Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.CO.C(Cl)(=O)C([Cl:30])=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([Cl:30])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Cl)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-Piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXXII) (12.0 g, 45.6 mmol) was taken in neat oxalyl chloride (30 ml), 0.2 mL of DMF was added and the mixture was stirred at room temperature for 1 hour. Completion of the reaction was monitored by TLC which showed the formation of a non-polar spot after treatment of a small amount with methanol. Then the reaction mixture was concentrated under reduced pressure to provide (S)-3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXXIII) (12.66 g) which was directly used in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7](=[O:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:39])([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)C>[N:13]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([NH:6][C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:20][CH:19]=2)=[O:18])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CCOC(=O)C(C)(C)CCCCBr
Reactant: O=C(CCCCCn1ccnc1)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(NC(=O)CCCCCn2ccnc2)cc1
Reaction time: 0.5 h

Procedure:
To 20 ml of ethanol were added 1.37 g of p-hydroxy-6-(1-imidazolyl)hexaneanilide and 0.69 g of anhydrous potassium carbonate and the mixture was stirred for 30 minutes with heating under reflux. After cooling, 1.26 g of ethyl 6-bromo-2,2-dimethylhexanoate was added thereto and the mixture was reacted overnight with heating under reflux. The solvent was removed from the reaction mixture by distillation under reduced pressure. Water was added to the resulting residue followed by extracting with chloroform. After the chloroform layer was successively washed with a 1N aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting residue was subjected to silica gel column chromatography. The product was eluted out using a chloroform-methanol liquid mixture (50:1 in a volume ratio). The solvent was removed by distillation under reduced pressure. The resulting crystals were recrystallized from a solvent mixture of n-hexane-ethylacetate to obtain ethyl 6-[p-[6-(1-imidazolyl)hexanamido]phenoxy]-2,2-dimethylhexanoate as white crystals.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][C:21]#[N:22]>O1CCCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: N#CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCCCOc1cccc(CN2CCCCC2)c1
Yield: 69.9 %

Procedure:
A solution of 3-(1-piperidinylmethyl)phenol (12.05 g) in dry tetrahydrofuran (50 ml) was added dropwise to a suspension of sodium hydride [from 6.0 g of 50% suspension in oil washed with petroleum ether] in dry tetrahydrofuran (70 ml). The mixture was stirred under reflux for 30 minutes and allowed to cool. 4-Bromobutyronitrile (14.89 g, 10.0 ml) was added to the cool mixture and the mixture so obtained was stirred under reflux for 22 hours. Tetrahydrofuran was evaporated under reduced pressure and the residue was dissolved in water (100 ml). The solution was extracted with ether (3×50 ml), and the aqueous layer was adjusted to pH 9 with K2CO3. The aqueous solution was extracted with chloroform (3×100 ml), the chloroform extracts were dried (K2CO3 and chloroform was removed under reduced pressure to give a pale brown oil, (16.22 g). This oil was purified by column chromatography (Kieselgel 60 70-230 mesh silica) using chloroform as eluant. The fractions containing the desired product were collected and the solvent was evaporated in vacuo to give 4-[3-(1-piperidinylmethyl)phenoxy]butyronitrile as an oil (11.37 g).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[CH:4][C:5]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:1][C:2]1[C:3]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:4][C:5]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(=O)c2cc(F)c(F)cc2n2ccccc12
Product: CCOC(=O)c1c(=O)c2cc(F)c(N3CCN(C)CC3)cc2n2ccccc12
Temperature: 110 °C
Yield: 79.1 %

Procedure:
A mixture of 2.0 g of ethyl 8,9-difluoro-6-oxo-6H-benzo[c]quinolizine-5-carboxylate and 3.3 g of N-methylpiperazine was heated at 110° C. for 2 hours. The solvent was evaporated and the residue partitioned between water and dichloromethane. The organic layer was dried and the solvent removed giving 2.0 g of the desired product, mp 167°-170° C.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]=2[C@@H:6]([CH2:5][C:4]([OH:18])=[O:3])[O:10]1
Reactant: CCOC(=O)C[C@H]1OB(O)c2cc(O)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(O)cc2c1[C@@H](CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3R)-(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.00 g, 4.00 mmol) in THF (9 mL) was added a solution of LiOH (0.479 g, 20.0 mmol) in water (8 mL) at 0° C. The resulting mixture was stirred at room temperature for 1.5 hours then acidified to pH=2 with dilute hydrochloric acid and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (DCM/MeOH/AcOH=20:1:trace) to give pure product as a white powder after lyophilization (0.579 g, 64.9%). 1HNMR (400 MHz, DMSO-d) δ12.26 (s, 1H), 9.25 (s, 1H), 9.04 (s, 1H), 6.86 (d, J=1.95 Hz, 1H), 6.64 (d, J=1.95 Hz, 1H), 5.36 (dd, J=9.76, 2.34 Hz, 1H), 2.98 (dd, J=15.22, 2.34 Hz, 1H), 2.17 (s, 3H), 1.98 (dd, 1H). MS (ESI) m/z=221 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]2[CH:39]=[CH:40][CH:41]=[CH:42][C:24]=2[C:23]2[CH:43]=[CH:44][CH:45]=[CH:46][C:22]1=2)=[O:19])[CH3:17]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:25]2[CH:39]=[CH:40][CH:41]=[CH:42][C:24]=2[C:23]2[CH:43]=[CH:44][CH:45]=[CH:46][C:22]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: C[C@H](N)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Product: C[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-S), the title compound was prepared. The product was purified by chromatography (silica, 1-2% MeOH/CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][C:21](=O)[C:22](F)(F)F)[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ICC[N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][S:37]1(=[O:43])=[O:42]>CN(C)C=O.C1(C)C=CC=CC=1>[O:42]=[S:37]1(=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][N:36]1[CH2:22][CH2:21][NH:20][C:11]1[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:10]=1
Reactant: O=S1(=O)CCCCN1CCI
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1CCCCS1(=O)=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 5-[(4-fluorophenyl)methyl]-3-[(trifluoroacetyl)amino]-2-pyridinecarboxylate (304 mg, 0.821 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (535 mg, 1.64 mmol) and 2-(2-iodoethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide (356 mg, 1.23 mmol), respectively. The reaction mixture was stirred at 80° C. for 5 hours. Additional cesium carbonate (535 mg, 1.64 mmol) and 2-(2-iodoethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide (356 mg, 1.23 mmol) were added and the reaction mixture was stirred overnight at 80° C. The reaction mixture was cooled and diluted with toluene. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by flash chromatography (0 to 5%, methanol in dichloromethane) to provide ethyl 3-{[2-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)ethyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate, which was slightly contaminated and taken on to the next step.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:10]([Cl:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)([C:23]3[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)[OH:22])[CH:8]=2)[N:3]=1.[O-:39][CH2:40][CH3:41].[Na+]>>[Cl:20][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)([C:23]3[CH:24]=[N:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)[OH:22])[CH:8]=2)[N:3]=[C:2]([O:39][CH2:40][CH3:41])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1
Reactant: CC[O-]
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Oc3ccc(F)cc3)c(Cl)c2c1
Agent: [Na+]
Product: CCOc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Oc1ccc(F)cc1

Procedure:
The title compound was prepared using (2,4-dichloro-3-(4-fluorophenoxy)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (Example 11) in place of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 1) according to the procedure of Example 2a except only one equivalent of sodium ethoxide was used. 1H NMR (400 MHz, MeOH-d4) δ 8.78 (d, J=1.96 Hz, 1H), 8.14 (d, J=1.96 Hz, 1H), 8.02 (dd, J=2.20, 8.31 Hz, 1H), 7.88 (d, J=8.56 Hz, 1H), 7.84 (d, J=8.31 Hz, 1H), 7.74 (s, 1H), 7.66 (dd, J=2.20, 8.80 Hz, 1H), 6.97-7.07 (m, 2H), 6.87 (dd, J=4.28, 9.17 Hz, 2H), 6.36 (s, 1H), 4.47 (q, J=7.09 Hz, 2H), 3.49 (s, 3H), 1.23 (t, J=7.09 Hz, 3H); MS m/e 574.2 [M+H]+.
Reaction SMILES: [NH3:1].CCO.F[C:6]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([F:17])[C:7]=1[C:8]#[N:9]>C1COCC1>[NH2:1][C:6]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([F:17])[C:7]=1[C:8]#[N:9]
Reactant: N
Reactant: N#Cc1c(F)ccc([N+](=O)[O-])c1F
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1c(F)ccc([N+](=O)[O-])c1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of NH3 in EtOH (19 mL, 8.6 M, 160 mmol) was added dropwise to a solution of 2,6-difluoro-3-nitrobenzonitrile (10 g, 54 mmol) in THF (50 mL) at 0° C. under Ar and the resulting mixture was stirred at 0° C. for 1 h. The mixture was concentrated and the residue washed with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated.
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].C(O)(=O)C.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.N1CCOCC1.C(O)(=O)C>C(#N)C>[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH:12]1[CH:3]=[CH:4][C:5]#[N:6]
Reactant: N#CC=CO
Reactant: C1COCCN1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC#N
Product: N#CC=CC1COCCN1
Temperature: 65 °C
Yield: 75.3 %

Procedure:
30.3 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 75%) is added to a solution of morpholine acetate (prepared from 26.1 g (0.3 mol) of morpholine and 18 g (0.3 mol) of acetic acid) in 200 ml of acetonitrile and is heated for 8 h at 65° C. After working up as in Example 55, 26.0 g (75.4%) of 3-morpholine acrylonitrile was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:17]3[CH2:26][CH2:25][C:20]4(OCC[O:21]4)[CH2:19][CH2:18]3)=[CH:8][C:9]=2[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[S:4][C:3]=1[C:27]([NH2:29])=[O:28].C(O)(=O)C.C([O-])(O)=O.[Na+]>O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([N:17]3[CH2:18][CH2:19][C:20](=[O:21])[CH2:25][CH2:26]3)=[CH:8][C:9]=2[O:11][CH2:12][C:13]([F:14])([F:16])[F:15])[S:4][C:3]=1[C:27]([NH2:29])=[O:28]
Reactant: NC(=O)c1sc2nc(N3CCC4(CC3)OCCO4)cc(OCC(F)(F)F)c2c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)c1sc2nc(N3CCC(=O)CC3)cc(OCC(F)(F)F)c2c1N
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A solution of 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-(2,2,2-trifluoro-ethoxy)-thieno[2,3-b]pyridine-2-carboxylic acid amide as a white powder (0.940 g, 2.17 mmol) in a 4:1 mixture of acetic acid: H2O (20 mL) was heated to 80° C. for 4h then cooled to room temperature and made basic by the addition of a saturated aqueous solution of NaHCO3 which caused a solid to precipitate from solution. The solid was collected by filtration and dried under reduced pressure to provide 0.680 g (80.5%) of 3-amino-6-(4-oxo-piperidin-1-yl)-4-(2,2,2-trifluoro-ethoxy)-thieno[2,3-b]pyridine-2-carboxylic acid amide as a clear oil.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)(=O)C.[CH2:17](O)[CH3:18]>Cl>[CH2:17]([O:11][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([NH2:4])=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15])[CH3:18]
Reactant: CC(=O)Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(N)cc1[N+](=O)[O-]

Procedure:
A solution of 4-acetylamino-2-nitrobenzoic acid (1.80 g, 8.0 mmol) in 12N hydrochloric acid (14 mL) and absolute ethyl alcohol (10 mL) was heated to 90°-100° C. for 5 h. Concentrated down in vacuo to remove ethyl alcohol only, adjusted pH to 4 with 1N sodium hydroxide and filtered off precipitate to give 140 mg (Y: 8%) of the title compound; 1H-NMR (CDCl3): δ 7.61 (d, J=8.5 Hz, 1H), 6.82 (d, J=2.1 Hz, 1H), 6.74 (dd, J=8.5, 2.1 Hz, 1H), 6.52 (bs, 2H), 4.17 (q, J=7.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H); MS (DCI) m/e: 211 (MH+).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][CH2:6][C@@H:5]([CH3:8])[NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([NH:17][CH3:18])[N:11]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:9][C:10]1[CH:15]=[C:14]([N:4]2[C@H:5]([CH3:8])[CH2:6][O:7][C@H:2]([CH3:1])[CH2:3]2)[N:13]=[C:12]([NH:17][CH3:18])[N:11]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CO[C@H](C)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1nc(Cl)cc(N2C[C@@H](C)OC[C@H]2C)n1

Procedure:
To a solution of (2R,5R)-2,5-dimethylmorpholine (400 mg, 3.47 mmol) and 4,6-dichloro-N-methyl-2-pyrimidinamine (742 mg, 4.17 mmol) in CH3CN (5 mL) stirred at room temperature was added Hunig's base (1.213 mL, 6.95 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 1 hour. After cooling the reaction, the mixture was concentrated under reduced pressure and the residue was added to a silica gel column and was eluted with Hex/EtOAc (10:1 to 3:1). Collected fractions:the first fraction was the starting material 4,6-dichloro-N-methyl-2-pyrimidinamine (300 mg), and the second fraction was the title compound (460 mg) as a light yellow solid. LC-MS (ES) m/z=257 [M+H]+.
Reaction SMILES: [K].[CH3:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].Cl[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)C(C)Cl
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C(C)=O)cc1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a solution of the potassium salt of 4-hydroxyacetophenone (25.0 g, 0.14 mol) in DMF (100 mL) is added ethyl 2-chloropropanoate (27.3 g, 0.20 mol) over 30 minutes and stirred at 85°-90° C. for 3 hours under nitrogen. The reaction is filtered to remove KCl and the filtrate is concentrated under reduced pressure to remove DMF and the product is analyzed by GLC. The product is dissolved in ethyl acetate (300 mL) and extracted with 2N NaOH (2×100 mL) and water (100 mL). The organic phase is dried and concentrated to give pure ethyl 2-(4-acetylphenoxy)propanoate (30 g) (yield 75%); m.p. 49.6° C.; IR (KBr) 1747.7 (vs), 1669.8 (vs); 1H NMR (CDCl3) delta 1.18 (t, J=7.2 Hz, 3H), 1.58 (d, J=6.8 Hz, 3H), 2.46 (s, 3H), 4.15 (q, J=7.2, 2H), 4.77 (q, J=32 6.8, 1H), 6.83 and 7.84 (dd, J=9.0 Hz, 4H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[N:36][CH:35]=[N:34]3)=[CH:29][CH:28]=2)[CH2:16][C:17]([NH:19][O:20]C(OC)(C)C)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[ClH:38]>CCOC(C)=O>[ClH:38].[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([N:33]3[CH:37]=[N:36][CH:35]=[N:34]3)=[CH:31][CH:32]=2)[CH2:16][C:17]([NH:19][OH:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)NOC(C)(C)OC)Cc2ccc(-n3cncn3)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc(S(=O)(=O)N(CC(=O)NO)Cc2ccc(-n3cncn3)cc2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 4.2 g (7.93 mmol) of 2-[(4-but-3-enyloxy-benzenesulfonyl)-(4-[1,2,4]triazol-1-yl-benzyl)-amino]-N-(1-methoxy-1-methyl-ethoxy)-acetamide (stage 79.6) in 100 ml of AcOEt, 28 ml of 5 N aqueous hydrochloride are added at r.t. After stirring for 5 min, precipitates are filtered off and dried in vacuo to give 2-[(4-but-3-enyloxy-benzenesulfonyl)-(4-[1,2,4]triazol-1-yl-benzyl)-amino]-N-hydroxy-acetamide-hydrochloride salt as colorless powder. 1H-NMR (400 MHz, DMSO-d6): 2.45-2.55 (m, 2H), 3.67 (s, 2H), 4.13 (t, 2H, J=6.56 Hz), 4.41 (s, 2H), 5.09-5.22 (m, 2H), 5.90 (m, 1H), 7.10 (d, 2H, J=9.04 Hz), 7.45 (d, 2H, J=8.56 Hz), 7.75-7.85 (m, 4H), 8.25 (s, 1H), 9.32 (s, 1H), 10.55 (brs, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: O=C(O)c1cc(Br)ccc1OCc1cccc(Cl)c1
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (110 mg, 1.17 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(3-chlorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 22; 200 mg, 0.59 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.70 mmol) and 1-Hydroxybenzotriazole (95 mg, 0.70 mmol) in DMF (20 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 70 mg.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.Cl.Cl.[CH:15]([CH:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:8]([O:7][C:1]([N:32]1[CH2:31][CH2:30][NH:29][CH:28]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:33]1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: c1ccc(C(c2ccccc2)C2CNCCN2)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCNC(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
Di-tert-butyl carbonate (996 mg) was added to a mixture of 2-benzhydrylpiperazine dihydrochloride (1.65 g) and N,N-diisopropylethylamine (3.5 ml) in N,N-dimethylformamide (17 ml) under ice-cooling. After being stirred at same temperature for 2 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give a crude oil. The oil was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (50:1) to give 1-tert-butoxycarbonyl-3-benzhydrylpiperazine (1.26 g) as a colorless powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][C:10](=[O:14])[NH:11]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][C:16]1([CH3:28])[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:26]=O)[CH:22]=2)[O:17]1.N1CCCCC1>O>[CH3:15][C:16]1([CH3:28])[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:26]=[C:9]3[C:8]4[C:12](=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=4)[NH:11][C:10]3=[O:14])[CH:22]=2)[O:17]1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Solvent: O
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C2=Cc1ccc2c(c1)CCC(C)(C)O2
Temperature: 90 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
A mixture of 6-acetamido-2-oxindole (285 mg), 2,2-dimethylchroman-6-carboxaldehyde (285 mg) and piperidine (0.2 ml) was stirred at 90° C. overnight. The reaction mixture was cooled and diluted with 20 ml of water. The sticky solid which formed was filtered and chromatographed (2% ethanol in ethyl acetate) to give 240 mg (44%) of N-[3-(2,2-dimethylchroman-6-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-6-yl]acetamide as an orange red solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:13][CH:14]([C:19]1[N:20]=[C:21]([CH3:24])[S:22][CH:23]=1)[C:15]([O:17][CH3:18])=[O:16])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[Br:1][C:23]1[S:22][C:21]([CH3:24])=[N:20][C:19]=1[CH:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(OC(C)(C)C)c1csc(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1nc(C)sc1Br
Temperature: 70 °C

Procedure:
Under a nitrogen atmosphere, N-bromosuccinimide (39 mg, 0.22 mmol) was added to a solution of methyl 2-(tert-butoxy)-2-(2-methyl-1,3-thiazol-4-yl)acetate (15c) (50 mg, 0.21 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was warmed at 70° C. for 30 minutes then concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and washed with water (2×20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give the desired product as a yellow oil without further purification (70 mg, 0.21 mmol, 100%).