Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32]>O1CCCC1>[Cl:29][CH2:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:9]2)=[CH:6][CH:7]=1)=[O:32]
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N)cc2)C1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC(=O)CCl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of (2S)-2-(4-aminophenyl)-4-((1R)-1-phenylethyl)morpholine (2.93 g, 10 mmol) and triethylamine (3.0 g, 30 mmol) in tetrahydrofuran (50 ml) was added chloroacetyl chloride (2.26 g, 20 mmol). The mixture was stirred at room temperature for 2 hours and partitioned between water and chloroform. The organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the precipitated crystals were collected by filtration, washed with isopropyl ether to give 2-chloro-N-{4-[(2S)-4-((1R)-1-phenylethyl)morpholin-2-yl]phenyl}acetamide (3.5 g, 97%) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]([C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.BrBr.[OH2:25]>C(O)(=O)C>[C:15]1([CH:14]2[C:12](=[O:13])[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:4]=3)=[C:10]([NH2:11])[O:25]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O
Reactant: N#CC(C(=O)Cc1ccccc1)c1cccc(C(F)(F)F)c1
Agent: BrBr
Solvent: CC(=O)O
Product: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In this example a solution containing 21.8 g of (3-trifluoromethylphenyl)-benzylcarbonyl-acetonitrile, dissolved in 60 ml of acetic acid was treated dropwise with a solution of 12.65 g of bromine in 20 ml of glacial acetic acid. The reaction mixture was stirred for about 16 hours at room temperature. The reaction mixture was poured into 250 ml of water and the resulting mixture was extracted three times with ethyl ether. The organic extracts were washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to yield 8.4 g of white solid which was dried affording 7.0 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+].Br[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:33](=[O:34])[O:32]1.CC(C)=O>C1(C)C=CC=CC=1.C(Cl)Cl.O>[C:33]1([C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]([O:14][C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=2[C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=2)=[O:16])[O:32]1)=[O:34]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CN1C(C(=O)Nc2ccccn2)=C(OC2OC(=O)c3ccccc32)c2ccccc2S1(=O)=O

Procedure:
To a round bottomed flask equipped with a reflux condenser and a stirring bar were added piroxicam (3.00 g, 9.1 mmol), potassium carbonate (2.50 g, 18.2 mmol), 3-bromophthalide (prepared according to U.K. Pat. No. 1,364,672; 2.51 g, 11.8 mmol) and acetone (45 mL). The heterogenous reaction mixture was heated to reflux under a nitrogen atmosphere. After 0.5 hour the solvent was removed in vacuo leaving a brown residue which was treated with water (200 mL) and methylene chloride (200 mL). The organic layer was separated and the aqueous layer extracted with additional methylene chloride (200 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried (Na2SO4) and concentrated in vacuo to a brown oil. Column chromatography on silica (1:9 ethyl acetate:methylene chloride) afforded a white foam which, when dissolved in hot toluene, precipitated within a few seconds as pure white crystals: 3.42 g (7.38 mmol, 81.5%); mp 151°-152° C.; IR (KBr) 1785, 1688 cm-1 ; 1H NMR (CDCl3) delta 3.13 (s, 3H), 6.97 (s, 1H), 7.07-7.35 (m, 1H), 7.58-8.18 (m, 9H), 8.30-8.44 (m, 2H), 9.18 (br s, 1H): precise mass calcd for C23H17N3O6S m/e 463.0855, found 463.0871.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:17])([CH3:16])[N:6](C(OC)=O)[CH2:7]2.[OH-].[K+]>C(O)CO.O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:17])([CH3:16])[NH:6][CH2:7]2
Reactant: COC(=O)N1Cc2cccc(Br)c2CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: CC1(C)Cc2c(Br)cccc2CN1
Temperature: 150 °C
Yield: 40.5 %

Procedure:
To a solution of Intermediate 24E (4.6 g) in ethylene glycol (50 mL) was added 50% aqueous KOH solution (23 mL) and the reaction was heated at 150° C. for 3 days. The reaction mixture was cooled, diluted with H2O, extracted with EtOAc twice. The combined organics were extracted with 1.5 N HCl solution, the aqueous layer was basified with 10% NaOH solution, extracted with EtOAc twice and the combined organics were washed with H2O, brine, dried over Na2SO4, filtered and concentrated to give Intermediate 24 (1.5 g, 39.4%) as a brown liquid. MS (ESI) m/z: 242.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1.[CH2:24]=[O:25].C[O-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([CH2:24][OH:25])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reactant: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1(CO)COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a mixture of methyl 6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-carboxylate (400 mg) and DMSO (11 mL) were added paraformaldehyde (37.4 mg) and sodium methoxide (6.8 mg). The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and 1N HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (332.6 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:12][O-:13].[Na+]>O1CCOCC1>[CH3:12][O:13][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: OCCOc1ccc(Cl)nc1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(OCCO)cn1
Temperature: 130 °C

Procedure:
A mixture of the product of Example 203, Step 1 (513 mg, 2.96 mmol) and freshly prepared NaOMe (3.06 g, 56.6 mmol) in dry dioxane (25 mL) was heated in a sealed Pyrex tube at 130° C. for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2. The organic phase was washed with brine, dried (MgSO4), and concentrated to give the crude product as an oil (430 mg). Purification by column chromatography, using isohexane/EtOAc (1:1) as an eluent, gave the title product as a white solid. Yield 258 mg (51%); MS m/z 169 (M)+. Anal. (C8H11NO3) C, H, N.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][NH:21][NH2:22]>>[CH3:20][N:21]1[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])=[CH:14][C:15]([CH3:16])=[N:22]1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Reactant: CNN
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(C)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and methylhydrazine according to the procedure of Example 28.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH2:23][CH2:22][CH2:21][CH2:20][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[F:19])=[O:10].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH2:23][CH2:22][CH2:21][CH2:20][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[F:19])=[O:10])(=[O:27])[CH3:26]
Reactant: O=C(NCCCO)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCNC(=O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In pyridine (20 ml) was dissolved N-(3-hydroxypropyl)N'-(2-fluoro-4-chlorophenyl)-3,4,5,6-tetrahydrophthalamide (1.5 g), followed by addition of acetic anhydride (10 ml). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 200 ml of ice-water and, after stirring, the precipitate was recovered by filtration and rinsed with water. After drying, it was recrystallized from ethyl acetate-n-hexane. Yield 0.9 g; m.p. 127°-128° C.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[O:15]1[C:19]2([CH2:29][CH2:28][C:22]3([CH2:26][CH2:25][O:24][CH:23]3O)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:15]1[C:19]2([CH2:29][CH2:28][C:22]3([CH2:26][CH2:25][O:24][CH2:23]3)[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1
Reactant: OC1OCCC12CCC1(CC2)OCCO1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CC2(CCC3(CC2)OCCO3)CO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of triethylsilane (1.965 mL, 12.30 mmol) in DCM (40 mL), under nitrogen, at −78° C. was successively added trifluoroacetic acid (0.948 mL, 12.30 mmol) and [1,4,10-trioxadispiro[4.2.4.2]tetradecan-9-ol](0.878 g, 4.1 mmol) in DCM (40 mL) at −78° C. The resulting mixture was slowly warmed to 0° C. and stirred for 2 hours. Saturated aqueous NaHCO3 solution was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].[Al+3].[Cl-].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:15](=[O:17])[CH3:16])=[CH:7][C:6]=3[CH2:5]2)=[CH:13][CH:14]=1
Reactant: Brc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc2c(c1)Cc1cc(Br)ccc1-2

Procedure:
1-(7-bromo-9H-fluoren-2-yl)-ethanone is prepared by the reaction of 2-bromofluorene (available from Aldrich Chemical Company, Milwaukee, Wis.) with acetic anhydride/AlCl3/nitrobenzene according to Tsuno et al., Bull. Chem. Soc. Jpn., 51, 601-607 (1978), incorporated herein by reference.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[Cl:30])=[CH:14][CH:13]=2)[C:9]#[N:10])=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.[CH3:35][O:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>>[Cl:30][C:23]1[CH:24]=[C:25]([CH3:29])[CH:26]=[C:27]([Cl:28])[C:22]=1[O:21][CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:45]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH2:39][CH2:38][CH2:37][O:36][CH3:35])=[CH:3][C:4]=2[C:31]([F:34])([F:33])[F:32])[C:9]#[N:10])=[CH:13][CH:14]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(Br)cc3C(F)(F)F)cc2)c(Cl)c1
Reactant: COCCCc1ccccc1B(O)O
Product: COCCCc1ccccc1-c1ccc(C(C#N)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using 2-[4-bromo-2-(trifluoromethyl)phenyl]-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propanenitrile from step 1 and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3, step 1 as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (5 to 10%, in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([OH:33])=O)([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH2:14][C:13](=[O:34])[NH:12][CH:11]3[C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:56][S:57]([NH2:60])(=[O:59])=[O:58].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:31]([NH:60][S:57]([CH3:56])(=[O:59])=[O:58])=[O:33])([CH2:25][CH2:26][CH3:27])[CH2:28][CH2:29][CH3:30])[CH2:14][C:13](=[O:34])[NH:12][CH:11]3[C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:5]2=[CH:4][CH:3]=1
Reactant: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-propyl-butoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (80 mg, 0.13 mmol) and CDI (40 mg, 0.25 mmol) in DMF (2 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of methanesulfonamide (123 mg, 1.3 mmol) and NaH (52 mg, 60%, 1.3 mmol) in DMF (2 mL), which had been stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water and the aqueous solution was acidified by concentrated HCl solution. After the aqueous phase was extracted with EtOAc twice, the combined organic layers were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (60 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BrH:20].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Br
Reactant: CCCCCc1ccc(-c2ccc(CO)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
A solution of 9.4 g of 4-(hydroxymethyl)-4'-pentylbiphenyl in 150 ml of methylene chloride was placed at 0° C. in a sulphonation flask under argon gasification and treated within 5 minutes with 3.4 ml of a 62% aqueous hydrogen bromide solution. The mixture was subsequently stirred at room temperature for a further 15 hours, then poured into 50 ml of 5% sodium hydrogen carbonate solution and extracted three times with 100 ml of methylene chloride each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (10.8 g) on silica gel with 5% ethyl acetate/petroleum as the eluant gave 7.5 g (64%) of 4-(bromomethyl)-4'-pentylbiphenyl as a colourless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:10]1[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]=1[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:22]#[N:23])([CH3:9])[CH3:8].[CH2:28](I)[CH3:29].C(OCC)(=O)C>CN(C=O)C>[CH2:28]([N:12]1[C:11]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=2)[C:22]#[N:23])=[C:10]([CH:7]([CH3:9])[CH3:8])[C:15](=[O:16])[NH:14][C:13]1=[O:17])[CH3:29]
Reactant: CCI
Reactant: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(Oc2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
Potassium carbonate (24 mg, 0.172 mmol, 1.0 eq.) was added to 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzonitrile (103) (59 mg, 0.207 mmol, 1.2 eq.) in 2.0 mL DMF. The reaction mixture was stirred at room temperature for 10 minutes, then ethyl iodide (14 μL, 0.172 mmol) was added. The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, which was then washed with brine. The organic layer was concentrated and purified (silica gel, 20-80% EtOAc/hexane), followed by reverse phase HPLC (MeCN/water) to give a white powder (15 mg, 28%). LC-MS shows 314.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.17 (br, 1H), 7.25 (s, 1H), 7.08 (s, 1H), 7.00 (s, 1H), 3.77 (t, 2H), 2.69 (m, 1H), 2.42 (s, 3H), 1.2 (m, 9H).
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: CCN(CC)CCCCl
Reactant: COc1ccc2[nH]cc(CC3NC(=O)NC3=O)c2c1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
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: C([Li])CCC.Br[C:7]1[CH:22]=[CH:21][C:10]([CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[C:9]([CH2:23][CH3:24])[CH:8]=1.[B:25](OC)([O:28]C)[O:26]C.Cl>C1COCC1>[Si:14]([O:13][CH2:12][CH2:11][C:10]1[CH:21]=[CH:22][C:7]([B:25]([OH:28])[OH:26])=[CH:8][C:9]=1[CH2:23][CH3:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: COB(OC)OC
Reactant: CCc1cc(Br)ccc1CCO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(B(O)O)ccc1CCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 0 %

Procedure:
n-Butyl Lithium (4.7 mL) was added to a solution of 46A (2.1 g, 6.1 mmol) in THF at −78° C. After stirring to 10 min at −78° C., trimethyl borate (1.0 mL, 12.3 mmol) was added dropwise. After warming to ambient temperature, the reaction mixture was stirred an additional 2 h. HCl (1.0 M, 30 mL, aqueous) was added to the mixture at −40° C. and stirred at −20° C. for 30 min. The solution was extracted with diethyl ether. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (0% to 20% MeOH in CH2Cl2) to yield 46B (0.90 mg, 48%) as a clear oil. MS (ESI) m/z 307.4 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH:12]([CH3:17])[C:13]([NH:15][NH2:16])=O.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C(O)CCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]2[N:15]([C:13]([CH:12]([C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)[CH3:17])=[N:20][N:21]=2)[N:16]=1
Reactant: CC(C(=O)NN)c1cc2cccnc2cc1F
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCO
Product: CC(c1cc2cccnc2cc1F)c1nnc2ccc(Cl)nn12
Temperature: 140 °C
Yield: 44.3 %

Procedure:
A sealed tube was charged with 2-(7-fluoroquinolin-6-yl)propanehydrazide (11.4 g, 48.9 mmol), 3,6-dichloro-pyridazine (8.01 g, 53.8 mmol) and 190 mL of n-butanol. The mixture was heated at 140° C. for 12 h. After cooling, the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound (7.1 g, 44%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.95 (d, 1H), 8.49-8.46 (m, 2H), 7.96 (d, 1H), 7.84 (d, 1H), 7.58 (dd, 1H), 7.48 (dd, 1H), 5.17 (q, 1H), 1.88 (d, 3H). LCMS (method A): [MH]+=328, tR=5.00 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=O)[CH:3]=1.O[C:11]1[CH:16]=[C:15](C)O[C:13](=O)[CH:12]=1.P(Br)(Br)Br.FC(F)(F)C(O)=O.C(ON=O)CC(C)C.C(O)(=O)C1C(=CC=CC=1)N>COCCOC.CCCCCC.C(OC(=O)C)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:13]2[C:4]([CH:3]=1)=[CH:15][CH:16]=[CH:11][CH:12]=2
Reactant: Cc1cc(Br)cc(=O)o1
Reactant: Cc1cc(O)cc(=O)o1
Agent: BrP(Br)Br
Agent: CC(C)CCON=O
Agent: Nc1ccccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: Cc1cc(Br)cc2ccccc12
Yield: 68 %

Procedure:
A 250 ml three-neck round bottomed flask was equipped with a reflux condenser and two addition funnels. 430 mg(2.2 mmol) of 4-bromo-6-methyl-2-pyrone prepared according to the procedure described in a literature(see: M. Cervera, Tetrahedron, 46, 7885, 1990) from 4-hydroxy-6-methyl-2-pyrone and phosphorus tribromide was dissolved in 100 ml of ethyleneglycol dimethylether(DME), which was then introduced into the flask. Catalytic amount of trifluoroacetic acid was added and the resulting mixture was heated under reflux. While refluxing, isoamylnitrite(0.48 ml, 3.4 mmol) and anthranilic acid (470 mg, 3.4 mmol) in DME which were contained in the funnels, respectively, were added dropwise simultaneously. After confirming that the starting materials were completely reacted, addition was stopped and the reaction solution was cooled. The solvent was removed under reduced pressure and the remaining materials were diluted with 250 ml of dichloromethane. The resulting solution was sequentially washed with 5% aqueous hydrochloric acid solution, 5% aqueous sodium hydroxide solution and water, and then dried over anhydrous magnesium sulfate. The solvent was removed and the residue was subjected to column chromatography(eluent: n-Hexane/ethylacetate=20/1, v/v) to give 340 mg(Yield 68%) of the title compound.