Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:44][S:45]([CH2:48][CH2:49][CH2:50][O:51][C:52](=[O:54])[CH3:53])(=[O:47])=[O:46].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH:44][S:45]([CH2:48][CH2:49][CH2:50][O:51][C:52](=[O:54])[CH3:53])(=[O:46])=[O:47])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(Cl)cc3)c12)c1ccc(C(=O)O)cc1
Reactant: CC(=O)OCCCS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4ccc(Cl)cc4)c23)cc1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a mixture of 4-[(1S)-1-({[1-(4-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid (250 mg) and DMF (5 mL) was added 1,1′-carbonyldiimidazole (187 mgl) at room temperature, followed by stirring for 5 minutes, and then 3-(aminosulfonyl)propylacetate (209 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (173 μL) were added in this order, followed by stirring for 3 days. The reaction mixture was ice-cooled, and 10% aqueous citric acid (30 mL) was added thereto, followed by stirring for 30 minutes. The precipitated solid was collected by filtration and washed with cold ethanol (4 mL) to obtain 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-acetoxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (210 mg) as a pale yellow solid.
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][C:33]1[S:34][C:35]([C:39]([C:41]2[N:45]([CH3:46])[N:44]=[N:43][CH:42]=2)=[O:40])=[C:36]([CH3:38])[N:37]=1.O>O1CCCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:35]3[S:34][C:33]([CH3:32])=[N:37][C:36]=3[CH3:38])([C:41]3[N:45]([CH3:46])[N:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1nc(C)c(C(=O)c2cnnn2C)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2ccc(C(O)(c3sc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 0.47 mL, 1.2 mmol) was added dropwise to a stirring solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (500 mg, 1.2 mmol, Intermediate 10) in tetrahydrofuran (9 mL) at −78° C. After 5 minutes, a solution of (2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (259 mg, 1.2 mmol, Intermediate 23: step b) in tetrahydrofuran (2 mL) was added dropwise. After 2 minutes, the flask was placed into an ice-water bath. After 90 minutes, water (4 mL) was added and the mixture was allowed to warm to 23° C. The biphasic mixture was partitioned between saturated aqueous sodium chloride solution (20 mL) and ethyl acetate (50 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (5 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with 40% ethyl acetate-hexanes initially, grading to 90% ethyl acetate-hexanes provided the title compound as an off-white foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (d, J=2.2 Hz, 1H), 7.89-7.81 (m, 2H), 7.67 (d, J=1.7 Hz, 1H), 7.59-7.54 (m, 2H), 7.54-7.48 (m, 1H), 7.41-7.34 (m, 2H), 7.23 (s, 1H), 6.45-6.41 (m, 1H), 4.32 (s, 2H), 4.11 (s, 3H), 3.91 (s, 3H), 3.71 (s, 1H), 2.58 (s, 3H), 2.15 (s, 3H); MS (ESI): mass calcd. for C29H26ClN7O2S, 571.2. m/z found, 572.1 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([S:7]([CH:10]=[CH2:11])(=[O:9])=[O:8])=[CH2:6].[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:14]=1[NH2:15]>ClC1C=CC=CC=1>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:14]=1[N:15]1[CH2:11][CH2:10][S:7](=[O:9])(=[O:8])[CH2:5][CH2:6]1
Reactant: C=CS(=O)(=O)C=C
Reactant: Nc1c(F)cccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=S1(=O)CCN(c2c(F)cccc2F)CC1
Temperature: 110 °C

Procedure:
Aluminum chloride (310 g, 2.3 mol) is added to chlorobenzene (2.5 L) to give a cloudy green suspension. Vinyl sulfone (230 mL, 2.3 mol) is added via funnel, followed by 2,6-difluoroaniline (250 mL, 2.3 mol). The light brown solution is heated to 110° C. Upon completion of the reaction, the heat is removed and the black solution is self-cooled to 70° C. The reaction mixture is then quenched in methylene chloride (4 L) and ice water (5 L), the aqueous phase is extracted with methylene chloride (3 L, 2 L, 2 L, 2 L) and the combined organic layers are concentrated, rediluted with branched octane (3 L), and then cooled to 0° C. for 30 minutes. The solids are filtered and washed with branched octane (2×500 mL) and are then dissolved in methylene chloride (3 L) and loaded onto a silica gel plug (1.8 kg). The column is eluted with dichloromethane (16 L) until clear. The methylene chloride solution is concentrated, and the solids are dissolved in hot ethyl acetate (3 L) followed by the addition of hexanes (900 mL). The black solution is self-cooled to room temperature overnight, and the resulting light amber crystal needles are filtered and washed with hexanes (4×250 mL). The solids are dried under reduced pressure at 50° C. overnight to give the title compound, 1H NMR (CDCl3) δ 7.08 (m, 1H), 6.91 (m, 2H), 3.67 (m, 4H), 3.18 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])=[N:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
1.0 g of 4-hydroxy-1-indanone, 1.07 g of 2-chloro-5-nitropyridine and 5 g of anhydrous potassium carbonate were dissolved in 10 ml of N,N-dimethylformamide (DMF) and the mixture was stirred at room temperature for 17 hours. After the completion of the reaction, 50 ml of water was added to the reaction solution and the solution was extracted with ethyl acetate. After the organic (ethyl acetate) layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off. The resulting residue was recrystallized from ethyl acetate to obtain the titled compound (1.36 g, pale yellow powder).
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16]4[N:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=4)[CH:12]=3)[CH2:7]2)[C:5](=[O:25])[NH:4][C:3]1=[O:26].[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:27]1([C:22]([C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:15][C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[CH2:7][C:6]3([C:5](=[O:25])[NH:4][C:3](=[O:26])[N:2]3[CH3:1])[CH2:14]4)[CH:17]=2)=[O:24])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(Nc3cc(C(=O)O)ncn3)cc1C2
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)NC(=O)C12Cc1ccc(Nc3cc(C(=O)N4CCc5ccccc54)ncn3)cc1C2

Procedure:
80.0 mg (0.23 mmol) 6-(3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidin-4,2′-inden]-5′-ylamino)pyrimidine-4-carboxylic acid, 30 μL (0.27 mmol) 2,3-dihydro-1H-indole, 70 μL (0.50 mmol) triethylamine and 80.0 mg (0.25 mmol) TBTU in 1.5 mL DMF were stirred for 4 h at RT. The reaction mixture was filtered through a syringe filter and purified by preparative HPLC. The product fractions were combined, concentrated by rotary evaporation and dried.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:27]([F:28])=[CH:26][C:8]([O:9][C:10]2[CH:24]=[CH:23][C:13]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]3)=[O:15])=[CH:12][C:11]=2[F:25])=[C:7]([O:29][CH3:30])[CH:6]=1)[CH3:4].Br[CH2:32][C:33]([NH2:35])=[O:34].C(OCC)(=O)C>O1CCCC1.O>[CH2:3]([C:5]1[C:27]([F:28])=[CH:26][C:8]([O:9][C:10]2[CH:24]=[CH:23][C:13]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:32][C:33]([NH2:35])=[O:34])[C:18](=[O:22])[CH2:17]3)=[O:15])=[CH:12][C:11]=2[F:25])=[C:7]([O:29][CH3:30])[CH:6]=1)[CH3:4]
Reactant: NC(=O)CBr
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCN(CC(N)=O)C(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% in oil, 49 mg, 1.2 mmol) was added to a solution of 4-[4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoy]-piperazin-2-one (which may be prepared in accordance with the experimental described in Example 5, step 1; 400 mg, 1 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 15 minutes prior to the addition of 2-bromoacetamide (212 mg, 1.5 mmol). After stirring for 2 days at room temperature, the reaction mixture was diluted by addition of ethyl acetate (20 mL) and water (20 mL). After separation, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (2×20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (98:2 to 95:5) as eluent. The title product was obtained as a white solid (300 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a 4-(5-Chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (3.87 g, 8.06 mmol) (Example 313, Step 1) was dissolved in TFA (81 mL), trifluoromethanesulfonic acid (2.1 mL, 24 mmol) was added, and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was then concentrated in vacuo. The residue was partitioned between EtOAc (150 mL) and sodium bicarbonate (saturated, aqueous). The organic layer was the separated, washed 2 times with 100 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 40% EtOAc/hexanes) provided the title compound (51% yield). m/z (ESI, +ve ion) 240.1 (M+H)+.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.Br.C(=O)([O-])O.[Na+].[NH2:16][C:17]1[C:22]([Cl:23])=[N:21][CH:20]=[CH:19][N:18]=1>CC(O)C.C(OCC)C.O>[Cl:23][C:22]1[C:17]2[N:18]([CH:8]=[CH:9][N:16]=2)[CH:19]=[CH:20][N:21]=1
Reactant: Nc1nccnc1Cl
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CCOCC
Product: Clc1nccn2ccnc12
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
Bromoacetaldehyde diethyl acetal (45 ml, 0.29 mol) was treated with water (33 ml) and 48% hydrobromic acid (33 ml) and this mixture was heated at 95° C. for 90 min. The reaction was cooled, diluted with propan-2-ol (300 ml) and treated with sodium hydrogencarbonate (33 g) added in portions. This mixture was stirred for 30 min then filtered. The filtrate was treated with 2-amino-3-chloropyrazine (25 g, 0.19 mol) and then heated at 90° C. for 16 h. The reaction was cooled to ambient temperature, concentrated to about one-third volume and then treated with 48% hydrobromic acid (25 ml). More propan-2-ol (300 ml) was added and the mixture aged for 1 h. The resulting solid was collected by filtration, washed with propan-2-ol and then dissolved in water (500 ml). This solution was made basic by adding solid sodium hydrogencarbonate and then extracted with chloroform (3×250 ml). The organics were combined, dried over anhydrous magnesium sulphate, filtered and concentrated to give a solid. Trituration with diethyl ether afforded 8-chloroimidazo[1,2-a]pyrazine as an off-white solid (18.6 g, 63%): δH (360 MHz, DMSO) 7.73 (1H, d, J 4.5), 7.87 (1H, d, J 1), 8.28 (1H, d, J 1), 8.67 (1H, d, J 4.5).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]2[N:12]=[CH:13][CH:14]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])O.[Na+].[CH3:20][NH2:21]>C(O)C>[CH2:1]([C:5]1[CH:10]=[C:9]([NH:21][CH3:20])[N:8]2[N:12]=[CH:13][CH:14]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN
Reactant: CCCCc1cc(Cl)n2nccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCCc1cc(NC)n2nccc2n1
Temperature: 120 °C

Procedure:
5-n-Butyl-7-chloropyrazolo[1,5-a]pyrimidine (the compound prepared in step (2) of Reference Example 1; 8.60 g), sodium hydrogen carbonate (3.44 g) and 40% methylamine (3.18 g) were added to 50 ml of ethanol and heated at 120° C. for 2 hours. After completion of the reaction, ethanol was distilled off under reduced pressure. After addition of some water, the residue was extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:2) to provide 2.33 g of 5-n-butyl-7-methylaminopyrazolo[1,5-a]pyrimidine as crystals.
Reaction SMILES: [F-:1].C([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])CCCC)CCC.O.[CH2:20]1[CH2:24]OC[CH2:21]1>>[CH2:15]([N:6]1[CH2:11][CH2:12][C@H:13]([F:1])[CH2:14]1)[C:16]1[CH:17]=[CH:18][CH:24]=[CH:20][CH:21]=1
Reactant: C1CCOC1
Reactant: [F-]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: F[C@H]1CCN(Cc2ccccc2)C1
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of (R)-1-benzyl-3-pyrrolidinoltosylate (3.06 g, 9.24 mmol) in THF (30 ml) was added 1.0M solution of tetrabutylammonium fluoride in THF (37.0 ml, 37.0 mmol) at room temperature. After 1.5 h stirring at reflux temperature, water (150 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 ml×2). The combined extract was washed with water, brine, dried (Na2SO4), and concentrated to give brown oil, which was purified by column chromatography (silica gel: 80 g, CH2Cl2/MeOH:50/1) to afford 1.18 g (71%) of brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH2:18][N:19]([C:41]([C:40]3[S:39][C:38]4[CH:44]=[CH:45][CH:46]=[CH:47][C:37]=4[C:36]=3[Cl:35])=[O:42])[CH:20]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:22][CH2:21]3)[CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 19 (400 mg, 0.86 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (237 mg, 1.03 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](C#CCCCCC(O)=O)=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>>[NH2:1][C:2]1[C:3]([C:34]#[C:33][CH2:32][CH2:31][OH:35])=[N:4][C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: Cc1ccc(-c2nc(N)c(C#CCCCCC(=O)O)nc2-c2ccc(C)cc2)cc1
Reactant: C#CCCO
Product: Cc1ccc(-c2nc(N)c(C#CCCO)nc2-c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared analogously to 7-(3-amino-5,6-di-p-tolylpyrazin-2-yl)hept-6-ynoic acid (Ex 7 step 1) by replacing hept-6-ynoic acid with but-3-yn-1-ol;
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.CCN(CC)CC.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:37][CH:38]([C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=1)[C:39]1[CH:44]=[CH:43][C:42]([PH:45](=[O:47])[OH:46])=[CH:41][CH:40]=1>C(#N)C>[OH:1][C:2]1[C:7]([C:8]([NH:37][CH:38]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[C:39]2[CH:44]=[CH:43][C:42]([PH:45](=[O:46])[OH:47])=[CH:41][CH:40]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1O
Reactant: COc1ccc(C(N)c2ccc([PH](=O)O)cc2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C(NC(=O)c2cnc(-c3ccccn3)nc2O)c2ccc([PH](=O)O)cc2)cc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 6.6 %

Procedure:
To a solution of 4-hydroxy-2-(pyridin-2-yl)pyrimidine-5-carboxylic acid (1-1-h, 1.1 g, 5.1 mmol) in acetonitrile (20 ml) was added Et3N (1.02 g, 10.2 mmol). The mixture was aged for 15 min at room temperature. To the mixture was added CDI (800 mg, 5.1 mmol) and the resulting mixture was heated to 70° C. for 3 h. To the hot homogeneous solution was then added in one portion 4-(amino(4-methoxyphenyl)methyl)phenylphosphinic acid hydrochloride (1-1-e, 1.4 g, 5.1 mmol). Heating was continued for 2 h at 70° C. Then it was concentrated under vacuum and the residue was purified on prep-HPLC to provide the 1-1-6 (160 mg, 6%). 1H NMR (CD3OD, 300 MHz,): δ 13.35 (br, 1H), 8.80 (m, 1H), 8.62 (m, 2H), 8.45 (m, 1H), 7.23 (m, 7H), 7.79 (m, 2H), 6.52 (s, 1H), 6.25 (m, 1H), 3.70 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][C:16]=2[OH:20])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: COc1cccc(O)c1
Product: COc1ccc(C(=O)Cc2cccc(F)c2)c(O)c1
Temperature: 65 °C
Reaction time: 9 h

Procedure:
(3-Fluorophenyl)acetic acid (3.7 g) and 3-methoxyphenol (3.0 g) were dissolved into BF3Et2O (60 ml, 20 eq) under argon. The mixture was stirred at 60-70° C. until disappearance of the starting materials (9 h) and poured into large volume of ice water. After extraction with ethyl acetate the combined organic layers were washed with water, dried and evaporated. The crude product was purified by column chromatography using CH2Cl2 as an eluant. 1H NMR (400 MHz, d6-DMSO) δ: 12.41 (br s, 1H), 8.02 (d, 1H, J 9.0 Hz), 7.34-7.38 (m, 1H), 7.09-7.13 (m, 3H), 6.56 (dd, 1H, J 9.0, 2.5 Hz), 6.49 (d, 1H, J 2.5 Hz), 4.41 (s, 2H), 3.83 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH3:16][O:17]C1C=CC(C=O)=CC=1.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([O:17][CH3:16])=[CH:8][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(OC)cc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 4-methoxybenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][CH:9]=2)[N:4](COC)[CH:3]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:14][N:15]3[CH2:16][CH2:17][N:18]([C:21](=[O:28])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:19][CH2:20]3)[N:13]=2)=[N:4][CH:3]=1
Reactant: COCn1cc(Br)sc1=Nc1cccc(CN2CCN(C(=O)c3ccccc3)CC2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C(c1ccccc1)N1CCN(Cc2cccc(Nc3ncc(Br)s3)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.5 %

Procedure:
81 mg (0.161 mmol) of 1-(6-(5-bromo-3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridin-2-ylmethyl)-4-benzoyl-piperazine was dissolved in 10 ml of chloroform, a hydrochloric acid-1,4-dioxane solution (4 M, 4 ml) was added thereto and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, the residue was recrystallized from methanol-ether and filtered and the resulting white solid was dissolved in water (10 ml) and neutralized with sodium bicarbonate. The resulting precipitate was filtered to give 32 mg (0.070 mmol) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1)#[N:2].O[CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)=[O:12])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CCOC(=O)CCN1CCC(O)CC1
Product: CCOC(=O)CCN1CCC(OC(=O)c2cc3cc(C#N)ccc3o2)CC1
Yield: 37.1 %

Procedure:
In the same manner as in Example 75 (2), 5-cyano-2-benzofurancarboxylic acid (1.00 g, 5.34 mmol) was converted a corresponding acid chloride and reacted with ethyl 3-(4-hydroxypiperidino)propionate (1.08 g, 5.77 mmol). The reaction mixture was purified by silica gel column chromatography (chloroform) to give 733 mg of ethyl 3-[4-[(5-cyano-2-benzofuranyl)carbonyloxy]piperidino]propionate as a colorless solid (33%).
Reaction SMILES: Cl.[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([O:11][CH2:12][CH3:13])(=O)C.[CH2:14](O)[CH3:15]>>[C:4]1([C:15]2[CH:14]=[CH:7][C:6]3[C:13](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:12]=2[OH:11])[CH2:3][CH2:2][CH2:7][CH2:6][CH:5]=1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Reactant: CCO
Agent: Cl
Product: Oc1c(C2=CCCCC2)ccc2ccccc12
Yield: 62 %

Procedure:
A solution of the product of Part A (3.30 g, 0.012 mole) in ethanol (100 mL) and 1.0N hydrochloric acid (100 mL) was stirred at room temperature for 5 hours. The ethanol was removed under reduced pressure, and the crude product was isolated by extraction with ethyl acetate. Chromatography with 95:5 hexane/ethyl acetate provided a white solid which was recrystallized (hexane) to give the title compound (1.59 g, 62%) as white crystals, mp 82°-83°.