19]([C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([F:17])[CH:3]=1)#[N:20]
Reactant: O=C(NC1CCCCC1)c1ccc(Br)cc1F
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: NCCN
Product: N#Cc1ccc(C(=O)NC2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Heat a mixture of 4-bromo-N-cyclohexyl-2-fluoro-benzamide (1.24 g, 4.13 mmol) and copper cyanide (740 mg, 8.26 mmol) in DMF (20 mL) to reflux for 16 h. Cool the mixture to ambient temperature, add aqueous ethylenediamine and stir for 30 min. Extract the mixture with hexane/EtOAc (1:1), dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (5:1) to give the desired intermediate as a white solid (620 mg, 61%). MS (ES−) m/z: 245 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl-:12].[NH2:13][N+:14]1[CH:18]=[CH:17][N:16]([NH2:19])[C:15]=1[CH2:20][CH3:21]>C(O)(=O)C>[Cl-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:7][C:6]3[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=3)[C:15]=2[CH2:20][CH3:21])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCc1n(N)cc[n+]1N
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reaction time: 50 h

Procedure:
2.98 g (20 mmol) of p-dimethylaminobenzaldehyde are added to a solution of 3.24 g (20 mmol) of 1,3-diamino-2-ethylimidazolium chloride in 180 ml of glacial acetic acid. The mixture is stirred at room temperatured for 50 hours, the precipitated 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-ethylimidazolium chloride is then filtered off and washed with ethanol. The mother liquor is evaporated and the residue is placed on a column loaded with 200 g of silica gel (particle size: 0.063-0.200 mm). By elution with methylene chloride/methanol (9:1 v/v) there is obtained a further portion of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-ethyl-imidazolium chloride.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:17](C4CCCCO4)[N:16]=[CH:15][CH:14]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:24].CC(OC)(C)C>CO>[ClH:24].[C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:13]3[CH:14]=[CH:15][NH:16][N:17]=3)=[CH:11][N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc(-c3ccnn3C3CCCCO3)cn2)cc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CO
Product: c1ccc(-c2ncc(-c3cc[nH]n3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Phenyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5yl)pyrimidine (Step A, 51 mg) was added to a 1 N hydrochloric acid solution in methanol (5 mL). The solution was stirred at room temperature for two hours. MTBE (40 mL) was added to precipitate a white solid which was filtered and rinsed with MTBE and dried under high vacuum. The title compound was obtained as a white powder (11.4 mg, 27% yield); melting point 264-273° C.; 1H-NMR (300 MHz; CD3OD) δ 10.0 (s, 1H), 9.29 (s, 2H), 8.44 (dd, 2H), 7.86 (d, 1H), 7.54 (m, 3H), 6.95 (d, 1H); MS (ESI+) m/z 223 (M+1); H-PGDS FPBA IC50: 2.4 μM.
Reaction SMILES: [ClH:1].Cl.CN(C)C(C1C=CC2C=C(C3C(C)=CN=C(NCCC4CCN(C)CC4)N=3)SC=2C=1)=O.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]3[CH:46]=[C:47]([C:50]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:51])[CH:48]=[CH:49][C:43]=3[CH:42]=2)[C:38]([CH3:58])=[CH:37][N:36]=1.C(O[C:64]([N:66]1[CH2:71][CH2:70][CH:69]([CH2:72][CH2:73][CH2:74][NH2:75])[CH2:68][CH2:67]1)=O)(C)(C)C>>[ClH:34].[ClH:1].[CH3:58][C:38]1[C:39]([C:41]2[S:45][C:44]3[CH:46]=[C:47]([C:50]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:51])[CH:48]=[CH:49][C:43]=3[CH:42]=2)=[N:40][C:35]([NH:75][CH2:74][CH2:73][CH2:72][CH:69]2[CH2:68][CH2:67][N:66]([CH3:64])[CH2:71][CH2:70]2)=[N:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2ccc(C(=O)N3CCOCC3)cc2s1
Agent: Cc1cnc(NCCC2CCN(C)CC2)nc1-c1cc2ccc(C(=O)N(C)C)cc2s1
Agent: Cl
Product: Cc1cnc(NCCCC2CCN(C)CC2)nc1-c1cc2ccc(C(=O)N3CCOCC3)cc2s1

Procedure:
Using the method of 2-{5-methyl-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-6-carboxylic acid dimethylamide di-hydrochloride, the title compound is synthesized from [2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophen-6-yl]-morpholin-4-ylmethanone and 4-(3-aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester and isolated as yellow foam. ES+(m/z) 494 [M(free base)+H].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[Cl:12])=[O:4].O(CC)CC.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.CN(C)C=O>O>[ClH:12].[Cl:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: O=C(CBr)c1ccc(F)cc1Cl
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cl
Product: O=C(Cn1ccnc1)c1ccc(F)cc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 78.7 parts of 2-bromo-1-(2-chloro-4-fluorophenyl)ethanone in 140 parts of 1,1'-oxybisethane are added carefully 106.4 parts of 1H-imidazole. Upon completion, there are added 180 parts of N,N-dimethylformamide and the whole is stirred for 2 hours at 50° C. After the addition of water, the product is extracted twice with trichloromethane. The combined extracts are washed three times with water, dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 4-methyl-2-pentanone, 2,2'-oxybispropane and 2-propanol. The salt is filtered off and crystallized from a mixture of ethanol and 2,2'-oxybispropane, yielding 1.5 parts of 1-(2-chloro-4-fluorophenyl)-2-(1H-imidazol-1-yl)ethanone hydrochloride; mp. 197.4° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH:11]([CH2:13]I)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:15]1([N:21]2[C:25]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:24](=[O:31])[NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32](=[O:35])([O-:34])[O-].[K+].[K+].O>CN(C)C=O>[C:8]([OH:31])(=[O:9])/[CH:12]=[CH:11]\[C:32]([OH:34])=[O:35].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH:11]([CH2:13][N:28]3[CH2:27][CH2:26][C:25]4([N:21]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:22][NH:23][C:24]4=[O:31])[CH2:30][CH2:29]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: Fc1ccc(C2CC(CI)CO2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)/C=C\C(=O)O
Product: O=C1NCN(c2ccccc2)C12CCN(CC1COC(c3ccc(F)cc3)C1)CC2
Temperature: 70 °C
Reaction time: 21 h

Procedure:
A mixture of 3.2 g of 2-(4-fluorophenyl)-4-(iodomethyl)tetrahydrofuran, 2.4 g of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one and 1.4 g of potassium carbonate in 60 ml of dimethylformamide is heated with stirring at 70° C. for 21 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluant. The thus obtained purified crystals are treated with maleic acid and recrystallized from ethanol-water to give 8-[2-(4-fluorophenyl)-tetrahydro-4-furylmethyl]-1-phenyl-1,3,8-triazaspiro[4.5]-decan-4-one maleate, melting at 175° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH:25]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:25][CH2:24][C:23]([CH3:28])([CH3:27])[CH3:22])[CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC=O
Reactant: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)CCN1CCN(c2ncn(Cc3ccc(Cl)cc3)c(=O)n2)CC1
Yield: 28.2 %

Procedure:
To a dichloromethane solution (1 mL) of 1-(4-chlorobenzyl)-4-(piperazin-1-yl)-1,3,5-triazin-2(1H)-one (31 mg, 0.10 mmol) synthesized in Reference Synthesis Example 9 and 3,3-dimethylbutanal (13 μL, 0.10 mmol), sodium triacetoxyborohydride (42 mg, 0.20 mmol) was added and the resultant mixture was stirred at room temperature for 4 hours. After the completion of the reaction, saturated sodium bicarbonate water was added to the reaction solution and extraction with ethyl acetate from the resultant reaction solution was performed. The organic layer was concentrated under reduced pressure and to the resultant residue, ethyl acetate was added. A resultant solid was filtered and was dried under reduced pressure to obtain the title compound (11 mg, yield: 28%).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14]C(=O)OC(C)(C)C)=[N:12][CH:13]=2)[CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CC[C@H](F)C2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CN2CC[C@H](F)C2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.3 %

Procedure:
To a solution of (S)-tert-butyl 5-((3-fluoropyrrolidin-1-yl)methyl)pyridin-2-ylcarbamate 119 (7.00 g, 23.7 mmol) in dichloromethane (70 mL) was added TFA (15.5 g, 142 mmol). The mixture was stirred for 12 h at room temperature. The solvent was removed in vacuo and sat. aq Na2CO3 was added. The mixture was extracted with dichloromethane, dried (MgSO4) and concentrated to give 120 (4.50 g, 97% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].N.[ClH:18]>C(O)C.CCOCC.C(O)=O>[ClH:18].[C:12]([NH:16][CH2:5][C:4]1[CH:7]=[C:8]([Br:10])[CH:9]=[C:2]([Br:1])[C:3]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1cc(Br)cc(Br)c1O
Reactant: CC(C)(C)N
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CCOCC
Solvent: O=CO
Product: CC(C)(C)NCc1cc(Br)cc(Br)c1O

Procedure:
7 gm of 3,5-dibromo-salicylaldehyde, 17.5 gm of tert. butylamine and 7.7 gm of formic acid were heated for 6 hours at 70°-80° C. Subsequently, the reaction mixture was admixed with aqueous 2 N ammonia, vigorously shaken, and the precipitate formed thereby was sucked off. The residue was dissolved in ethanol, acidified with ethanolic hydrochloric acid and admixed with ether in order to crystallize the product out. N-tert.butyl-3,5-dibromo-2-hydroxy-benzylamine hydrochloride, m.p. 216°-220° C (decomp.), was obtained after recrystallization from absolute ethanol/ether.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH2:14]([O:16][P:17]([C:22](=[N:28][OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:21])[O:18][CH2:19][CH3:20])[CH3:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:19]([O:18][P:17]([C:22](=[N:28][O:29][C:8](=[O:9])[CH:7]([O:6][C:5]1[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:21])[O:16][CH2:14][CH3:15])[CH3:20]
Reactant: CC(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: CCCCCC(=NO)P(=O)(OCC)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC(=NOC(=O)C(C)Oc1ccc(Cl)cc1)P(=O)(OCC)OCC
Temperature: 55 °C
Reaction time: 9 h
Yield: 79.5 %

Procedure:
8.8 g (0.04 mole) of 2-(4-chlorophenoxy)-propionyl chloride, dissolved in 20 ml of toluene, were added dropwise to a solution of 10.0 g (0.04 mole) of 1-hydroximinohexanephosphonic acid diethyl ester and 5.0 g (0.05 mole) of triethylamine in 80 ml of toluene. The mixture was subsequently stirred at 55° C. for 9 hours and cooled, the triethylamine hydrochloride which had precipitated was filtered off with suction and the organic phase was washed with water. After drying with Na2SO4, evaporating off the toluene on a rotary evaporator and removing, under a high vacuum, the solvent which still adhered, 13.8 g (77.8%) of 1-[2-(4-chlorophenoxy)-propionyloximino]-hexanephosphonic acid diethyl ester of nD22 =1.4919 were obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:10](F)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]([S:10]([N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(S(=O)(=O)F)c1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1cccc(C(C)=O)c1
Yield: 88.1 %

Procedure:
A solution of 40.4 g (0.20 mol) of 3-acetylbenzenesulfonyl fluoride, 32.2 g (0.44 mol) of diethylamine in 200 ml of dry tetrahydrofuran is stirred overnight at 23° C. and then refluxed for two days. Diethylamine (10 ml) is added and the solution refluxed for 24 hours and the solvent removed. The residue is dissolved in CH2Cl2 and the solution washed with 1NHCl and H2O. The CH2Cl2 layer is dried (MgSO4) and the solvent removed to give 45 g (88%) of thick oil. A sample is chromatographed (silica gel column) with CH2Cl2 to give a viscous oil.
Reaction SMILES: Cl.C([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7])#N.[CH3:12][N:13]=[C:14]=[O:15].[CH2:16]([N:18](CC)CC)C.O>ClCCl>[N+:18]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH:7][C:14]([NH:13][CH3:12])=[O:15])#[C-:16]
Reactant: CN=C=O
Reactant: N#Cc1ccccc1CN
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: [C-]#[N+]c1ccccc1CNC(=O)NC
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
2-cyanobenzylamine hydrochloride (90 g) and Dichloromethane (800 ml) were taken into a round bottomed (RB) flask. Methyl isocyanate (45.6 g) was added at 5° C. Triethylamine (81 g) in Dichloromethane (300 ml) was added at the same temperature and stirred at room temperature for 16 h. Water (1 L) was added and stirred for 30 min. The obtained solid was collected by filtration and dried in oven at 50° C. for 12 h. The yield is 85% and the purity 99.8%.