Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[C:12]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[CH:13][CH:14]=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]([CH3:23])([CH3:22])[NH:16]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:35](=O)([O-])[O-]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:9][CH2:10][C:11]1[C:12]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]([CH3:35])[C:18](=[O:21])[C:17]([CH3:23])([CH3:22])[NH:16]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)cc1-c1ccc2c(c1COC(=O)c1ccccc1)NC(=O)C(C)(C)N2
Reactant: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1ccc2c(c1COC(=O)c1ccccc1)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
A mixture of 8-benzoyloxymethyl-7-(5-fluoro-2-methoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 1-3, 42.9 mg, 0.099 mmol), methyliodide (30.7 μL, 0.49 mmol), and cessium carbonate (89.0 mg, 0.27 mmol) was suspended in anhydrous N,N-dimethylformamide (1 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate (100 mL). The mixture was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (35.0 mg) as a colorless amorphous product. (Yield 79%)
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:22]([NH:24][N:25]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].COC1C=CC(CBr)=CC=1>>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:22]([NH:24][N:25]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: COc1ccc(CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c2ccccc2)C(=O)NOC2CCCCO2)S(C)(=O)=O)cc1
Agent: COc1ccc(CBr)cc1
Product: COc1ccc(CN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c2ccccc2)C(=O)NO)S(C)(=O)=O)cc1

Procedure:
The (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-2′-(4-methoxybenzyl)-4-methylvalerohydrazide used as the starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-(2R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesuophonyl)-4-methylvalerohydrazide by reaction with 4-methoxybenzyl bromide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH2:18]=O.[SH:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[C:14]([N+:15]([O-:17])=[O:16])[CH2:18][S:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Reactant: C[Si](C)(C)CS
Reactant: C=O
Solvent: CCO
Product: C[Si](C)(C)CSCC(=C1NCCN1Cc1ccc(Cl)nc1)[N+](=O)[O-]
Yield: 39.5 %

Procedure:
0.5 g of 1-(6-chloro-3-pyridylmethyl)-2-nitromethyleneimidazolidine, 0.18 g of 37% formaldehyde aqueous solution and 0.24 g of mercaptomethyl trimethylsilane were added to 15 ml of ethanol, and were reacted under reflux for 1 hour. After completing the reaction, the reaction liquor was cooled by ice to precipitate a crystal. The crystal thus precipitated was taken out by filtration, and was washed with a cold ethanol to obtain 0.3 g of the aimed product (Compound No. 20) having a melting point of from 162.3° to 164.3° C.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.C1COCC1.[O:14]=[C:15]1[N:21]2[C@H:17]([CH2:18][C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:35][Si](CC)(CC)CC)[CH:29]=3)=[C:20]2[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[C@H:16]1[C@H:43]([O:45][Si](CC)(CC)CC)[CH3:44].C(=O)([O-])O.[Na+]>O>[OH:45][C@@H:43]([C@H:16]1[C:15](=[O:14])[N:21]2[C@@H:17]1[CH2:18][C:19]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][OH:35])[CH:29]=1)=[C:20]2[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH3:44]
Reactant: C=CCOC(=O)C1=C(c2cccc(CO[Si](CC)(CC)CC)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(c2cccc(CO)c2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 1 h

Procedure:
Anhydrous trifluoromethanesulfonic acid was added to THF (7 ml) and water (4 ml), and the solution was adjusted to pH2.2. To the solution was added at 0° C. allyl (5R,6S)-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-3-(3-{[(triethylsilyl)oxy]methyl}phenyl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (520 mg). After stirring for 1 hour, thereto was added a saturated aqueous sodium hydrogencarbonate solution, and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give allyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-[3-(hydroxymethyl)phenyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate. This product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11][C:12]1([CH3:19])[C:16]([CH3:18])([CH3:17])[O:15][BH:14][O:13]1.CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:10][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[C:7]([CH3:8])[C:2]=1[B:14]1[O:15][C:16]([CH3:18])([CH3:17])[C:12]([CH3:19])([CH3:11])[O:13]1
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(O)cc(C)c1B1OC(C)(C)C(C)(C)O1
Yield: 180.3 %

Procedure:
Following the procedure described in Example 220, step a, reaction of 4-bromo-3,5-dimethyl-phenol (1.5 gm, 7.6 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.3 mL, 23 mmol, Aldrich Chemical Company), PdCl2(PPh3)2 (530 mg, 0.76 mmol, Strem Chemicals Inc, Newburyport, Mass.), Et3N (634 μL, 46 mmol), and dioxane (30 mL) afforded 3.4 gm of a tan glassy solid after chromatography (50 gm, silica SPE column) which was used without further purification. 1H-NMR (CDCl3; 400 MHz): δ 6.4 (s, 2H), 2.3 (s, 6H), 1.4 (s, 12H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:7](=[O:14])[CH:8]=[CH:9][C:10](=[O:13])[C:11]=2[CH:12]=1)[CH3:2].CN(C)[N:18]=[CH:19][C:20]([CH3:22])=[CH2:21]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:7](=[O:14])[C:8]3[C:9]([C:10](=[O:13])[C:11]=2[CH:12]=1)=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=3)[CH3:2]
Reactant: CCc1cc2c([nH]c1=O)C(=O)C=CC2=O
Reactant: C=C(C)C=NN(C)C
Solvent: ClC(Cl)Cl
Product: CCc1cc2c([nH]c1=O)C(=O)c1ncc(C)cc1C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.2 %

Procedure:
A suspension of 3-ethyl-1H-quinoline-2,5,8-trione (200 mg, 0.99 mmol) in chloroform (40 ml) is treated with 145 mg (1.3 mmol) of 2-methylpropenal dimethylhydrazone. The reaction was stirred at room temperature for 5 minutes and evaporated, and the residue was chromatographed on silica gel, eluting with ethyl acetate, to yield 120 mg (45%) of 7.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:31]=[C:32]([NH:36][C:37](=[O:53])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(COC)OC>[NH2:1][C:2]1[C:3]([C:40]2[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=2)[C:37]([NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([OH:29])[CH:31]=2)=[O:53])=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cccc(C(=O)Nc3cccc(O)c3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cccc(C(=O)Nc4cccc(O)c4)c3)n(-c3ccccc3)c(=O)c12
Yield: 16 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (55 mg, 0.12 mmol) was treated with N-(3-hydroxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (106 mg, 0.31 mmol, prepared from 3-bromo-N-(3-hydroxyphenyl)benzamide and bis(pinacolato)diboron according to Preparation 119b), sodium carbonate (40 mg, 0.38 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (6 mg, 0.01 mmol) in water (1 ml) and dimethoxyethane (3 ml) according to the method described in Example 3 to give 11 mg (15% yield) of the title compound. Purity 100%.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:6]([N+:15]([O-])=O)=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>C1(C)C=CC=CC=1.[Pd]>[NH:15]1[C:6]2[C:5](=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])[CH:4]=[CH:3]1
Reactant: [H][H]
Reactant: COC(=O)c1cccc(/C=C/N(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2cc[nH]c12

Procedure:
A solution of methyl 3-[2-(E)-(dimethylamino)ethenyl]-2-nitrobenzoate (12.0 g, 48 mmol) in toluene (200 ml) was hydrogenated at 60 psi over 10% palladium on charcoal (1.5 g) until hydrogen uptake ceased. The catalyst was filtered off, the filtrate was evaporated and the residue was chromatographed on silica to give the product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([NH2:38])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1>C1COCC1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2([NH:38][C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])[N:5]=[C:4]([NH:14][C:15]4[CH:16]=[CH:17][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[CH:26][CH:27]=4)[N:3]=3)[CH2:36][CH2:37]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: NC1(c2ccc(Cl)cc2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Yield: 37.8 %

Procedure:
To a slurry of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (3.6 g) and 1-(4-chlorophenyl)cyclopropanamine (1.49 g) in THF (50 mL) was stirred for 5 hours at 80° C. The precipitate was filtrated through a plug washing with THF to give acrude product that was purified by Biotage eluting with 4/1-hexane/ethyl acetate to give 1.8 g of tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate as a solid.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:16][N:17]([CH2:19][CH:20]([OH:30])[CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH3:18]>C(O)CCC.CO>[NH:1]([C:8]1[N:13]=[C:12]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH2:21][CH:20]([OH:30])[CH2:19][N:17]([CH3:16])[CH3:18])=[CH:24][CH:25]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc(Nc2ccccc2)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Solvent: CCCCO
Solvent: CO
Product: CN(C)CC(O)COc1ccc(Nc2ccnc(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 65.7 %

Procedure:
2-Anilino-4-chloropyrimidine (145 mg, 0.71 mmol) was dissolved in n-butanol (20 ml). To this solution was added a hot solution of 4-[3-(N,N-dimethyl)amino-2-hydroxy-propoxy]aniline hydrochloride (Reference Example D-1; 178 mg, 0.63 mmol) in methanol (2 ml). The reaction mixture was heated at 80° C. for 18 hours, allowed to cool to ambient temperature and then evaporated onto silica (3 ml). The residue was purified by column chromatography eluting with 0–8% 2.0M methanolic ammonia solution in DCM to give the title product as a colourless solid (157 mg, 65%). NMR (300 MHz): 2.18 (s, 6H), 2.33 (m, 2H), 3.83 (m, 3H), 4.77 (d, 1H), 6.11 (d, 1H), 6.86 (m, 3H), 7.19 (m, 2H), 7.51 (d, 2H), 7.69 (d, 2H), 7.96 (d, 1H), 9.01 (s, 1H), 9.08 (s, 1H); m/z: (ES+) 380.4 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>ClCCl>[N:21]1([S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 65 %

Procedure:
4-(Chlorosulfonyl)benzoic acid (CAS 10130-89-9) (441 mg, 2.0 mmol) and triethylamine (202 mg, 2.0 mmol) are dissolved in dichloromethane (20 mL) and stirred under nitrogen while piperidine (340 mg, 4.0 mmol) in dichloromethane (5 mL) is added to the mixture at room temperature. After 18 h the reaction mixture is concentrated. The crude material is slurried in aqueous NaHCO3, washed with diethyl ether, and separated. Ethyl acetate is added to the aqueous layer and the pH adjusted to 2 with 1N HCl. The layers are separated and the aqueous layer is extracted with EtOAc (2×). The EtOAc extracts are combined, washed with brine, dried over Na2SO4 and evaporated. The residue is purified by silica-gel column chromatography (0-8% MeOH/CH2Cl2 gradient) to give 350 mg (65%) of the title compound. MS (ES+) 270.1 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:35])[C:29]5[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1cccnc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1cccnc1

Procedure:
The title compound, white solid (18.3 mg, 51.4%), MS (ISP) m/z=437.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 mmol) and nicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28].Cl.CCOCC>C1COCC1>[ClH:1].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:10]1[CH2:11][CH2:12][C:7]2[NH:6][C:5]3[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=3[C:8]=2[CH2:9]1)=[O:28]
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2.00 ml). 2-Chlorobenzoyl chloride (0.04 mL, 0.29 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 20 (47 mg, 51% yield) as a pale yellow solid. LC-MS (M+H=347, obsd.=347).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH:13]=[CH:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][CH:33]=1>>[NH:8]1[CH:12]=[C:11]([CH:13]=[CH:14][CH2:15][O:16][CH2:40][CH2:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)[N:10]=[CH:9]1
Reactant: CCCc1ccc(F)cc1
Reactant: [O-]CC=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: Fc1ccc(CCCOCC=Cc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)-2-propenolate and of 3-(4-fluorophenyl)propane chloride are treated as described in Example 5.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:15])[CH:5]=1)(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1.C(N(CC)CC)C>CCCCCCC>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]([OH:29])([C:25]([F:26])([F:27])[F:28])[CH2:2][C:1]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:15])[CH:5]=2)=[O:3])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1C
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
0.63 g of ethyl 4-acetyl-2-methylbenzoate, 0.73 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 0.73 g of n-heptane and 0.30 g of triethylamine were fed and the mixture was stirred for 4 hours at 60° C. The mixture was left to cool, and further stirred for one night at room temperature. 0.53 g of n-heptane was added to the slurry-state reaction solution, and the mixture was filtered under reduced pressure. The solid was washed with a small amount of n-heptane, and dried under reduced pressure. 0.97 g of ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoate as a light yellow solid was obtained by drying under reduced pressure.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:20](=[O:30])[C@H:19]([NH:31]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:31][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:20]1=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2ccccn2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2ccccn2)C1=O
Reaction time: 18 h

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(pyridin-2-ylmethyl)azepan-3-ylcarbamate (202 mg, 0.468 mmol) in dichloromethane (4 mL). After 18 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 332.2 (M+1).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([O:18]CC)=O)=[C:4]12.[CH:21]1([C:24](=[N:26]O)[NH2:25])[CH2:23][CH2:22]1.C(Cl)Cl>C(O)C>[CH:21]1([C:24]2[N:26]=[C:16]([C:15]3[N:14]=[CH:13][N:5]4[C:6]5[CH:12]=[CH:11][S:10][C:7]=5[C:8](=[O:9])[N:3]([CH3:2])[C:4]=34)[O:18][N:25]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ncn2c3ccsc3c(=O)n(C)c12
Reactant: NC(=NO)C1CC1
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(=O)c2sccc2n2cnc(-c3nc(C4CC4)no3)c12
Temperature: 25 °C

Procedure:
Sodium (50 mg) was dissolved in dry ethanol (20 ml). Ethyl 4,5-dihydro-4-methyl-5-oxo-imidazo[1,5-a]thieno[2,3-e]-pyrimidine-3-carboxylate (0,55 g, 2 mmole), cyclopropanecarboxamide oxime (0,5 g, 5 mmole), and 5 g crushed mol. sieves 4 Å were added. The mixture was refluxed for 6 hours, then cooled to room temperature, where methylene chloride was added (30 ml). The mol. sieves were filtered off and the filtrate was reduced to 5 ml by evaporation in vacuo. Addition of water (25 ml) afforded a crystalline precipitate of the title compound which was collected by filtration. M.p. 215°-21° C. (Compound 8).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: Oc1ccccc1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-c2nc(N)nc(Oc3ccccc3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, phenol and DBU in DME. ES-MS m/e (%): 379 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18](I)[CH3:19]>CC(C)=O>[CH3:17][CH:18]([O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: CC(C)I
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cccc(OC(C)C)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
1-(3-Hydroxyphenyl)ethanone (1.36 g, 10 mmol) was dissolved in acetone (50 mL) and potassium carbonate (2.76 g, 20 mmol) and 1-methylethyl iodide (1.5 mL, 15 mmol) were added sequentially, and the mixture was stirred at 70° C. overnight. The reaction solution was filtered, washed with acetone and concentrated in vacuo. The obtained residue was added water and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with 1N aqueous solution of sodium hydroxide and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. 1-(3-(1-methylethoxy)-phenyl)ethanone (1.67 g (yield 94%)) was obtained as a yellow oil.