Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.Cl.[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[C:22](=[O:23])[C:21]([N:24]3[CH:28]=[CH:27][N:26]=[N:25]3)=[CH:20][NH:19]2)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:11].[ClH:1].[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:12]2[N:17]=[CH:16][N:15]=[C:14]([N:18]3[C:22](=[O:23])[C:21]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)=[CH:20][NH:19]3)[CH:13]=2)[CH2:6]1
Reactant: CN(C)C1CNC1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CN(c2cc(-n3[nH]cc(-n4ccnn4)c3=O)ncn2)C1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
271 mg (1.5 mmol) of N,N-dimethylazetidine-3-amine dihydrochloride, 400 mg (1.5 mmol) of the compound from Example 12A and 847 mg (6.1 mmol) of potassium carbonate are suspended in 8 ml of N,N-dimethylformamide and stirred at 100° C. for 16 h. The reaction mixture is concentrated under reduced pressure and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% strength trifluoroacetic acid). Further purification is carried out by preparative HPLC (RP 18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% strength formic acid). 2 ml of 1 N hydrochloric acid is added to the product-containing fractions, and the mixture is stirred at RT for 1 h. The solid is filtered off and dried under high vacuum. Yield: 62 mg (17% of theory)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1.O>CN(C=O)C.C(O)(=O)C>[C:25]1([C:23]2[N:24]=[C:20]([CH2:19][O:3][C:4]3[CH:17]=[CH:16][C:7]([CH2:8][CH:9]4[S:13][C:12](=[O:14])[NH:11][C:10]4=[O:15])=[CH:6][CH:5]=3)[S:21][CH:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClCc1nc(-c2ccccc2)cs1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(OCc3nc(-c4ccccc4)cs3)cc2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Sodium hydride (60% in oil, 1.2 g) was added to a solution of 5-(4-hydroxybenzyl)-2,4-thiazolidinedione (3.4 g) in DMF (30 ml), and the mixture was stirred at room temperature for 30 minutes, followed by dropwise addition of a solution of 2-chloromethyl-4-phenylthiazole (4.4 g) in DMF (20 ml) at room temperature. The mixture was stirred at room temperature for 1 hour and at 60° C. for 1 hour, poured into water, neutralized with acetic acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was then distilled off and the oily residue was subjected to column chromatography using silica gel (100 g). Elution with benzene-acetone (25:1, v/v) gave 5-[4-(4-phenyl-2-thiazolylmethoxy)benzyl]-2,4-thiazolidinedione (2.9 g, 49.2%). Recrystallization from ethanol gave light-yellow crystals. M.p. 164°-165° C.
Reaction SMILES: [Zn:1].[Br:2]CCBr.Cl[Si](C)(C)C.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=1>O1CCCC1>[Br-:2].[F:23][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20])[CH2:12][Zn+:1]
Reactant: [Zn]
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Reactant: BrCCBr
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: Fc1cc(C[Zn+])ccc1C(F)(F)F
Product: [Br-]
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
In a dried flask was zinc powder (3.05 g, 46.69 mmol) suspended in anhydrous tetrahydrofuran (25 mL) under nitrogen. The resulting suspension was warmed to 60° C., then 1,2-dibromoethane (0.168 mL, 1.95 mmol) was added and stirred at that temperature for 15 min. It was cooled to room temperature, then chlorotrimethylsilane (0.2 mL, 1.58 mmol) was added and stirred at room temperature for 1 h 15 min. Then, 4-(bromomethyl)-2-fluoro-1-(trifluoromethyl)benzene (10 g, 38.91 mmol) in tetrahydrofuran (5 mL) was added in 6 equal portions every 10 minutes under ice-cooling. After complete addition the ice-bath was removed and the reaction mixture stirred at room temperature for 18 h. Then was stirring switched off to let the solids settle. The supernatant was used in next transformation.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2>[Pd].CO.C(OCC)(=O)C>[S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2
Reactant: O=C(O)C=Cc1csc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CCc1csc2ccccc12

Procedure:
A suspension of 3-benzo[b]thiophen-3-yl-acrylic acid: (5.6 g, 0.027 mol) and 10% Pd/C (600 mg) in 1:1 methanol/ethyl acetate (50 mL) was hydrogenated in a Parr apparatus at 50 psi overnight. The mixture was filtered and concentrated to give the crude product without further purification (ca. 100% conversion). Mass spec.: 205(MH)−.
Reaction SMILES: FC(F)(F)C(O)=O.C(Cl)Cl.[C:11]([NH:19][C:20]1[CH:21]=[C:22]([CH:40]=[CH:41][C:42]=1[C:43]([O:45]C(C)(C)C)=[O:44])[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29](C(OC(C)(C)C)=O)[CH:28]=[CH:27]2)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:11]([NH:19][C:20]1[CH:21]=[C:22]([O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][CH:28]=[CH:27]3)[CH:40]=[CH:41][C:42]=1[C:43]([OH:45])=[O:44])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccc3c(ccn3C(=O)OC(C)(C)C)c2)cc1NC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cc(Oc2ccc3[nH]ccc3c2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 mL of trifluoroacetic acid was added to 4.0 mL of methylene chloride solution containing the obtained tert-butyl 5-(3-(benzamido)-4-(tert-butoxycarbonyl)phenoxy)-1H-indole-1-carboxylate while ice-cooled and stirred at the same temperature for 2 hours and 30 minutes. After the reaction mixture was warmed to room temperature, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added. The aqueous layer was separated and washed with ethyl acetate after adjusted to pH 6.5 with 6.0 mol/L hydrochloric acid and allowed to stand still for 17 hours. A solid substance was separated by filtration to obtain 10 mg of 2-(benzamido)-4-(1H-indol-5-yloxy)benzoic acid as white solid.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH2:11]Cl)=[CH:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[CH3:38])([CH3:29])[CH3:28])[CH3:24].[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:11][C:10]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH:9]=2)=[CH:33][C:32]=1[CH3:38])([CH3:28])[CH3:29])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
To a solution of 400 mg (1.22 mmol) 4-butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 115C]) and 290 mg (1.22 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) in 4 ml DMF was added 90 mg (2.06 mmol) of sodium hydride (55% in oil). The reaction mixture was stirred for 2 h at RT, taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 to provide 347 mg pure 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH3:16]>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCOc1ccc(S(N)(=O)=O)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 ml of methanolic ammonia solution are added dropwise with ice-cooling to 10 g of 4-n-butoxybenzenesulfonyl chloride. After stirring at 20° C. for 1/2 hour, the mixture is concentrated, the residue is treated with water, acidified to pH 1-2 and filtered off with suction, M.p. 99°-101° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[Li+].[Li+].[C:7]1([CH:15]=[CH:14][CH:13]=[C:11]([OH:12])[C:9]=1[OH:10])[OH:8].CI.O>CN(C)C=O>[CH3:1][O:10][C:9]1[C:7]([OH:8])=[CH:15][CH:14]=[CH:13][C:11]=1[OH:12]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(O)c1O
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(O)cccc1O
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 39.9 %

Procedure:
Lithium carbonate (281 mg, 1.98 mmol) was added to pyrogallol (100 mg, 0.79 mmol) in N,N-dimethylformamide (3.0 mL) at room temperature. After 5 minutes, methyl iodide (130 μL, 1.98 mmol) was added and the resulting solution was heated to 50° C. for 48 hours. Upon cooling to room temperature, water (20 mL) was added and the solution was extracted with EtOAc (3×20 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 5:1→1:1 Hexane:EtOAc) to afford 19 as a colorless amorphous solid (44.2 mg, 34%): 1H NMR (CDCl3, 400 MHz) 6.89 (td, J=8.0, 0.9 Hz, H), 6.53 (dd, J=8.2, 0.8 Hz, 2H), 5.83 (bs, 2H), 3.90 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:5]=[N:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(Cl)Cl>[C:16]([O:20][C:21]([NH:23][C@H:24]1[CH2:28][CH2:27][N:26]([S:12]([C:10]2[C:11]3[C:2]([Br:1])=[CH:3][N:4]=[CH:5][C:6]=3[CH:7]=[CH:8][CH:9]=2)(=[O:14])=[O:13])[CH2:25]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
A solution of 4-bromo-5-isoquinolinesulfonyl chloride (0.50 g) prepared according to a known method (described in Japanese Patent No. 2763791), and (S)-3-(tert-butoxycarbonylamino)pyrrolidine (0.33 g, Tokyo Kasei Kogyo) in methylene chloride (5 ml) was added with triethylamine (0.68 ml, Wako Pure Chemical Industries) at 0° C., and the mixture was stirred at the same temperature for 30 minutes, and then further stirred at room temperature for 5 hours. The reaction mixture was washed with saturated brine (10 ml), and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (0.62 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:8])[NH:6][CH:7]=1.C.[Cl:18][CH2:19][C:20](Cl)=[O:21].[OH-].[Na+]>O>[C:9]([C:4]1[C:3]([NH:2][C:20](=[O:21])[CH2:19][Cl:18])=[CH:7][NH:6][C:5]=1[CH3:8])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1[nH]cc(N)c1C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]cc(NC(=O)CCl)c1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
4-Amino-3-benzoyl-2-methylpyrrole hydrochloride (0.019 mole) was dissolved in water (40 ml) and the solution was treated with charcoal (0.1 g) and filtered. Toluene was added and chloroacetylchloride (0.067 mole) and aqueous NaOH (58.1 ml, 20% w/v) were added separately but simultaneously during 1 hour to the stirred two-phase solution. The reaction mixture was maintained under an inert atmosphere and at room temperature for 1.5 hour. The compound of the title which spontaneously crystallized out of the reaction mixture, was collected by filtration.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([OH:13])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH:12]([O:13][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10][N:9]([CH3:14])[C:8]2=[O:15])=[N:4][N:3]=1
Reactant: Cc1nnc(N2C(=O)N(C)CCC2O)s1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C)C(=O)N1c1nnc(C)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2 (1H)-pyrimidinone (0.1 mole), acetic anhydride (0.11 mole), toluenesulfonic acid (0.05 gram) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is heated on a steam bath with stirring for a period of about 2 hours. After this time the reaction mixture is cooled to room temperature and is stripped of solvent under reduced pressure leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-methyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acetyloxy-2 (1H)-pyrimidinone.
Reaction SMILES: [H-].[Na+].N1C=[CH:6][N:5]=[N:4]1.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][C@@H:15]([C:17]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[CH2:19][O:18]1)[CH3:16].O.[CH3:29][N:30](C)C=O>>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[C:17]([OH:18])([C@H:15]([O:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1)[CH3:16])[CH2:19][N:5]1[CH:6]=[N:30][CH:29]=[N:4]1
Reactant: c1c[nH]nn1
Reactant: CN(C)C=O
Reactant: C[C@@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C[C@@H](OC1CCCCO1)C(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In dimethylformamide (50 ml) was dispersed 60% sodium hydride (2.64 g) in mineral oil, to which was added, under ice-cooling, triazole (6.84 g), and the mixture was stirred for 15 minutes. To the mixture was added a dimethylformamide solution (10 ml) of 2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]-2-(2,4-difluorophenyl)oxirane (4.7 g). The resultant mixture was heated for 3 hours at 80° C. The reaction mixture was cooled, which was then poured into cold water (200 ml), followed by extraction with ethyl acetate (150 ml) three times. Ethyl acetate layers were combined, washed with water (100 ml×3) and a saturated aqueous solution (100 ml) of sodium chloride successively, and dried over anhydrous sodium sulfate, followed by distilling off the solvent. The residue was purified by means of a silica gel chromatography (eluent: dichloromethane-ethyl acetate-acetone=6:1:1) to afford (3R)-2-(2,4-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-(1H- 1,2,4-triazol-1-yl)-2-butanol (4.4 g) as a colorless viscous oil.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].S([O-])([O-])(=O)=O.[Mg+2]>[N+](C)([O-])=O.CCOCC>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: COc1ccc(C(C)=O)cc1
Temperature: 21 °C
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
The scandium salt of dibutylaminosulfonylmalononitrile, obtained in Example 40, was used as catalyst in a Friedel-Crafts reaction of acylation, by operating in the following manner. In 40 ml of anhydrous nitromethane, there is added 570 mg (700 μmoles) of Sc(DBSM)3, and 1.08 g (10 mmoles) of anisol and 2.04 g of acetic anhydride. After stirring during 10 min at 21° C., the reaction mixture was diluted with 50 ml of ether and the reaction was inhibited by using 100 ml of a saturated solution of sodium bicarbonate NaHCO3. After filtration on Celite, the solution was extracted with three fractions of 50 ml of ether, and the collected ether phase was washed with a saturated solution of potassium chloride. After drying the ether phase with magnesium sulfate and evaporation, 1.46 g of p-methoxyacetophenone (97% yield) was recovered, with a purity characterized by a proton RMN higher than 99%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:8][CH2:9][C:10](=O)[CH3:11])[CH3:2].[NH2:21][C:22]1[C:27]([CH:28]=O)=[CH:26][CH:25]=[CH:24][N:23]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:28][C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1)[CH3:2]
Reactant: CCOC(=O)CN(CCCC(C)=O)C(=O)OC(C)(C)C
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CN(CCCc1ccc2cccnc2n1)C(=O)OC(C)(C)C

Procedure:
A solution of 2-6 (28 g, 97.4 mmol), 2-amino-3 formylpyridine (15.5 g, 127 mmol), proline (11.2 g, 97.4 mmol) in ethanol (250 mL) was heated at reflux for 15 h. After cooling and evaporation, the residue was chromatographed (silica gel, 1:1 chloroform/ethyl acetate) to give 2-7 as a yellow oil. TLC Rf =0.41 (silica, 70:25:5 chloroform/ethyl acetate/methanol) 1H NMR (300 MHz, CDCl3) δ 9.09 (m, 1H), 8.14 (m, 2H), 7.43 (m, 2H), 4.17 (q, 2H, 7 Hz), 3.9 (2s, 2H), 3.43 (q, 2H, J=7 Hz), 3.07 (m, 2H), 2.18 (m, 2H), 1.42 (s, 9H), 1.25 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=[O:22])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:23](O)[CH3:24]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=[O:22])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:23][CH3:24])=[O:7]
Reactant: CCC1CCC(=O)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(C2=CC(=O)CCC2CC)c(Cl)c1Cl

Procedure:
A stirred solution of [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid (3.43 g, 0.01 mole) in ethanol (50 ml) containing sulfuric acid (4 drops) was heated at reflux for 4 hours. The ethanol was evaporated at reduced pressure, the residue dissolved in ether, washed with dilute sodium hydroxide, water, dried over magnesium sulfate and evaporated in vacuo to give 3.31 g of ethyl [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)-phenoxy]acetate which melted at 110°-112° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](C=C[CH:26]=1)[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][C:17]([CH3:23])([CH3:22])[CH2:16]1)=[O:13])=O)([O-:3])=[O:2].[NH2:27]/[C:28](/[CH3:35])=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31].[CH2:36](O)[CH3:37]>>[CH3:36][C:37]1[NH:27][C:28]([CH3:35])=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:9]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:26]=2)[C:11]=1[C:12]([O:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][C:17]([CH3:22])([CH3:23])[CH2:16]1)=[O:13]
Reactant: CC1CC(OC(=O)CC(=O)C=Cc2cccc([N+](=O)[O-])c2)CC(C)(C)C1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC2CC(C)CC(C)(C)C2)C1c1cccc([N+](=O)[O-])c1
Temperature: -5 °C
Yield: 37 %

Procedure:
21.87 g (0.06 moles) of 3,3,5-trimethylcyclohexyl 2-(3-nitrobenzylidene)acetylacetate and 7.84 g (0.06 moles) of ethyl 3-aminocrotonate are heated under reflux in 60 ml of ethanol for 8 hours. The solution is then cooled to -5° C. to obtain 3,3,5-trimethylcyclohexyl 2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate as yellow crystals melting--after recrystallisation in ethanol--at 125°-129° C. The yield is 37% of the theoretical yield.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[C:11]([CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([OH:15])=[O:14])=[C:10]([OH:19])[N:9]=[C:8]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:7]=1.[CH3:26]O>>[O:5]=[C:6]1[CH:11]([CH:12]([CH2:16][CH2:17][CH3:18])[C:13]([O:15][CH3:26])=[O:14])[C:10](=[O:19])[NH:9][C:8]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:7]1
Reactant: CCCC(C(=O)O)c1c(O)nc(N2CCCCC2)nc1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCC(C(=O)OC)C1C(=O)N=C(N2CCCCC2)NC1=O

Procedure:
To a solution cold solution of methanol (50 mL) was added thionyl chloride (7.25 mL; 100 mmol) dropwise. The acidic solution was added to a flask containing 2-(4,6-dihydroxy-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoic acid (3.07 g; 10.4 mmol) and the mixture was heated to reflux for 18 h. The reaction mixture was concentrated under reduced pressure and the product was used as such in the next reaction.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH:13]([C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18])([CH3:15])[CH3:14].[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:27]2>C(N(CC)CC)C.ClCCl>[C:37]([O:36][C:34]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][CH:33]=[C:24]([NH:23][C:2]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[CH:13]([CH3:15])[CH3:14])=[O:4])[CH:25]=2)[CH2:30]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)c1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1NC(=O)Nc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 2 h
Yield: 201.8 %

Procedure:
To a dichloromethane (10 mL) solution of triphosgene (474 mg), a dichloromethane (10 mL) solution of 2-isopropylaniline (540 mg) and triethylamine (1.2 mL) was gradually added at room temperature. After 2 hours, a dichloromethane (10 mL) solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (993 mg) and triethylamine (1.2 mL) was added thereto. The reaction mixture was stirred for 30 minutes and concentrated. The residue was purified by chromatography (dichloromethane/ethyl acetate) to obtain the title compound (1.32 g, 81%) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([Br:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 103.1 %

Procedure:
To a solution of 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.71 mmol) (as prepared in the previous step) in DCM (3 mL) was added N-bromosuccinimide (NBS) (0.13 g, 0.71 mmol), and the reaction stirred at RT for 10 h. The reaction was diluted with EtOAc (10 mL) and washed with NaHCO3 (2×10 mL) and brine (10 mL). Concentration of the organic layer gave 0.26 g (100%) of the title compound as a yellow foam. Mass spectrum (ESI, m/z): Calcd. for C16H23BrN2O2, 355.1 (M+H), found 355.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:34][CH2:33][C:29]4[CH:28]=[C:27]([C:26]([F:36])([F:25])[F:35])[CH:32]=[CH:31][N:30]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: NCc1cc(C(F)(F)F)ccn1
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCc4cc(C(F)(F)F)ccn4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), 4-trifluoromethyl-pyridin-2-ylmethylamine and DIEA to give 4-ethoxy-6-[4-oxo-2-[(4-trifluoromethyl-pyridin-2-ylmethyl)-amino]-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 484 (MH+).