Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])=[N:37][CH:38]=5)[CH:30]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[ClH:55]>CO.CCOCC>[ClH:55].[ClH:55].[ClH:55].[CH3:53][O:52][C:50](=[O:51])[NH:49][CH:45]([C:44]([N:40]1[CH2:41][CH2:42][CH2:43][CH:39]1[C:36]1[NH:35][C:34]([C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][NH:8]6)=[N:17][CH:16]=5)=[CH:19][CH:20]=4)[CH:25]=3)[CH:30]=2)=[CH:38][N:37]=1)=[O:54])[CH:46]([CH3:48])[CH3:47]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a slurry of 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.14 mmol) in MeOH (0.15 mL) was added HCl in dioxanes (4 M, 0.7 mL). The resulting solution was stirred at room temperature for 1 hour and diluted with Et2O. The resulting precipitate was filtered and dried to provide {2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloric acid salt (0.09 g, 87%) as a white powder. LCMS-ESI+: calc'd for C37H41N7O3: 631.3 (M+). Found: 632.7 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21]>>[CH2:19]([NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:20][CH3:21]
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: CCCN
Product: CCCNc1ncnc2ccc(-c3ccc(F)cc3)cc12
Yield: 83 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and n-propylamine in 83% yield, using the procedure described for example 37, and was characterized by its mass spectrum as follows: MS (m/z): 282 ([M+H]+, 100).
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:10]([F:28])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].N12CCCN=C1CCCCC2.Cl>C1(C)C=CC=CC=1>[F:28][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:19][C:20]=1[CH3:21])[CH:7]=[CH:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Br)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(F)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(F)c1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A mixture of methyl 2-bromo-3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propionate (14.1 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.8 g) and toluene (150 ml) was stirred for 2 hours at temperatures ranging from 80 to 90° C. The reaction mixture was poured into 2N HCl, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent under reduced pressure to yield methyl 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate (10.0 g). The product was recrystallized from dichloromethane-methanol to give colorless prisms, m.p.167-168° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:9][OH:10])=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C=C/c1ccc(C=C(C(=O)O)c2ccc(F)cc2)cc1
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccc(/C=C(/CO)c2ccc(F)cc2)cc1
Temperature: 5 °C
Yield: 79 %

Procedure:
To a suspension of 2-(4-fluorophenyl)-3-(4-(3-(E)-methoxy-3-oxoprop-1-en-1-yl)phenyl)acrylic acid (2 g, 6.1 mmol, prepared according to the procedure described in Example 1, step-II) in THF (10 mL), triethylamine was added (0.85 mL, 6.67 mmol) under constant stirring at 5° C. To this solution, methyl chloroformate (0.53 mL, 6.67 mmol) was added dropwise over a period of 30 minutes at 5° C. and stirred at the same temperature for 30 minutes. To this reaction mixture, sodium borohydride (0.9 g, 24.5 mmol) was added at one portion and methanol (5 mL) was added dropwise under stirring and the reaction mixture was stirred at 30° C. for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (300 mL) and washed successively with water (2×100 mL) and brine (1×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the crude compound, which was purified by column chromatography using 12% ethylacetate/hexanes as the eluent to afford a pure compound as a white solid (1.5 g, 79% yield).
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH:24]([CH2:25][C:26]([OH:28])=[O:27])[O:23][C:22]4[CH:21]=[C:20]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:19]=[CH:18][C:17]=4[C:12]=3[CH2:13][O:14][C:15]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42]O.CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][O:27][C:26](=[O:28])[CH2:25][CH:24]1[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:38])[CH3:37])=[CH:16][C:15]=3[O:14][CH2:13][C:12]=2[C:17]2[CH:18]=[CH:19][C:20]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])=[CH:21][C:22]=2[O:23]1
Reactant: CN(C)CCO
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OC(CC(=O)O)C1=C2COc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)CCOC(=O)CC1Oc2cc(O[Si](C)(C)C(C)(C)C)ccc2C2=C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC2
Reaction time: 13 h

Procedure:
A mixture of [2,8-Bis-(tert-butyl-dimethyl-silyloxy)-5,11-dihydro-chromeno[4,3-c]chromen-5-yl]-acetic acid, the compound prepared as in Example 95 above, (56 mg, 0.1 mmol), 2-dimethylamino-ethanol (30 μL, 27 mg, 3.0 eq.), DIC (14 mg, 18 μL) and DMAP (12 mg) in DCM (2 mL) was stirred for 13 hours. The reaction mixture was then concentrated to yield [2,8-Bis-(tert-butyl-dimethyl-silyloxy)-5,11-dihydro-chromeno[4,3-c]chromen-5-yl]-acetic acid 2-dimethylamino-ethyl ester as a crude foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])C.[OH-].[Na+].O>C1COCC1>[CH3:21][O:20][C:18]1[C:17]([O:22][CH3:23])=[CH:16][C:15]2[N:11]([C:9]3[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:8]=3)[CH:12]=[N:13][C:14]=2[CH:19]=1
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C(=O)O)s3)c2cc1OC
Yield: 86.4 %

Procedure:
2-(5,6-Dimethoxybenzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid ethyl ester (180 mg, 0.44 mmol) was suspended in THF (4 ml), NaOH (15%, 1.5 ml) and water (2 ml) and the mixture was stirred at 40-50° C. for 3 hrs. After THF was removed, the residue was extracted with ethyl acetate (2×2 mL). The aqueous was then neutralized with 3N HCl to pH=3. The solid was collected by filtration and was washed with water, dried in airflow to give 2-(5,6-Dimethoxybenzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid (147 mg, 0.38 mmol, 88%). 1H-NMR (DMSO-D6) 8.74 (s, 1H); 7.80 (s, 1H); 7.57-7.63 (m, 2H); 7.40-7.56 (m, 3H); 7.38 (s, 1H); 3.83 (d, 6H). MS M/z 382 (M+1).
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=O)C1C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32].[OH-].[Na+]>C1COCC1.CO>[CH2:34]([O:33][C:31]([C:30]1[CH:29]=[C:28]([NH:27]/[C:18](=[C:11]2\[C:10](=[O:26])[NH:9][C:17]3[C:12]\2=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:38]=[CH:37][CH:36]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C1C(=C(Cl)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 9c and 8 from 1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and ethyl 3-aminobenzoate in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]([Cl:9])[Cl:8])=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].O.C(Cl)(Cl)(Cl)[Cl:16]>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])([Cl:8])[Cl:9])=[CH:5][CH:4]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCc1ccc(C(Cl)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(C(Cl)(Cl)Cl)cc1
Yield: 88.7 %

Procedure:
22.7 gms of 4-ethyl benzal chloride dissolved in 100 gms of carbon tetrachloride was charged into a reaction vessel with 2.0 gms of Aliquot 4. 150 ml of 50% sodium hydroxide was added and the mixture heated to reflux for a period of about 1 hour. After the completion of the reaction, water was added to the mixture and the organic layer separated by phase separation. The organic solvent was stripped on a rotovac and product distilled on Krughrohr to give 23.8 gms of pale yellow liquid. (Yield 89%). [Pot temperature 90° -100° C. (at 0.15 mm/Hg - 0.2×105 pascals)]. Elemental analysis for C9H9Cl3 :
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]O>>[Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Reactant: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cc1Br

Procedure:
Compound 26 in methanol was treated with SO2Cl2 and the resulting solution heated at reflux for18 h. The reaction mixture was then evaporated, pre-absorbed on silica (Merck, 9385) and purified by chromatography, eluting with 10% ethyl acetate/i-hexane. Appropriate fractions were combined and evaporated to give methyl 2-bromo-4-nitro-benzoate (compound 27).
Reaction SMILES: C(=O)([O-])O.[Na+].[Cl:6][C:7]1[NH:8][CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[N:11]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>C(#N)C>[Cl:6][C:7]1[N:8]([CH2:18][CH:17]([OH:19])[CH2:15][Cl:16])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[N:11]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: ClCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1cn(CC(O)CCl)c(Cl)n1
Yield: 62.7 %

Procedure:
Sodium hydrogencarbonate (1.25 g, 14.91 mmol) was added to a solution of 2-chloro-4-nitro-1H-imidazole (2 g, 13.56 mmol) and epichlorohydrin (1.38 g, 14.91 mmol) in acetonitrile (60 ml), and the resulting mixture was stirred under reflux for 4 hours. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. To the residue, water (20 ml) was added, the resulting mixture was extracted with methylene chloride (15 ml) twice, and the extracts were dried over sodium sulfate, and then filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to afford 2-chloro-1-(3-chloro-2-hydroxypropyl)-4-nitroimidazole (2.04 g, yield 63%) as a light yellow oil.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7][CH2:8][C:9]1[O:13][C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3O)=[CH:11][CH:10]=1)(=[O:4])=[O:3].P(Cl)(Cl)(O[Cl:28])=O.C1(C)C=CC=CC=1.C(N(CC)CC)C>CCCCCC.C(OCC)(=O)C>[Cl:28][C:17]1[C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:12]3[O:13][C:9]([CH2:8][NH:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:11]=3)[CH:15]=2)[N:20]=[CH:19][N:18]=1
Reactant: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(O)c3c2)o1
Reactant: O=P(Cl)(Cl)OCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Cl)c3c2)o1
Reaction time: 0.17 h

Procedure:
In a 4-neck glass flask provided with a mechanical stirrer, condenser and thermometer, the entirety having been previously dried, 63.8 g of 6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)furan-2-yl] quinazoline-4-ol of formula (VI) (0.184 moles), 33.7 g (20.1 mL) of phosphoryl oxychloride (POCl3; 0.220 moles) and 150 mL of toluene were introduced, under nitrogen. Stirring was carried out at ambient temperature for 10 minutes then 22.3 g (30.7 mL) of triethylamine (0.220 moles) was dosed, maintaining the T below 30° C. After introduction heating was carried out at 75° C. for 3 hours. The reaction was controlled by means of TLC using the Hexane/Ethyl acetate mixture (4:6) as eluent. Cooling was carried out at 0° C. and stirring was carried out for an hour at such temperature. The suspension was filtered washing the solid with 100 mL of toluene. The product was dried at 50° C. for 7-8 hours under vacuum. 63.8 g of product was added with a molar yield equivalent to 95%.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH2:46])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:39])([F:41])[F:40])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH:46][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:32]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
55 mg (0.11 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]triazolo[1,5-c]pyrimidine hydrochloride (Example 52A), 39.9 mg (0.14 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.12 ml (0.69 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 58 mg (81% of theory) of the product as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][N:5]2[N:15]=[C:16]([CH3:18])[N:17]=[C:4]2[N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[N:3][C:4]3[N:5]([N:15]=[C:16]([CH3:18])[N:17]=3)[CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc2nc(Cl)c(-c3cccc(F)c3)cn2n1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3cccc(F)c3)cn2n1
Temperature: 90 °C
Yield: 91.3 %

Procedure:
To a mixture of 0.73 g (2.8 mmol) 5-chloro-6-(3-fluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidine and 458.3 mg (3.1 mmol) 4-formylphenylboronic acid in 14 mL 1,2-dimethoxyethane are added 5.2 mL of a sodium carbonate solution (10%) and 102 mg (0.13 mmol) dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II). The resulting mixture is heated to 90° C. under an inert gas atmosphere over night. The reaction mixture is diluted with water and extracted three times with dichloromethane. The combined organic layers are washed with brine and dried over sodium sulphate. After evaporation of the solvent the residue is purified by chromatography on silica gel (dichloromethane/methanol) to yield 0.85 g (87.3%) of the desired aldehyde.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:21]>CO.C(O)(C)C>[ClH:21].[ClH:21].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCCCC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COC(=O)[C@H](CN)N1CCCCC1
Yield: 100 %

Procedure:
A solution of 830 mg (2.8 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-piperidin-1-yl-propanoate in 15 ml of methanol and 3 ml of hydrochloric acid in isopropanol having a concentration of 5-6N is stirred at 40° C. for 18 h. After concentrating under vacuum, the residue is taken up in ethyl acetate, filtered and dried under vacuum. 630 mg (100%) of methyl (S)-3-amino-2-piperidin-1-ylpropanoate dihydrochloride are obtained in the form of a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[CH2:12][CH2:11][C:9](=O)[CH2:8][CH2:7]1)=[O:5].Cl.[C:14]1([NH:20]N)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:2]([O:3][C:4]([CH:6]1[CH2:12][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:20][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2[nH]c3ccccc3c2C1
Yield: 102 %

Procedure:
4-Cyclohexanonecarboxylic acid ethyl ester (25 g, 147 mmol) and phenylhydrazine hydrochloride (20 g, 139 mmol) were refluxed in 550 mL of anhydrous ethanol overnight. The reaction was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 34.5 g (96%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:12])[CH3:11])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[CH3:11][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[OH:3])[CH:5]=1)[OH:12]
Reactant: CC(=O)c1cccc(C(C)=O)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cccc(C(C)O)c1

Procedure:
This mixture of stereoisomers was prepared from 1,3-diacetylbenzene by reduction with sodium borohydride as described above for the para stereoisomers. The mixture of stereoisomers was isolated as a semisolid. It appeared as a single spot on TLC and as a single peak on VPC.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])(C)(C)C.O1CCOCC1.[ClH:25]>>[ClH:25].[NH2:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1cc(C)c(CNC(=O)OC(C)(C)C)c(=O)[nH]1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
tert-butyl((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate (40 g, 0.27 mol) was added into dioxane/HCl (1 L) and the mixture was stirred at room temperature for 4 hr. The reaction solution was filtrated and concentrated to give crude product. The crude was washed with ethyl acetate (100 mL*2) and EtOH (50 mL*1) and concentrated to give 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one hydrochloride (15 g, 40%). LCMS (M+H+) m/z: calcd. 152.19. found 153.1. 1H NMR (DMSO, 400 MHz) δ 11.84 (s, 1H), 8.07 (s, 3H), 5.96 (s, 1H), 3.76-7.75 (d, J=5.6 Hz, 2H), 2.21 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.[Br:27][CH:28]=[CH:29][CH2:30][CH2:31]Br.Cl>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:31][CH:30]=[CH:29][CH2:28][Br:27])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: BrC=CCCBr
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(O)ccc21
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(OCC=CCBr)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
To 304 mg (1 mmol) 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester in 4 ml DMF 420 mg (3 mmol) K2CO3 (powdered) and 416 mg (2 mmol) 1,4-dibromobutene were added. The mixture was stirred at 50° C. for 1 h, diluted with EtOAc and water. 2M HCl was added and the inorganic phase was extracted with EtOAc. The combined organic phases were washed with water and dried over Na2SO4. The crude-product was purified by column chromatography on silica gel with hexane/EtOAc 9:1 to 4:1 to yield 250 mg (46%) 6-(4-Bromo-but-2-enyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless gum, MS: 436 (MH+, 1Br, 1Cl).
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])(=O)C.[Na+].C(O)(=O)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:21]([NH:11][NH:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(=O)c1ccccc1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(NNC(=O)c1ccccc1O)c1ccccc1

Procedure:
A four neck flask (1 liter) equipped with a thermometer and a stirrer was charged with 60.8 g (0.4 mol) of salicylohydrazide, 49.2 g (0.6 mol) of sodium acetate and 700 ml of acetic acid. Dropwise added thereto was 67.4 g (0.48 mol) of benzoyl chloride in one hour while stirring, and stirring was continued at room temperature (20° C.) for 3 hours. After finishing the reaction, 1.5 liter of deionized water was added and crystal was filtered off. After washing sufficiently the crystal with 500 ml of methanol, it was dried under reduced pressure to obtain slightly brown crystal.
Reaction SMILES: ClC1C(F)=CC(F)=C([N+:8]([O-:10])=[O:9])C=1.[Cl:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([Cl:22])[CH:15]=1>>[Cl:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([Cl:22])[C:15]=1[N+:8]([O-:10])=[O:9]
Reactant: Fc1cc(F)c(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Product: O=[N+]([O-])c1c(Cl)c(F)cc(F)c1Cl

Procedure:
A synthesis proceeding via four stages can be taken from EP 562 435. 2,4,5-Trichloronitrobenzene is first reacted with an alkali metal fluoride to give 5-chloro-2,4-difluoronitrobenzene. By means of chlorinating denitration the 5-chloro-2,4-difluoronitrobenzene can be converted to 1,3-dichloro-4,6-difluorobenzene. The 1,3-dichloro-4,6-difluorobenzene is nitrated to give 2,6-dichloro-3,5-difluoronitrobenzene. The desired 3,5-difluoroaniline can be prepared from the 2,6-dichloro-3,5-difluoronitrobenzene by reaction with hydrogen with elimination of hydrogen chloride and reduction of the nitro group.