Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14]1([C:17]2[CH:18]=[C:19]([C:36]([OH:38])=[O:37])[C:20](=[O:35])[N:21]3[C:26]=2[C:25]([CH3:27])=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:23]([F:34])=[CH:22]3)[CH2:16][CH2:15]1.NCC1CCN(C2C(F)=CN3C(C=2C)=C(C2CC2)C=C(C(O)=O)C3=O)C1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:31]2[CH2:32][CH2:33][N:28]([C:24]3[C:23]([F:34])=[CH:22][N:21]4[C:26]([C:25]=3[CH3:27])=[C:17]([CH:14]3[CH2:16][CH2:15]3)[CH:18]=[C:19]([C:36]([OH:38])=[O:37])[C:20]4=[O:35])[CH2:29][CH2:30]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(N2CCNCC2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: Cc1c(N2CCC(CN)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Product: Cc1c(N2CCN(C3CCN(C(=O)OC(C)(C)C)C3)CC2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
The title compound was prepared as described in Step 1 of Example 9 (1974) except 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester was used in place of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 1-cyclopropyl-7-fluoro-9-methyl-4-oxo-8-piperazin-1-yl-4H-quinolizine-3-carboxylic acid was used in place of (8-(3-aminomethyl-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: C(OC(C1C=C(C2C=CC(F)=CC=2)N(C2C=CC=CC=2)C=1C)=O)C.[CH2:25]([O:27][C:28](=[O:40])[CH:29]([C:37](=O)[CH3:38])[CH2:30][C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:26].[F:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1>>[CH2:25]([O:27][C:28]([C:29]1[CH:30]=[C:31]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:46]([C:45]2[CH:47]=[CH:48][C:42]([F:41])=[CH:43][CH:44]=2)[C:37]=1[CH3:38])=[O:40])[CH3:26]
Reactant: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O
Reactant: Nc1ccc(F)cc1
Agent: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccccc2)c1C
Product: CCOC(=O)c1cc(C(C)(C)C)n(-c2ccc(F)cc2)c1C

Procedure:
Prepared in analogy to that of 5-(4-fluoro-phenyl)-2-methyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 2-Acetyl-5,5-dimethyl-4-oxo-hexanoic acid ethyl ester and 4-fluoroaniline. The title compound, ESI MS (m/z): 304 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:12][CH2:13][CH2:14][NH2:15].C(N(C(C)C)CC)(C)C>C(O)C>[F:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: NCCF
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NCCF)nc1
Yield: 45 %

Procedure:
A stirred mixture of 2-chloro-5-nitropyridine (2.4 g, 0.015 mol), 2-fluoroethylamine hydrochloride (1.75 g, 0.0175 mol) and diisopropylethylamine (7.0 ml, 0.040 mol) in absolute ethanol (50 ml) was kept under nitrogen at ambient temperature (24° C.) for 22 hours, warmed slowly to the reflux temperature during 6 hours and refluxed for 18 hours. It was then concentrated in vacuo. The residue was mixed with saturated NaHCO3 and extracted with EtOAc. The extract was washed with water and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with CH2 cl2. The product was crystallized from methyl tert butyl ether to give 1.25 g of the titled product, mp 126°-127° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:18])[CH3:2].[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[CH:7]=2)[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4]1=[O:18]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CCn1c(=O)[nH]c2cc(C(=O)OC)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCn1c(=O)c2ccc(C(=O)OC)cc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 73 %

Procedure:
A mixture of 3-ethyl-7-(methoxycarbonyl)-2,4(1H,3H)-quinazolinedione (2.17 g), 2,4-dichlorobenzyl chloride (2.05 g), potassium iodide (1.45 g) and potassium carbonate (5.0 g) in acetone (80 ml) was heated under reflux for 1.5 hr. After cooling, water (50 ml) was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with water (30 ml) and methyl t-butyl ether (30 ml) and dried to give the object compound (2.60 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]CC)=O.[CH:12]1([C:15]([CH3:17])=[O:16])[CH2:14][CH2:13]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:12]1([C:15](=[O:16])[CH2:17][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1ccccn1
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1ccccn1

Procedure:
A stirred mixture of 24 g. of ethyl picolinate, 18 g. of cyclopropylmethyl ketone and 11 g. of sodium methoxide in 250 ml. of benzene is heated under reflux for 6 hours. The mixture is diluted with 200 ml. of water and the water phase is removed. The aqueous solution is made weakly acidic with dilute hydrochloric acid. A solid precipitates and is collected by filtration. Recrystallization from cyclohexane provided colorless crystals, melting point 77°-78°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].Br[CH2:33][C:34]([O:36]C)=[O:35]>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:14][CH:15]=2)[CH:5]=[C:6]([Br:9])[C:7]=1[O:8][CH2:33][C:34]([OH:36])=[O:35]
Reactant: COC(=O)CBr
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2cc(Br)c(O)c(Br)c2)cc1
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2cc(Br)c(OCC(=O)O)c(Br)c2)cc1

Procedure:
The title compound was prepared from 3,5-dibromo-4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol, and methyl bromoacetate in substantially the same manner, as described in Example 5, and was obtained as an off-white solid, mp 165–166° C.; MS m/e 609 (M+);
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].C(Cl)(Cl)Cl.C(C(CC)=[O:16])C.C(N(CC)CC)C.[C:26]1([CH3:32])[CH:31]=[CH:30]C=[CH:28][CH:27]=1>>[CH2:31]([C:26]1([CH2:27][CH3:28])[C:32](=[O:16])[O:6][CH2:5][C:4]([CH3:8])([CH3:7])[NH:3]1)[CH3:30]
Reactant: Cc1ccccc1
Reactant: CC(C)(N)CO
Reactant: CCC(=O)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC1(CC)NC(C)(C)COC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
120 g (3 mol) of finely ground sodium hydroxide are added, with stirring, to a solution of 53.5 g (0.6 mol) of 2-amino-2-methylpropanol and 73 ml (0.9 mol) of chloroform in 635 ml (6 mol) of diethylketone at 5-10° C. The reaction mixture is stirred at room temperature for 16 hours and is then filtered. The solid is made into a slurry with 2×350 ml of methanol and filtered. The filtrates are concentrated to dryness by evaporation in a rotary evaporator and the residue is charged with 200 ml of 32% hydrochloric acid and 100 ml of water and refluxed for 6 hours. Subsequently, 600 ml of toluene are added and the water is completely removed by distillation in a water separator. 91 ml (0.66 mol) of triethylamine are then added dropwise to the toluene solution and the mixture is refluxed for another 6 hours. The precipitated triethylamine hydrochloride is removed by filtration and the filtrate is subjected to distillation at 123-127° C./20 mbar, giving compound (207) in the form of a colourless liquid, yield 63.7 g (57%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:18]3[N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:13][N:14]2[CH3:17])=[CH:10][C:9]=1[O:37][CH3:38].Br[CH:40]([CH3:42])[CH3:41]>CN(C)C=O.O>[CH:40]([O:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([C:18]3[N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:13][N:14]2[CH3:17])=[CH:10][C:9]=1[O:37][CH3:38])([CH3:42])[CH3:41]
Reactant: CC(C)Br
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC(C)C
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (70 mg) was added to a solution of 2-(6-hydroxy-5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [112 mg, Reference Example 83] in dry dimethylformamide (5 mL) under an argon atmosphere at ambient temperature. The mixture was allowed to stir for 10 minutes then treated with 2-bromopropane (66 μl) and heated at 70° C. for 3 hours. Additional portions of potassium carbonate (70 mg) and 2-bromopropane (66 μl) were then added and the mixture was stirred and heated at 70° C. for 4 hours. The cooled reaction mixture was poured in water (20 mL) and extracted three times with ethyl acetate (40 mL). The combined organic phases were washed with brine (20 mL), then dried over magnesium sulfate and then evaporated. The brown residue was subjected to flash column chromatography on silica eluting with a mixture of cyclohexane and ethyl acetate (3:2, v/v) to give the title compound (56 mg) as an off-white foam. TLC: RF=0.47 (cyclohexane/ethyl acetate, 1/1). MS: CI (NH3); m/z=490 MH+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-:16].[Na+].[Na+].C([SiH](CC)CC)C.[C]=O>CN(C=O)C>[CH:15]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1)=[O:16]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](NS(C)(=O)=O)c1ccc(Br)cc1
Agent: CC[SiH](CC)CC
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NS(C)(=O)=O)c1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Combine N-[(1R)-1-(4-bromophenyl)ethyl]-methanesulfonamide (10 g, 35 mmol), (1,1′-bis(diphenylphosphino)-ferrocene)palladium(II) chloride (733 mg, 0.9 mmol), sodium carbonate (3.81 g, 35 mmol) and DMF (50 mL) in a 300 mL PARR reactor. Add triethylsilane (11.6 mL, 0.72 mmol) and purge the reactor with carbon monoxide three times. Charge the reactor with carbon monoxide (50 psi) and stir the mixture at 90° C. for 15 h. Cool the reactor to ambient temperature; open; filter mixture through a Celite® pad; and wash the pad with DCM (150 mL). Sequentially wash the filtrate with water then brine (2×80 mL). Concentrate the organic phase under reduced pressure to obtain the residue as an orange oil. Purify the orange oil by silica gel flash chromatography eluting with hexane/EtOAc (0 to 30% EtOAc) to provide the title compound (5.6 g, 70%, ee>98%). MS (m/z): 228 (M+1).
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=O.P(Cl)(Cl)([Cl:16])=O>[OH-].[NH4+]>[Cl:16][C:2]1[N:3]2[C:12]3[C:7]([CH2:6][CH2:5][CH2:4]2)=[CH:8][CH:9]=[CH:10][C:11]=3[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cccc3c2n1CCC3
Agent: [NH4+]
Agent: [OH-]
Product: Clc1nc2cccc3c2n1CCC3
Reaction time: 1.5 h
Yield: 65.8 %

Procedure:
A slurry of 13.60 g of 5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one and phosphorus oxychloride (35 ml) was heated under reflux, with stirring, for 1.5 hrs and stirred at ambient temperature overnight. 10% Ammonium hydroxide (100 ml) and ice were added. The mixture was filtered, and the filtrate was extracted with dichloromethane. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated. The residue was purified by flash chromatography (silica; 10:1 dichloromethane-ethyl acetate). The appropriate fractions were collected and evaporated to give 9.90 g (65.8%) of product, mp 78° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([C:17]([NH2:19])=O)[S:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([C:17]#[N:19])[S:15][CH:16]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2csc(C(N)=O)n2)cc(Cl)c1OC
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COc1cc(-c2csc(C#N)n2)cc(Cl)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
A solution of 4-(3-chloro-4,5-dimethoxyphenyl)-thiazole-2-carboxamide (1.58 g) (Example 1c) in pyridine (9 ml) was cooled to 0° C. and treated with trifluoroacetic anhydride (4 ml) whilst maintaining the internal temperature below 10° C. The mixture was stirred at room temperature for 10 min, then cooled and treated dropwise with water (45 ml) whilst maintaining the internal temperature below 30° C. The precipitated solid was collected by filtration and dried under vacuum at 60° C. Recrystallisation from dichloromethane-ether afforded 4-(3-chloro-4,5-dimethoxyphenyl)-thiazole-2-carbonitrile (1.25 g), m.p. 147°-149° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1([CH3:24])[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:12]([C:13]1([CH3:24])[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:11]
Reactant: CCOC(=O)N1CCC(C)(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)N1CCC(C)(C=O)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a 100 mL round bottom flask was added DCM (30 mL) and oxalyl chloride (0.88 mL; 10.13 mmol). The solution was cooled to −78° C. and treated with DMSO (1.19 mL; 16.88 mmol). The solution was stirred at −78° C. for 20 minutes and then treated with ethyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (1.7 g; 8.44 mmol, dissolved in 10 mL of DCM). The solution was stirred for 30 minutes at −78° C. and then treated with Et3N (3.53 mL; 25.32 mmol). The solution was stirred at −78° C. for 20 min and then slowly warmed to room temperature and stirred at room temperature for an additional 2 hours. The solution was then treated with saturated aqueous NaHCO3 (50 mL), diluted with DCM (50 mL), and the layers were separated. The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the product as an oil that was used without further purification. LC/MS m/z (M+1) 200.0, retention time 2.23 minutes; (10-99% CH3CN—H2O gradient with 0.03% TFA, 5 min). 1H NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.66 (dt, J=13.6, 4.7 Hz, 2H), 3.09 (dd, J=10.1, 3.5 Hz, 1H), 3.06 (dd, J=10.2, 3.4 Hz, 1H), 1.86 (dt, J=13.6, 4.4 Hz, 2H), 1.42-1.30 (m, 2H), 1.19 (t, J=7.1 Hz, 3H), 1.02 (s, 3H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]1([OH:21])[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:20][C:16]1[CH:15]=[C:14]([OH:21])[CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture (0.06 moles) of 2-chloromethylquinoline hydrochloride, (0.06 moles) of 1,3-benzenediol and 18 g of potassium carbonate in 50 ml of dimethylformamide is heated at 70° C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 3-(2-quinolinylmethyloxy)phenol having an m.p. of 151-53° C.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]2=[O:21])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][C:22](=[O:24])[CH3:23])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]2=[O:21])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC[C@]12CCC3=C(CCc4cc(OC(C)=O)ccc43)C1=CCC2=O
Reaction time: 16 h

Procedure:
Dissolve 13β-ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (2.45 g) in pyridine (7 cc) and acetic anhydride (4 cc) and allow to stand at room temperature for 16 hours. Remove the solvent under reduced pressure, add ethanol (20 cc) and again evaporate the solvent. Recrystallize the residue from ethanol to give a red crystalline solid, m.p. 122°-124°. Filter the solid through `Florisil` (100 g) with benzene, evaporate the solvent and recrystallize the product from ethanol to obtain 13β-ethyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one, m.p. 129°-130°C; ultraviolet absorption peak at 306 mμ (ε25,500), infrared absorption peaks at 5.78 μ, 8.27 μ, and 9.85 μ.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22].Cl>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:22][NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: NNc1ccccn1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(=NNc2ccccn2)CC1
Yield: 61.4 %

Procedure:
The following are charged to a round-bottomed flask with a magnetic stirrer: 5 g of N-Boc-piperidone, 2.45 g of pyridin-2-ylhydrazine, 100 ml of methanol and 95 ml of a solution of methanol saturated with HCl. The mixture is left to react under a nitrogen stream for 2 h at reflux temperature. The solvent is evaporated off under vacuum, the resulting product is dissolved with dichloromethane and washing is carried out with a saturated aqueous solution of NaHCO3. The organic phase is dried over Na2SO4 and the solvent is evaporated off, and 4.0 g of the title product are isolated in the form of a red oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[CH3:9])[NH2:5].[C:11]([N:18]1[CH:22]=[CH:21]N=[CH:19]1)(N1C=CN=C1)=[O:12].[CH3:23][O:24][C:25]1[CH:26]=[C:27]2C(=[CH:32][C:33]=1[C:34]([F:37])([F:36])[F:35])NCC2>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]([N:18]2[C:19]3[C:27](=[CH:26][C:25]([O:24][CH3:23])=[C:33]([C:34]([F:36])([F:37])[F:35])[CH:32]=3)[CH2:21][CH2:22]2)=[O:12])[CH:6]=[C:7]([Br:10])[C:8]=1[CH3:9]
Reactant: Cc1c(Br)cc(N)cc1Br
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(Br)c(C)c(Br)c1)CC2
Yield: 52 %

Procedure:
The title compound was prepared by the method of Example 1, from 3,5-dibromo-4-methylaniline (2.64 g, 10 mmol), 1,1′-carbonyldiimidazole (1.64 g, 10 mmol) and 5-methoxy-6-trifluoromethylindoline (D11) (2.2 g, 10 mmol). Crude product was recrystallised from DMSO/water and washed with methanol and ether, to give the title compound (2.64 g, 52%), mp>250° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=O.Cl.[NH2:19][OH:20].O>CO>[OH:1][C:2]1[C:3]([CH3:17])=[C:4]2[C:12](=[CH:13][C:14]=1[CH3:15])[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[N:19][OH:20]
Reactant: Cc1cc2c(c(C)c1O)C(=O)CC1(CCC1)O2
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc2c(c(C)c1O)C(=NO)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 98.6 %

Procedure:
A mixture of 1 g of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one and 0.91 g of hydroxylamine hydrochloride was dissolved in 5 mL of MeOH by way of brief heating. After all solids had dissolved, the solution was sealed in a microwave reaction vial and placed in a microwave reactor for 25 min at 125° C. The reaction was cooled to room temperature, added to H2O and extracted with EtOAc, washed with brine and dried over Na2SO4. Evaporation of solvent yielded 1.05 g of 6-hydroxy-5,7-dimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one oxime as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([N:19]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][O:27][C:21]=2[CH2:20]1)=[O:18].[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:26]1[O:27][C:21]2[CH2:20][N:19]([C:17]([C:2]3[CH:3]=[CH:4][C:5]4[C:6](=[O:16])[C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:13](=[O:15])[C:14]=4[CH:1]=3)=[O:18])[CH2:24][CH2:23][C:22]=2[CH:25]=1)[CH3:30]
Reactant: O=C1c2ccccc2C(=O)c2cc(C(=O)N3CCc4ccoc4C3)ccc21
Reactant: C=O
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1ccc3c(c1)C(=O)c1ccccc1C3=O)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.280 g (0.784 mmol) of 6-(anthraquinone-2-carbonyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 0.106 ml (1.18 mmol) of 50% aqueous dimethylamine and 0.096 ml (1.18 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][C@H:25]([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:6]2[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:3]=[C:2]([Cl:1])[N:7]=2)[C@H:25]([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(Cl)n1

Procedure:
Heat a mixture of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrimidine (2.8 g, 11.52 mmol), 3-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.42 g, 12.1 mmol), and K2CO3 (3.2 g, 23.0 mmol) in DMA at 60° C. for 16 h. Dilute with water, extract with EtOAc, and wash with brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:4) to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]2[CH2:39][O:38][B:37]([OH:40])[C:36]=2[CH:41]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:29])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:30][CH2:31][C:32]5[CH:33]=[CH:34][C:35]6[CH2:39][O:38][B:37]([OH:40])[C:36]=6[CH:41]=5)=[O:25])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: NCc1ccc2c(c1)B(O)OC2
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Product: O=C(NCc1ccc2c(c1)B(O)OC2)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12

Procedure:
The title compound can be prepared from 5-(5-(3,5-dichlorophenyl)-5-(trifluoro-methyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid and 6-(aminomethyl)benzo[c][1,2]oxaborol-1(3H)-ol as shown by the following scheme: