Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[O:10].C(O)CCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:8]([O:13][CH2:5][CH2:6][CH2:1][CH3:7])(=[O:12])[C:9]([CH3:11])=[O:10]
Reactant: CC(=O)C(=O)O
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)C(C)=O
Temperature: 25 °C
Yield: 70 %

Procedure:
A toluene solution (1 L) containing pyruvic acid (440 g, 5.0 mol), n-butanol (371 g, 5.0 mol) and p-toluenesulfonic acid monohydrate (2.5 g) was heated and refluxed for 16 hours under nitrogen flow. The reaction led to generation of water in the system. However, the water was removed using Dean-Stark trap. The resultant reaction solution was cooled down to room temperature, followed by removal of toluene using an evaporator under a reduced pressure. The residual was then purified using reduced pressure distillation (40 mmHg, 93 to 100° C.) to give butyl pyruvate (505 g, yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].C(=O)(O)[O-:28].[Na+]>COCCOC.O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][OH:28])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(CO)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
A solution of 1.14 g of isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 20 ml 1,2-dimethoxyethane is stirred at room temperature for 3 hours with a solution of 0.47 g of sodium bicarbonate in 10 ml of water. The solvent is evaporated off under reduced pressure and the residue is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is purifed by chromatography on a silica gel column using methylene chloride/ethyl acetate (2:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-hydroxymethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.83 ppm (d, 1H), 7.35 ppm (d, 1H), 5.24 ppm (m, 1H), 4.59 ppm (d, 1H), 4.54 ppm (d, 1H), 3.50 ppm (s, 3H), 2.44 ppm (s, 3H), 2.34 ppm (s, approx. 1H, very broad), 1.36 ppm (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[SH:9].O[CH2:11][C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH:21]([CH3:23])[CH3:22])[O:14][N:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:11][C:12]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH:21]([CH3:23])[CH3:22])[O:14][N:13]=1
Reactant: Sc1c(Cl)cccc1Cl
Reactant: COC(=O)c1c(CO)noc1C(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1c(CSc2c(Cl)cccc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2,6-dichlorobenzenethiol (530 mg, 2.96 mmol), methyl 3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (629 mg, 2.46 mmol) and triphenylphosphine (1.29 g, 4.93 mmol) in dichloromethane (20 mL) was added di-tert-butyl azodicarboxylate (1.14 g, 4.93 mmol). The solution was stirred at ambient temperature overnight. The solution was then adsorbed onto silica gel and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes gradient elution) to afford methyl 3-{[(2,6-dichlorophenyl)thio]methyl}-5-(1-methylethyl) -4-isoxazolecarboxylate (886 mg, 100%). 1H-NMR (400 MHz, CDCl3) δ 7.52-7.35 (m, 3H), 4.18 (s, 3H), 3.72 (s, 2H), 3.64 (septet, J=7 Hz, 1H), 1.20 (d, J=7 Hz, 6H). LRMS (APCI) m/z 360 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[OH-].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1Cl)([O-:17])=[O:16]>O1CCCC1.COC(C)(C)C.[Pd](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=[N+]([O-])c1ccccc1-c1cc(F)c(F)c(F)c1
Temperature: 105 °C

Procedure:
A well-inertized pressure vessel was initially charged with a mixture of 49.6 g (0.113 mol) of a 40% solution of 3,4,5-trifluorophenylboronic acid in tetrahydrofuran from preliminary stage a) with 121.6 g (0.304 mol) of a 10% sodium hydroxide solution and 19.7 g (0.124 mol) of 2-nitrochlorobenzene. The particular ligand was then added at room temperature, the mixture was stirred and the palladium(II) chloride was finally added. Subsequently, the reaction mixture was heated to 105° C. This established a pressure of approx. 3-4 bar. After about 12 hours of reaction time, the pressure vessel was decompressed to standard pressure and cooled to 30° C., and the reaction mixture was discharged. For workup, the reaction mixture was taken up in tert-butyl methyl ether, the phases were separated and the aqueous phase re-extracted twice with tert-butyl methyl ether. The solvents were distilled off completely under reduced pressure, the final weight was determined and the content of the crude 3,4,5-trifluoro-2′-nitrobiphenyl was analyzed by means of quantitative HPLC. If desired, the crude 3,4,5-trifluoro-2′-nitrobiphenyl can be purified further, for example by crystallization from isobutanol.
Reaction SMILES: CO.[CH3:3][NH:4][NH2:5].CN([CH:9]=[C:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=O)C>C(OCC)(=O)C>[CH3:3][N:4]1[CH:11]2[CH:10]([C:15](=[O:16])[CH2:14][CH2:13][CH2:12]2)[CH:9]=[N:5]1
Reactant: CNN
Reactant: CN(C)C=C1C(=O)CCCC1=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1N=CC2C(=O)CCCC21
Temperature: 50 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A MeOH solution of methylhydrazine 0.046 g (0.01 mol) and 2-dimethylaminomethylene-cyclohexane-1,3-dione 1.67 g (0.01 mol) was stirred at room temperature for 1 h, and then was stirred at 50° C. for 1 h. NMR of crude material indicated the reaction was completed. Work up: The reaction mixture was diluted with ethyl acetate and washed with brine. The organic phase was dried with MgSO4, and the solvent was rotary evaporated. The crude product was filtered through silica gel, and 1.03 g pure product was obtained, the yield is 69%.
Reaction SMILES: O1CCCC1.Cl.[N:7]1([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:28](Cl)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(N(CC)CC)C>[C:28]([N:10]1[CH2:11][CH2:12][N:7]([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=2)[CH2:8][CH2:9]1)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccccc4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 10 ml. of tetrahydrofuran were added 1.2 g. of 2-(piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.hydrochloride and 1.33 g. of triethylamine and the resulting mixture was stirred for 30 minutes. Thereafter, 0.66 g. of cinnamoyl chloride was added thereto and the resulting mixture was stirred at room temperature overnight. The crystalline substance thus separated was recovered by filtration, washed thoroughly with water and ethanol and then dried to afford 0.66 g. of the desired product.
Reaction SMILES: CO[C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3([CH3:19])[O:18]CCO3)[CH:12]=2)[N:7]([CH2:20][CH3:21])[C:6]1=[O:22])=[O:4].[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)=[O:28]>>[F:36][C:32]1[CH:31]=[C:30]([NH:29][C:27]([C:26]2[CH:25]=[C:24]([NH:23][C:3]([CH:5]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:18])[CH3:19])[CH:12]=4)[N:7]([CH2:20][CH3:21])[C:6]3=[O:22])=[O:4])[CH:39]=[CH:38][CH:37]=2)=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: Nc1cccc(C(=O)Nc2cccc(F)c2)c1
Reactant: CCN1C(=O)C(C(=O)OC)c2cc(C3(C)OCCO3)ccc21
Product: CCN1C(=O)C(C(=O)Nc2cccc(C(=O)Nc3cccc(F)c3)c2)c2cc(C(C)=O)ccc21

Procedure:
Prepared as in Example 1 from 1-ethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid methyl ester and 3-amino-N-(3-fluoro-phenyl)-benzamide. 1H NMR (CDCl3) δ 1.25 (t, 3 H), 2.6 (s, 3 H), 3.85 (q, 2 H), 4.45 (s, 1 H), 6.85-8.05 (m, 11 H), 8.3 (s, 1 H), 9.65 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[I:21]I>O1CCCC1>[I:21][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[NH:8][CH:9]=1
Reactant: II
Reactant: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Solvent: C1CCOC1
Product: Cc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.6 %

Procedure:
To a solution of 5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (8, 1 g, 2.0 mmol) in 10 mL of tetrahydrofuran, iodine (0.43 g, 1.7 mmol) in 5 mL of tetrahydrofuran was added. The reaction was stirred at room temperature overnight, then quenched with 20 mL of 1M aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layers were combined and washed with water, brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexanes. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a white solid (10, 20 mg). MS (ESI) [M+H+]+=258.70.
Reaction SMILES: C1(C)C=CC=CC=1.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:13]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[CH2:14][CH3:15]>O>[CH2:13]([CH:16]1[CH2:21][CH2:20][C:19]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:18][CH2:17]1)[CH2:14][CH3:15]
Reactant: C1CCNC1
Reactant: CCCC1CCC(=O)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CC=C(N2CCCC2)CC1
Temperature: 25 °C

Procedure:
Toluene (200 ml) and pyrrolidine (90 ml) were added to 4-propylcyclohexanone (53.0 g) in a reaction vessel equipped with a Dean-Stark apparatus under an atmosphere of nitrogen. The mixture was refluxed for 3 hours while the water formed was removed by a Dean-Stark apparatus. After the reaction mixture had been cooled to a room temperature, it was washed with brine, and dried over anhydrous magnesium sulfate. The toluene was distilled off under reduced pressure to give 1-(4-propylcyclohex-1-enyl)pyrrolidine (58.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][S:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]3)[S:11][C:10]=2[CH:25]=O)=[CH:5][CH:4]=1)#[N:2].[Na]>C(O)C>[C:1]([C:3]1[CH:28]=[CH:27][C:6]([C:7]2[S:8][C:9]3[CH:13]=[C:12]([CH:14]4[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]4)[S:11][C:10]=3[CH:25]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCCCC1CCC(c2cc(SCc3ccc(C#N)cc3)c(C=O)s2)CC1
Agent: [Na]
Solvent: CCO
Product: CCCCCC1CCC(c2cc3sc(-c4ccc(C#N)cc4)cc3s2)CC1
Reaction time: 5 h

Procedure:
A solution of 4.6 g of 3-p-cyanobenzylmercapto-2-formyl-5-(4-pentylcyclohexyl)-thiophene in 25 ml of ethanol is added dropwise, at room temperature and in the course of 5 minutes, to an alcoholate solution prepared from 1.9 g of sodium and 60 ml of ethanol, and the mixture is then boiled for 5 hours. The usual working-up procedure gives 2-p-cyanophenyl-5-(4-pentylcyclohexyl)-thieno[3,2-b]thiophene.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1.Br[CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]([P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])([F:41])[F:40].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:34][CH2:35][O:36][CH2:37][CH2:38][C:39]([P:42]([O:43][CH2:44][CH3:45])([O:46][CH2:47][CH3:48])=[O:49])([F:40])[F:41])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][C:4]=2[N:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCBr
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc3C)cc12
Temperature: 60 °C

Procedure:
To a solution of ethyl 3-(5-amino-2-(4-hydroxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-13) (1.0 equiv.) dissolved in DMF (0.14 M) was added a solution of diethyl 3-(2-bromoethoxy)-1,1-difluoropropylphosphonate (6-14: described in Example 7—Step 1) (1.3 equiv.) in DMF (0.7 M) and cesium carbonate (4 equiv.). The reaction was stirred at 60° C. After 1.5 hours (or until reaction is complete by LCMS), DCM (2 volume equivalent) was added to the reaction. The solids (inorganic) were filtered, and the filtrate was concentration. The crude product was purified by Combiflash using 0-5% MeOH in DCM to give ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-15) as an oil which upon standing became a white solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([CH:22]([OH:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22](=[O:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethanol (1.40 g, 4.28 mmol) in Methylene chloride (24.5 mL, 382 mmol) was added Dess-Martin periodinane (3.2 g, 7.6 mmol) and was stirred at room temperature for 1 hour. After pass through si gel plug, the solvent was concentrated down to give product as an oil (1.29 g, 93%). LCMS 2.28 min at m/z 326.20 ([M+1], 100%).
Reaction SMILES: [O:1]=[C:2]([CH3:15])[CH2:3]N1C(=O)C2C(=CC=CC=2)C1=O.CC(C)([O-])C.[Na+:21].[C:22]([O:29]CC)(=[O:28])[C:23]([O:25]CC)=O>C(O)C>[Na+:21].[O:25]=[C:23]([CH2:3][C:2](=[O:1])[CH3:15])[C:22]([O-:29])=[O:28]
Reactant: CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)CC(=O)C(=O)[O-]
Yield: 184.1 %

Procedure:
The method of Examples 1-4 Part A was followed to treat 2-(2-oxopropyl)-1H-isoindole-1,3(2H)-dione (10.2 g, 50.0 mmol) with a solution of sodium tert-butoxide (5.77 g, 60.0 mmol) in ethanol (60 mL) and diethyl oxalate (8.77 g, 60.0 mmol). Ethyl 541, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2,4-dioxopentanoate sodium salt (14.00 g) was obtained as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.NC(N)=[O:13].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N+:6]([O-:13])[CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: O=C(O)c1ccc(Br)c[n+]1[O-]
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a suspension of 5-bromopicolinic acid (25.0 g) and urea-hydrogen peroxide adduct (20.0 g) in acetonitrile (200 mL) was added trifluoroacetic anhydride (50 mL) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from diethyl ether to give the title compound (19.6 g) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][CH2:29][Cl:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
1-[2-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone (compound 314) (150 mg), 1-bromo-3-chloropropane (210 mg), and potassium carbonate (307 mg) were suspended in N,N-dimethylformamide (6 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (174 mg, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C:22]#[N:23])[CH:13]=[C:12]([C:24](O)=[O:25])[CH:11]=1)#[N:2].Cl.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C@H:35]([NH2:37])[CH3:36])[CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[C:22]#[N:23])[CH:13]=[C:12]([C:24]([NH:37][C@H:35]([CH3:36])[CH2:34][N:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:25])[CH:11]=1)#[N:2]
Reactant: C[C@@H](N)CN1CCOCC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cnccc3C#N)c2)c(C#N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3cnccc3C#N)c2)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 2′-cyano-5-(4-cyanopyridin-3-yl)-4′-methylbiphenyl-3-carboxylic acid (20 mg, 0.059 mmol), (R)-1-morpholinopropan-2-amine hydrochloride (112 mg, 0.62 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (49 mg, 0.13 mmol), N,N-diisopropylethylamine (360 μL, 2.1 mmol), N,N-dimethylformamide (0.555 mL) and the reaction was stirred overnight at room temperature. The mixture was purified by HPLC to get the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)=[O:20].O>CN(C=O)C>[Cl:1][C:2]1[N:12]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:19](=[O:20])[C:18]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:17]=3[Cl:16])=[CH:28][CH:27]=2)[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13]
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (404 mg) in DMF (70 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2 hours, after which a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 16 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with ether to provide the title compound as yellowish brown powder (471 mg, yield 49%).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7]Cl)[CH3:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:22][CH:23]1[NH:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].[Na]>CN(C=O)C.C(O)C>[CH2:2]([N:4]([CH2:9][CH3:10])[CH2:5][CH2:6][CH2:7][N:25]1[C:24](=[O:29])[CH:23]([CH2:22][C:16]2[C:15]3[C:19](=[CH:20][CH:21]=[C:13]([O:12][CH3:11])[CH:14]=3)[NH:18][CH:17]=2)[NH:27][C:26]1=[O:28])[CH3:3]
Reactant: COc1ccc2[nH]cc(CC3NC(=O)NC3=O)c2c1
Reactant: CCN(CC)CCCCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCN(CC)CCCN1C(=O)NC(Cc2c[nH]c3ccc(OC)cc23)C1=O
Reaction time: 8 h

Procedure:
3-Diethylaminopropyl chloride hydrochloride (3.75 g, 0.024 mole) and a solution of 5-(5-methoxyindol-3-ylmethyl)hydantoin (6.1 g, 0.024 mole) in 100 ml of DMF were added to a solution of sodium (1.1 g) in 200 ml of anhydrous ethanol and the mixture was heated to reflux with stirring for 8 hours, filtered and concentrated in vacuo. The residue was recrystallized from aqueous methanol, yield 1.8 g, mp 136°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][O:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:27])([F:28])[F:17])[CH:20]=2)=[CH:6][CH:7]=1
Reactant: OCc1cccc(C(F)(F)F)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 14, Step 4, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and (3-trifluoromethyl-phenyl)-methanol.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]2=[O:30])=[N:21][C:20]=1[CH3:31])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C:26](=[CH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[C:25]2=[O:30])=[N:21][C:20]=1[CH3:31])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCC(=Cc3cccnc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 17 %

Procedure:
Following the procedure as described in Example 10, making variations as required to use nicotinaldehyde in place of benzaldehyde to react with N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 17% yield: mp 206-208° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.69 (br s, 1H), 8.54 (br s, 1H), 7.91 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.39-7.21 (m, 6H), 6.26 (t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.32-4.22 (m, 2H), 2.93-2.82 (m, 2H), 2.64 (s, 3H), 2.09-1.96 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.8, 162.6, 157.3, 152.3, 150.7, 149.4, 138.0, 136.8, 135.5, 130.5, 128.8, 127.9, 127.6, 123.5, 120.1, 47.4, 44.0, 25.9, 22.2, 17.4; MS (ES+) m/z 419.2 (M+1).