Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Li]CCCC.CCCCCC.CON(C)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]
Reactant: Clc1cccc(Br)c1
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-bromo-3-chlorobenzene (15 g, 78.3 mmol) in anhydrous THF (150 mL) cooled to −78° C. was added dropwise a solution of 2.5 M n-BuLi in hexane (31.3 mL, 78.34 mmol). The reaction mixture was stirred at −78° C. for 1 h and a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (17.8 g, 65.3 mmol) in anhydrous THF (50 mL) was added dropwise. After addition, the mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl (250 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (PE/EtOAc 5:95) to give (R)-tert-butyl 3-(3-chlorobenzoyl)piperidine-1-carboxylate (12.9 g, 51%). 1H NMR (400 MHz, CDCl3): 1.45 (s, 9H), 1.54-1.73 (m, 2H), 1.75 (m, 1H), 2.00 (m, 1H), 2.71-2.78 (m, 1H), 2.93 (m, 2H), 3.30-3.35 (m, 1H), 4.22 (m, 1H), 7.39-7.42 (t, 1H), 7.52 (d, 1H), 7.89 (d, 1H), 7.90 (m, 1H). MS (E/Z): 324 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: NCCO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NCCO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 2-aminoethanol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CCCCCC.C([Li:25])CCC>C1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([Li:25])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(Br)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: [Li]c1ccc(OCCCCCC)cc1
Temperature: 25 °C

Procedure:
24.0g (0.093mol) of 4-hexyloxybromobenzene was dissolved in 30ml of benzene and stirred at room temperature in a stream of nitrogen. To the resulting solution was added drop-wise 50ml of hexane solution including 15% of butyllithium was added drop-wise for 30 minutes and the solution was maintained under stirring for 2 hours. The produced precipitate gathered by filtration in a stream of nitrogen was dried under reduced pressure to yield 11.1g of 4-hexyloxyphenyllithium.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14](=[O:15])[NH:13][C:12]2[N:11]=[CH:10][C:9](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:8][C:7]=2[CH2:6]1)=[O:4].Cl.[F:22][C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:18](=[O:20])/[CH:17]=[CH:16]/[C:9]3[CH:8]=[C:7]4[C:12](=[N:11][CH:10]=3)[NH:13][C:14](=[O:15])[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]4)[CH2:33][CH2:34]2)=[CH:35][CH:36]=1
Reactant: COC(=O)C1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reactant: Fc1ccc(OCC2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2cc(/C=C/C(=O)N3CCC(COc4ccc(F)cc4)CC3)cnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To a solution of (2E)-3-[6-(methoxycarbonyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylic acid (96 mg, 0.35 mmol; which may be prepared as described in Step 4) in DMF (8 mL) were added 4-[(4-fluorophenoxy)methyl]piperidine hydrochloride (102 mg, 0.42 mmol; which may be prepared as described in Step 2), DIPEA (144 μL, 0.83 mmol), 4-DMAP (17 mg, 0.14 mmol) and EDAC (80 mg, 0.42 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluent: dichloromethane/MeOH from 100/0 to 80/20) to give a first solid which is purified again on preparative TLC (eluent: dichloromethane/MeOH 95/5) to give the title compound (15 mg, 8%) as a white solid.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][C:22]([CH2:25]O)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:58]([NH:61][C:62]1[CH:67]=[CH:66][C:65]([CH2:68][C:69]([NH:71][C:72]2[C:73](=[O:88])[N:74]([CH2:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=3[F:87])[C:75](=[O:79])[NH:76][C:77]=2[NH2:78])=[O:70])=[CH:64][CH:63]=1)(=[O:60])[CH3:59]>O1CCCC1>[C:58]([NH:61][C:62]1[CH:63]=[CH:64][C:65]([CH2:68][C:69]([NH:71][C:72]2[C:73](=[O:88])[N:74]([CH2:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=3[F:87])[C:75](=[O:79])[N:76]([CH2:25][C:22]3[N:23]=[CH:24][N:20]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:21]=3)[C:77]=2[NH2:78])=[O:70])=[CH:66][CH:67]=1)(=[O:60])[CH3:59]
Reactant: OCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CC(=O)Nc2c(N)n(Cc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(=O)n(Cc3ccccc3F)c2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.6 %

Procedure:
A mixture of (1-trityl-1H-[1,2,4]triazol-3-yl)-methanol (320 mg, 0.47 mmol) and triphenylphosphine (136 mg, 0.47 mmol) in tetrahydrofuran (9.4 mL) cooled to 0° C. was treated with diethylazodicarboxylate (0.82 mL, 0.47 mmol). This solution was warmed to 25° C. for 5 min and then was re-cooled to 0° C. where it was stirred for an additional 10 min. At this time, the reaction was treated with 2-(4-acetylamino-phenyl)-N-[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (200 mg, 0.47 mmol). The reaction was then allowed to slowly warm to 25° C. The resulting solids were removed by filtration. The filtrate was diluted with ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh) afforded 2-(4-acetylamino-phenyl)-N-[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1-(1-trityl-1H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-pyrimidin-5-yl]-acetamide (55 mg, 15.6%) as a yellow foam: LR-APCI for C43H37FN8O4 (M+H)+at m/z=749.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[S:13][C:14]([CH:17]=[N:18]O)=[CH:15][N:16]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CS(Cl)(=O)=O>N1C=CC=CC=1.ClCCl>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[S:13][C:14]([C:17]#[N:18])=[CH:15][N:16]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2ncc(C=NO)s2)cn1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(Oc2ncc(C#N)s2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
To a 0° C. solution of Example 68E (464 mg, 1.66 mmol) in pyridine (10 mL) was added methanesulfonyl chloride (0.53 mL, 6.64 mmol). The reaction was warmed to 25° C., stirred for 4 hours and diluted with dichloromethane (50 mL). The mixture was washed with 10% HCl (2×50 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 20% ethyl acetate in hexanes to provide 363 mg of the title compound (84%) as a off-white solid, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31 (d, J=6.25 Hz, 6H) 5.14-5.30 (m, 1H) 6.89 (d, J=9.19 Hz, 1H) 7.87 (dd, J=9.01, 3.13 Hz, 1H) 8.23 (s, 1 H) 8.31 (d, J=2.57 Hz, 1H); MS (ESI) m/z 262.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[OH:22]>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[O:22][C@@H:11]1[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C@H:10]1[OH:13]
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: Oc1c(Cl)cccc1Cl
Solvent: ClCCl
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1c(Cl)cccc1Cl

Procedure:
A mixture of 35.0 g. of 1-benzyl-3,4-epoxypyrrolidine and 32.6 g. of 2,6-dichlorophenol was heated at 125° C. for 3 hr. The mixture was cooled, dissolved in methylene chloride and extracted with dilute sodium hydroxide. The residue after the solvent was evaporated was purified by column chromatography. The product was eluted with 30% ethyl acetate in benzene and crystallized from cyclohexane. Yield was 43 g (64%), m.p. 78°-80° C.
Reaction SMILES: [ClH:1].C([NH:5][CH2:6][CH2:7][N:8]1[C:24](=[O:25])[C:23]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=4)[NH:15][C:14]=3[C:13]([CH3:28])=[CH:12][C:11]=2[C:9]1=[O:10])(=O)C>C(O)C>[ClH:1].[NH2:5][CH2:6][CH2:7][N:8]1[C:24](=[O:25])[C:23]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=4)[NH:15][C:14]=3[C:13]([CH3:28])=[CH:12][C:11]=2[C:9]1=[O:10]
Reactant: COc1ccc2[nH]c3c(C)cc4c(c3c2c1)C(=O)N(CCNC(C)=O)C4=O
Agent: Cl
Solvent: CCO
Product: COc1ccc2[nH]c3c(C)cc4c(c3c2c1)C(=O)N(CCN)C4=O
Temperature: 25 °C
Yield: 68 %

Procedure:
20 ml of ethanol and 10 ml of concentrated hydrochloric acid were added to 150 mg of N-(2-acetylaminoethyl)- 6-methoxy-1-methylcarbazole-3,4-dicarboximide. The mixture was refluxed for 15 hours and then cooled to room temperature. The resulting crystals were collected by filtration, washed with ethanol, and dried to obtain 100 mg (yield: 68%) of N-(2-aminoethyl)-6-methoxy-1-methylcarbazole-3,4-dicarboximide hydrochloride as yellow crystals.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)N)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCO.C(O[CH:24](OCC)[CH2:25][CH2:26][CH2:27][NH:28][CH3:29])C>O.Cl>[CH:1]1([CH2:7][CH2:8][N:9]2[C:11]3[C:16](=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:25]([CH2:26][CH2:27][NH:28][CH3:29])=[CH:24]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(N(N)CCC2CCCCC2)cc1
Reactant: CCOC(CCCNC)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNCCc1cn(CCC2CCCCC2)c2ccc(C)cc12
Temperature: 90 °C
Reaction time: 6 h

Procedure:
The title compound was prepared by General Method 3. A solution of 1-(2-cyclohexylethyl)-1-p-tolylhydrazine (0.15 g) in water (1 mL) and conc. HCl (0.18 mL) was heated to 60° C. EtOH (1 mL) was added followed by 4,4-diethoxy-N-methylbutan-1-amine (0.12 g) and the temperature was raised to 90° C. Conc. HCl (0.1 mL) was added and the heating was continued for an additional 6 h after which the reaction mixture was cooled and stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (eluent EtOAc/EtOH/NH3: 9/1/0.1) to obtain 79 mg of product.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH:16]1[CH:21]=[C:20]2[C:22]([CH:25]=O)=[CH:23][S:24][C:19]2=[CH:18][CH:17]=1>CO>[CH2:9]([N:8]1[C:3]([NH:1][N:2]=[CH:25][C:22]2[C:20]3[CH:21]=[CH:16][CH:17]=[CH:18][C:19]=3[S:24][CH:23]=2)=[CH:4][C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: O=Cc1csc2ccccc12
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Solvent: CO
Product: CC(C)Cn1c(NN=Cc2csc3ccccc23)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Hydrazino-1-isobutyl-3-methyl-2,4(1H,3H)-pyrimidinedione (1.2 g, 5.65 mmol) was dissolved in methanol (100 mL). To the yellow/brown solution was added thianaphthene-3-carboxaldehyde (917 mg, 5.65 mmol). A brown precipitate began to form after about 20 min. The mixture was stirred at room temperature for 3 h under nitrogen gas. HPLC showed complete formation of hydrazone (Rt=1.87 min, Kromasil, C8) The solvent was removed in vacuo and the brown slurry was pumped down to reveal a brown/yellow powder. Yield=1.85 g (92%), TLC, Rf=0.14 (CHCl3/MeOH); Rt:1.87 min. MS:357 (M+H)
Reaction SMILES: O.NN.[C:4]1([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=O)=[CH:17][N:18]=3)[N:15]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].C(O)COCCO>O>[C:4]1([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([CH2:19][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)=[CH:17][N:18]=3)[N:15]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3ccccc3)nn12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cc1
Reaction time: 0.08 h

Procedure:
A 10-20 mL microwave vial was charged with hydrazine hydrate (0.0312 ml, 0.642 mmol), (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.150 g, 0.428 mmol), KOH (0.0961 g, 1.71 mmol), and diethylene glycol (4.09 ml, 42.8 mmol), sealed, then placed in a Personal Chemistry microwave at 130° C. for 20 minutes after a 5 minute pre-stir. The mixture was diluted with water (75 mL), then extracted with DCM (2×75 mL). The combined organics were washed with brine (75 mL), then dried with MgSO4, filtered, and concentrated to give a brown solid, then purified by prep HPLC to give the product as the formic acid salt. MS (ESI pos. ion) m/z: 337 (MH+). Calc'd exact mass for C22H16N4: 336.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[H-].[Na+].Br[CH2:32][CH2:33][CH2:34][Cl:35].O>CN(C)C=O>[Cl:35][CH2:34][CH2:33][CH2:32][NH:1][C:2]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: ClCCCBr
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCl)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
814 mg (2.09 mmol) of 5-amino-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one obtained in Example 66 was dissolved in 15 ml of dimethylformamide under argon atmosphere, 256 mg of sodium hydride (60% oil dispersion) and 0.42 ml of 1-bromo-3-chloropropane were added under ice-cooling and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to give 193 mg (20%) of 5-(3-chloropropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:5](=[O:7])[CH3:6])[CH2:19][CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (2.32 g, 24.6 mmol) was added dropwise to a cold (0° C.) solution of (4-fluorophenyl)(piperidin-4-yl)methanone (5.00 g, 20.5 mmol) in DCM (33 mL) and triethylamine (10.0 mL, 71.8 mmol). The resulting mixture was removed from the ice bath after 5 minutes and stirred at room temperature for 2 hours. The reaction was then added to a mixture of 1 M aqueous K3PO4 (100 mL), H2O, and DCM was added. The layers were separated and the aqueous layer again extracted with DCM. The combined organic layers was dried (Na2SO4), filtered, concentrated under reduced pressure and chromatographed (CH2Cl2/EtOAc) to provide the title compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.N[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(C)(N)CO
Solvent: CCO
Product: CC(C)(CO)Nc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 66.2 %

Procedure:
A mixture of 20 g of 4-chloro-1,2-dinitrobenzene and 36 g of 2-amino-2-methylpropan-1-ol in 100 ml of EtOH is refluxed for 36 hours. The reaction mixture is evaporated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of HCl and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM as the eluent to give 16 g of the expected product, which is used as such in the next step.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[C:25]([CH2:33][C:34](=O)[CH3:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[C:25]([C:33]1[C:34]([CH3:35])=[N:2][C:3]2[C:4]([C:5]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=[CH:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2c(C(=O)c3ccccc3)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 69.8 %

Procedure:
A mixture of 2-amino-4,5,3',4'-tetramethoxy-benzophenone hydrochloride (2.0 g), benzoylacetone (0.917 g) and ethanol (35 ml) was stirred under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was poured into a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (10:1, v/v) gave 3-benzoyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methylquinoline (1.75 g, 70%). This compound was recrystallized from ethanol to give colorless prisms, mp. 151°-152° C.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[CH2:12]([O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][C:28]#[CH:29])=[CH:21][CH:22]=2)[CH:17]=1)[C:13]#[CH:14]>O>[CH:27]([O:26][C:20]1[CH:21]=[CH:22][C:23]2[C:18](=[CH:17][C:16]([O:15][CH:12]=[C:13]=[CH2:14])=[CH:25][CH:24]=2)[CH:19]=1)=[C:28]=[CH2:29]
Reactant: C#CCOc1ccc2ccc(OCC#C)cc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C=COc1ccc2ccc(OC=C=C)cc2c1
Yield: 45.3 %

Procedure:
Into a similar reaction vessel, as used in the abovementioned reaction, were placed 2.316 parts of t-BuOK and 13.108 parts of THF and to this, a mixture of 10,000 parts of 2,7-dipropargyloxynaphthalene and 23.333 parts of THF was added dropwise. The content was reacted at 50° C. for 60 minutes and then a deionized water was added to stop the reaction. THF layer and water layer were removed off by using an evaporator, and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 2,7-diallenyloxy naphthalene as white rystals (M.P. 80.5°-83.5° C.)
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[S:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1.C1(C)C=CC=CC=1>O>[Br:2][CH2:6][C:7]1[S:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(CO)s1
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(CBr)s1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 261.6 %

Procedure:
Phosphorus tribromide (PBr3) (10.45 g) was added dropwise to a mixture of 2-hydroxymethyl-5-nitrothiophene (17.7 g) and toluene (150 ml) and this mixture was stirred at 70° C. for 1.5 hours. The reaction mixture was poured into water and extracted with ether. The ether layer was washed with water and dried (MgSO4), after which the solvent was evaporated off. The residual oil was subjected to solica gel column chromatography and eluted with chloroform to yield 2-bromomethyl-5-nitrothiophene (22.43 g, 92%) as an oil.
Reaction SMILES: S(C1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=O)=O.CC([O-])(C)C.[K+].O.[CH3:19][CH2:20][O:21][C:22]([CH3:24])=O>C1COCC1>[CH:10]([C:8]1[C:9]2[CH2:19][CH2:20][O:21][C:22]=2[CH:24]=[CH:6][CH:7]=1)=[CH2:11]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cccc2c1CCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
The Part C tosylate (100 g, 314 mmol) was dissolved in THF (1200 mL) in a 2000 mL three-neck round bottomed flask equipped with a mechanical stirrer, a digital thermometer, and a pressure equalizing addition funnel at room temperature. The reaction mixture was cooled to 0° C. by an ice-water bath. To this was added a solution of t-BuOK (1 M, 345.5 mL) in THF dropwise at 0° C. over a period of 110 min. The reaction mixture was warmed to ambient temperature and stirred for additional 2 hr. Water (350 mL) and EtOAc (600 mL) were added and the two layers were separated. The aqueous layer was further extracted with EtOAc (2×150 mL). The combined EtOAc layers were washed with brine (2×150 mL) dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give 46 g of the title styrene in 100% yield.
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H][H]>[Pt].C(N(CC)CC)C>[CH3:1][CH:2]([CH:8]([OH:9])[C:10]([F:13])([F:11])[F:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pt]
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)C(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Ethyl 2-methyl-4,4,4-trifluoroacetoacetate (50 g), under a blanket of nitrogen gas, is heated to 40° C. and treated with platinum (0.1 g of 5% Pt/C, 0.01% load) and triethylamine (0.2 g, 0.4 % load). Hydrogen is charged to a pressure of 5 bars, and the mixture agitated at 40° C. for 6h. After filtration to remove the catalyst, 48.5 g (96% yield) of ethyl 2-methyl-4,4,4-trifluoro-3-hydroxybutyrate is obtained.