Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=O)=O.C([Li])CCC.[Si](Cl)(C(C)(C)C)(C)C.[C:25]1(=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>O1CCCC1.CCCCCC>[C:27]1([C:10]2[N:6]=[CH:7][NH:8][CH:9]=2)[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH:26]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: O=C1CCc2ccccc21
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C1=C(c2c[nH]cn2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(N,N-dimethylsulfamoyl)-1H-imidazole (1.9 g, prepared according to Chadwick, D. J. and Ngochindo, R. I., J. Chem. Soc., Perkin Trans. (1984, 481) in dry tetrahydrofuran (90 ml) at −70° C. under nitrogen, is added dropwise 2.5 M butyllithium in hexane (5.1 ml). After 30 minutes tert-butyldimethylsilyl chloride (2.0 g) in dry tetrahydrofuran (5 ml) is added and the mixture is allowed to warm to 25° C. After 1.5 hours the mixture is again cooled to −70° C. and treated with 2.5 M butyllithium in hexane (5.3 ml). After 30 minutes, 1-indanone (2.1 g) in dry tetrahydrofuran (5 ml) is added and the mixture is allowed to warm to room temperature. The reaction mixture is then quenched with saturated Na2CO3 solution (2 ml), and the solvent is removed under reduced pressure. The residue is dissolved in methylene chloride and washed with water, dried with sodium sufate and evaporated to dryness under reduced pressure. The bis-protected intermediate is refluxed with 2 N hydrochloric acid (200 ml) for 2 hours. The cooled solution is made basic by ammonium hydroxide solution, and extracted with methylene chloride. The organic layer is washed with water, dried with sodium sulfate and the solvent removed under reduced pressure. The crude product is purified by flash chromatography using methylene chloride-methanol as eluent. The product is converted to the hydrochloride salt in ethyl acetate-ethanol solution, m.p. 232-240° C.
Reaction SMILES: [Zn](CC)[CH2:2]C.[CH2:6]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19](=[CH2:22])[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(I)I>C1(C)C=CC=CC=1>[CH2:6]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19]2([CH2:2][CH2:22]2)[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[Zn]CC
Reactant: C=C1CCC(C(=O)OCc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: ICI
Product: O=C(OCc1ccccc1)C1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
Et2Zn (1.08 M solution in hexane, 5.23 ml, 5.65 mmol) was added to a solution of 4-methylene-cyclohexanecarboxylic acid benzyl ester (86.3 mg, 375 μmol) in toluene (1.4 ml), and the mixture was stirred at room temperature for 30 minutes. CH2I2 (500 μl, 6.22 mmol) was added to the reaction mixture at 0° C., and the mixture was stirred at 60° C. for 28 hours. Thereafter, Et2Zn (1.08 M solution in hexane, 2.60 ml, 2.22 mmol) and CH2I2 (260 μl, 3.23 mmol) were added to the reaction mixture, and the mixture was stirred at 60° C. for four days. Further, Et2Zn (1.08 M solution in hexane, 2.60 ml, 2.22 mmol) and CH2I2 (500 μl, 6.22 mmol) were added to the reaction mixture, and the mixture was stirred at 60° C. for one day. The reaction mixture was quenched by adding a 1% aqueous HCl solution and diluted with ethyl acetate and Et2O. The organic layer was then washed with a 1% aqueous HCl solution, a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→65/35) to give spiro[2.5]octane-6-carboxylic acid benzyl ester (70.6 mg, 77%).
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][C:22]([OH:24])=O)[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH:33]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([CH3:35])[CH3:34].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:33]([C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:22](=[O:24])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]2[CH:5]=[C:6]([C:14]([F:16])([F:15])[F:17])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=2)[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[CH:38][CH:37]=1)([CH3:35])[CH3:34]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)CCC(Cc2ccc(Cl)cc2)N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Reaction time: 18 h

Procedure:
A mixture consisting of 41.6 mg of 4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-pentanoic acid, 12.8 mg of 4-isopropylaniline, 36.65 mg of propanephosphonic acid anhydride, 37 mg of triethylamine and 1.5 ml of methylene chloride is left to stand at room temperature for 18 hours. 0.5 ml of 1N potassium carbonate solution is then added and the mixture is shaken vigorously. After separation of the phases, the organic phase is separated off and concentrated by evaporation. In this way the title compound is obtained in the form of a white foam. Rf value=0.26 (ethyl acetate)
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][NH:28][CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C>C(Cl)Cl>[C:33]([N:28]1[CH2:29][C:26]([CH2:30][C:31]#[N:32])([N:23]2[CH:24]=[CH:25][C:21]([C:9]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]4[CH:13]=[CH:14][C:15]5[N:16]([C:17]([CH3:20])=[N:18][N:19]=5)[C:11]=4[CH:10]=3)=[N:22]2)[CH2:27]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(CC#N)(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3ccccc3)n2)C1
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
To {3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (8.0 mg, 0.019 mmol, from Example 90) was added acetyl chloride (1.6 μL, 0.022 mmol, Aldrich) in DCM (0.50 mL), followed by triethylamine (5.3 μL, 0.038 mmol). The reaction was complete in 5 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded desired product (8.2 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:11]1.[Br:20]Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([Br:20])[C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:11]1
Reactant: BrBr
Reactant: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br
Reaction time: 1 h
Yield: 83.9 %

Procedure:
54.5 g (0.17 mol) of 1-(2,4,6-trichlorophenyl)-3-acetylamino-5-oxo-2-pyrazoline was dissolved in 300 ml of acetic acid, to which there was then gradually added dropwise 27.2 g (0.17 mol) of bromine. After stirring for 1 hour, the reaction mixture was poured into 900 ml of water and the crystals thus-separated were collected by filtration to obtain 57 g (84% yield) of 1-(2,4,6-trichlorophenyl)-3-acetylamino-4-bromo-5-oxo-2-pyrazoline.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]([OH:16])[CH3:15].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH2:13][CH:14]([O:16][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)COc1c([N+](=O)[O-])ccc(F)c1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)COc2c([N+](=O)[O-])ccc(F)c2F)cc1
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a solution of 4.5 g of the compound obtained in Example 5 in 8.6 ml of pyridine was added 4.36 g of p-toluenesulfonyl chloride and the mixture was stirred under cooling with ice for 4 hours, and then at room temperature for 4 hours. To the mixture were added ethyl acetate and 1 N hydrochloric acid. The mixture was shaken, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 6.52 g of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:22]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[S:12]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(N(Cc2ccccc2)S(=O)(=O)c2ccc(F)cc2)cc1OC
Reaction time: 8 h
Yield: 79.1 %

Procedure:
N-(3,4-Dimethoxy-phenyl)-4-fluoro-benzenesulfonamide (0.51 g, 1.61 mM) was added to a solution of benzyl bromide (0.57 g, 4.82 mM) and potassium carbonate (0.66 g, 4.82 mM)in anhyrous acetone(10 ml). The reaction was stirred overnight. The undissolved solids were removed by filtration and the mother liquor was concentrated. This gum was triturated with hexanes to afford 0.52 g of the desired product as an off-white solid. H1 NMR(CDCl3) δ 3.66(s, 3H), 3.81(s, 3H), 6.42(m, 2H), 6.66(d, 1H, J=8.70 Hz), 7.23(m, 7H), 7.71(m, 2H). MS(ES) m/z 401.9; (MH+); HRMS for C21H20SFNO4: 401.1094.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](OC)=[O:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:34])(=[O:33])[CH2:24][CH2:23]2)[CH:9]=1.O>O1CCCC1>[Cl:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][OH:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[S:25](=[O:34])(=[O:33])[CH2:24][CH2:23]2)[CH:9]=1
Reactant: COC(=O)c1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN(c2cc(Cl)c3cc(CO)ccc3n2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a slurry of lithium aluminum hydride (46 mg, 1.21 mmol) in tetrahydrofuran (5 mL) was added a solution of methyl 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinoline-6-carboxylate (400 mg, 0.96 mmol) in tetrahydrofuran (10 mL) at 0° C. under a nitrogen atmosphere. After being allowed to warm to room temperature and stirred for 2 hours, the reaction mixture was cooled to 0° C. and treated with water (0.2 mL) to quench the reaction. The resulting mixture was stirred for 30 minutes, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 321 mg of the desired product as a white solid (yield was 86%).
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]([O:11][CH3:12])=[N:8][C:7]([NH:13][CH:14]=[O:15])=[N:6][C:5]=2[N:4]([C@@H:16]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[C@@H:18]([O:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:17]2)[CH:3]=1.CC(C)C(O[C@@H]1[C@@H](COC(=O)C(C)C)O[C@@H](N2C3N=C(NC=O)N=C(OC)C=3C=C2)C1)=O.[I:66]N1C(=O)CCC1=O>C1CCCCC1>[CH3:22][CH:21]([CH3:23])[C:20]([O:19][C@@H:18]1[C@@H:25]([CH2:27][O:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[O:26][C@@H:16]([N:4]2[C:5]3[N:6]=[C:7]([NH:13][CH:14]=[O:15])[N:8]=[C:9]([O:11][CH3:12])[C:10]=3[C:2]([I:66])=[CH:3]2)[CH2:17]1)=[O:24]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Agent: COc1nc(NC=O)nc2c1ccn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Solvent: C1CCCCC1
Product: COc1nc(NC=O)nc2c1c(I)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Reaction time: 23 h

Procedure:
Compound (46) is prepared as described for compound (45) by proceeding from compound (18) (500 mg, 1.11 mmol) and N-iodosuccinimide (264 mg, 1.16 mmol). The duration of the reaction is 23 h. Colorless crystals (590 mg, 92%) are obtained from cyclohexane. 1H-NMR ([D6 ] DMSO): δ=1.9 (d, J=7.0, CH3), 1.15 (d, J=7.0, CH3), 2.46, 2.60, 2.9 (3 m, CH and Hα, β--C (2'), 4.06 (s, OCH3), 4.17 (m, H--C(5')), 4.27 (m, H--C(4')), 5.35 (m, H--C(3')), 6.46 (m, H--C (1')), 7.62 (s, H--C(6), 9. 55 (d, J=9.7, NH), 10.81 (d, J=9.9 HCO). Anal. calculated for C21H27JN4O7 (574.4) : C 43.91, H 4.74, N 9.75; found: C 43.98, H 4.75, N 9.82.
Reaction SMILES: [C:1]([Br:4])(=O)[CH3:2].[N+](C1C=[C:12]([CH2:14][C:15]([F:18])([F:17])[F:16])[N+:11]([O-:19])=[C:10]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH:9]=1)([O-])=O.[OH-].[Na+]>CC(O)=O>[Br:4][C:1]1[CH:9]=[C:10]([CH2:20][C:21]([F:22])([F:23])[F:24])[N+:11]([O-:19])=[C:12]([CH2:14][C:15]([F:16])([F:17])[F:18])[CH:2]=1
Reactant: O=[N+]([O-])c1cc(CC(F)(F)F)[n+]([O-])c(CC(F)(F)F)c1
Reactant: CC(=O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: [O-][n+]1c(CC(F)(F)F)cc(Br)cc1CC(F)(F)F
Temperature: 90 °C
Yield: 72 %

Procedure:
Acetyl bromide (14 mL) was added to a solution of 4-nitro-2,6-bis-(2,2,2-trifluoro-ethyl)-pyridine 1-oxide (2.7 g, 8.9 mmol) dissolved in AcOH (25 mL). The reaction mixture was heated to 90° C. for 5 hours. The reaction was cooled to room temperature, poured into ice, made basic with NaOH pellets and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 30% EtOAc in hexanes) gave the product as a yellow oil (2.18 g, 72%). 1H NMR (400 MHz, CDCl3): δ 3.92 (t, J=10.1 Hz, 4H), 7.59 (s, 2H).
Reaction SMILES: N1CCCCC1.[C:7]1([CH3:15])[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][CH:8]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].C(=O)=O>N1C=CC=CC=1>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([CH:15]=[CH:17][C:18]([OH:20])=[O:19])=[CH:8][CH:9]=1)=[O:14]
Reactant: Cc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: O=C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=Cc1ccc(C=CC(=O)O)cc1
Yield: 78 %

Procedure:
A drop of piperidine was added to a mixture of 13.4 g of p-tolualdehyde, 5 g of malonic acid and 50 ml of pyridine. The mixture was heated to reflux until evolution of carbon dioxide was discontinued. The reaction mixture was concentrated under reduced pressure and, 200 ml of water and 12 g of hydrogen sodium carbonate were added thereto. The mixture was washed with ethyl acetate and made acidic with conc. hydrochloric acid. The precipitated crystals were taken out by filtration, thoroughly washed with water and dried to give 6.6 g of p-formylcinnamic acid.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH2:11]([C:27](O)=[O:28])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.ClCCCl>[OH:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:27]([O:9][CH2:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([OH:10])=[CH:2][CH:1]=3)=[O:28])=[CH:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: O=C(O)CCc1ccc(Oc2ccc(O)cc2)cc1
Reactant: OCCc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: O=C(CCc1ccc(Oc2ccc(O)cc2)cc1)OCCc1ccc(O)cc1
Temperature: 25 °C

Procedure:
Into a 500 mL round bottomed flask fitted with an overhead stirrer, and a modified Dean-stark trap for solvents heavier than water are added 10 g (72 mmol) of tyrosol, 30 g (78 mmol) of desaminothyronine, 0.65 g (3.4 mmol) of 4-toluenesulfonic acid monohydrate and 200 mL of 1,2-dichloroethane (DCE). A water-cooled reflux condenser is placed on top of the modified Dean-stark trap and the contents of the flask are heated to reflux while being stirred. The reaction is continued until approximately 1.4 mL of water collected in the modified Dean-stark trap above the DCE and the water collection essentially stops (about 4 hours of reflux). The reaction mixture is cooled to room temperature and the crude product is dissolved in 100 mL of ethyl acetate and washed twice with 100 mL portions of 5% sodium bicarbonate solution. After drying over magnesium sulfate the organic layer is concentrated and precipitated with hexane. The resulting white crystalline solid is collected by filtration and dried in a vacuum oven at 25° C. The product is characterized by elemental analysis, hplc, and 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[NH:5][C:6]1[N:7]2[CH:12]=[N:13][C:14]=1[C:15]1[O:19][N:18]=[C:17]([CH:20]2[CH2:22][CH2:21]2)[N:16]=1.C(N(CCC)CCC)CC.P(Cl)(Cl)([Cl:36])=O>ClCCl>[Cl:36][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]2[CH:12]=[N:13][C:14]([C:15]3[O:19][N:18]=[C:17]([CH:20]4[CH2:22][CH2:21]4)[N:16]=3)=[C:6]2[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2c(-c3nc(C4CC4)no3)ncn2c2cccc(Cl)c12
Agent: CCCN(CCC)CCC
Solvent: ClCCl
Product: Clc1cccc2c1c(Cl)nc1c(-c3nc(C4CC4)no3)ncn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 6-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-oxo-imidazo[1,5-a]quinazoline (1.0 g), tripropylamine (0.5 ml) and phosphorus oxychloride (5 ml) was heated at 140°-150° C. After 1 hour, more POCI3 (5 ml) and tripropylamine (0.5 ml) was added, and heating was continued for 11/2 hours. Then the warm mixture was poured into 200 ml of ice water with vigorous stirring. After 15 min. 100 ml of dichloromethane was added. Undissolved material was collected by filtration, rinsed with diethyl ether and dried to give the title compound as tan crystals, m.p. 238°-240° C. Yield 0.47 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[CH:10][C:9]([C:18](O)=[O:19])=[CH:8][C:7]=1[O:6]2.[CH:21]([N:24](CC)[CH:25](C)[CH3:26])(C)[CH3:22].C(NCC)C>CN(C)C=O>[CH2:21]([N:24]([CH2:25][CH3:26])[C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:17])[C:14]3[C:5]([O:6][C:7]=2[CH:8]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=3)=[O:19])[CH3:22]
Reactant: COc1ccc2c(=O)c3ccc(C(=O)O)cc3oc2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccc(OC)cc3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
A mixture of compound 6i (0.707 g, 2.62 mmol) and O-benzotriazol-yl-N,N,N′,N-tetramethyluronium hexafluorophosphate (HBTU, 1.05 g, 2.74 mmol) in N,N-dimethylformamide (10 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.685 mL, 3.92 mmol) and allowed to stir at rt for 15 min. Diethylamine (0.541 mL, 5.23 mL) was added and the resultant mixture was stirred for 2 h. The mixture was poured into ice water. A solid was collected by filtration, washed with water and air dried to give the title compound (0.445 g). MS: m/z 326.0 (MH+). 1H NMR (DMSO-d6): δ 1.07 (br t, 3 H), 1.19 (br t, 3 H), 3.20 (br q, 2 H), 3.48 (br t, 2 H), 3.95 (s, 3 H), 7.08 (m, 1 H), 7.17 (d, 1 H, J=2.1 Hz), 7.40 (d of d, 1H, J=1.3 & 8.1 Hz), 7.59 (d, 1 H, J=1.2 Hz), 8.12 (d of d, 1 H, J=1.3 & 8.9 Hz) and 8.21 (d, 1 H, J=8.1 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:26]=[O:27])=[CH:10][N:9]=1)[CH3:2].[Se](=O)=[O:32]>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:26]=[O:27])=[CH:10][N:9]=1)=[O:32])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOCCOc1cc2c(C=O)cnc(Cc3cccc(OCC)c3)c2cc1OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOCCOc1cc2c(C=O)cnc(C(=O)c3cccc(OCC)c3)c2cc1OC
Temperature: 120 °C

Procedure:
To a stirred solution of 1-(3-ethoxy-benzyl)-6-(2-ethoxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde (61 mg, 0.15 mmol) was added selenium dioxide (132 mg, 1.20 mmol). The reaction mixture was heated at 120° C. for 1 h. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-(2-ethoxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (60 mg, 95% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([N:15]2[C:20]3[N:21]=[C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[CH:28][C:27]=4[O:39][CH3:40])[N:23]=[CH:24][C:19]=3[CH:18]=[CH:17][C:16]2=[O:41])[CH:12]=[CH:13][CH:14]=1.[C:42](Cl)(=[O:46])/[CH:43]=[CH:44]/[CH3:45]>>[CH3:40][O:39][C:27]1[CH:28]=[C:29]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[CH:30]=[CH:31][C:26]=1[NH:25][C:22]1[N:23]=[CH:24][C:19]2[CH:18]=[CH:17][C:16](=[O:41])[N:15]([C:11]3[CH:10]=[C:9]([NH:8][C:42](=[O:46])/[CH:43]=[CH:44]/[CH3:45])[CH:14]=[CH:13][CH:12]=3)[C:20]=2[N:21]=1
Reactant: C/C=C/C(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: C/C=C/C(=O)Nc1cccc(-n2c(=O)ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nc32)c1
Yield: 13.6 %

Procedure:
This compound (10 mg, 14% yield) as a yellow amorphous solid was prepared according to the procedures described for Example 1, using 8-(3-aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one 2,2,2-trifluoroacetate (1b, 78 mg, 0.14 mmol) and (E)-crotonoyl chloride (Sigma Aldrich, 0.013 mL, 0.14 mmol) as the starting materials. m/z (ESI, +ve ion) 526.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.17 (1H, s), 8.76 (1H, s), 8.17 (1H, br. s.), 7.92 (1H, d, J=9.4 Hz), 7.84 (1H, br. s.), 7.61 (1H, s), 7.50 (1H, t, J=8.0 Hz), 7.29 (1H, d, J=8.8 Hz), 6.99 (1H, d, J=7.6 Hz), 6.76-6.86 (1H, m), 6.54 (1H, s), 6.46 (1H, d, J=9.4 Hz), 6.14 (1H, d, J=15.1 Hz), 6.05 (1H, d, J=16.0 Hz), 3.79 (3H, s), 3.05 (4H, br. 2.45 (4H, d, J=4.5 Hz), 2.24 (3H, s), 1.85-1.91 (3H, m).
Reaction SMILES: FC(F)(F)C(O)=O.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:32][CH2:31][C:19]3([N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][CH2:20]3)[CH2:18]2)=[CH:13][C:12]=1[O:33][CH:34]([CH3:36])[CH3:35])([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:32][CH2:31][C:19]3([NH:23][CH2:22][CH2:21][CH2:20]3)[CH2:18]2)=[CH:13][C:12]=1[O:33][CH:34]([CH3:36])[CH3:35])([O-:10])=[O:9]
Reactant: CC(C)Oc1cc(N2CCC3(CCCN3C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(N2CCC3(CCCN3)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.8 %

Procedure:
0.33 ml of trifluoroacetic acid is added to a solution of 300 mg of 2-methylpropan-2-yl 7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane-1-carboxylate in 30 ml of dichloromethane. The mixture is stirred at ambient temperature for 15 hours and then 3 ml of trifluoroacetic acid are again added. After stirring for 15 hours, the reaction mixture is run into 50 ml of a saturated potassium carbonate solution. The aqueous phase is extracted three times with 50 ml of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and then concentrated to dryness under reduced pressure, so as to give a yellow oil. The residue is purified by chromatography on silica gel, elution being carried out with dichloromethane/methanol (100/0 to 95/5), so as to obtain 221 mg of 7-[4-nitro-3-(propan-2-yloxy)phenyl]-1,7-diazaspiro[4.4]nonane in the form of a yellow solid.