Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Na].[O:11]1[CH2:26][CH:12]1[CH2:13][N:14]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:15][CH:16]1[O:18][CH2:17]1.O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][CH:16]2[CH2:15][N:14]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:13][CH:12]([CH2:26][OH:11])[O:18]2)=[CH:5][CH:4]=1
Reactant: c1ccc(CN(CC2CO2)CC2CO2)cc1
Reactant: COc1ccc(O)cc1
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(OCC2CN(Cc3ccccc3)CC(CO)O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
A solution of 6.21 g of p-methoxyphenol (0.05 mole) in 150 ml of dry dioxane is stirred under dry nitrogen and 0.4 g of finely cut sodium added. The mixture is stirred at room temperature for 1 hour and then 10.96 g of N,N-bis(2,3-epoxypropyl)benzylamine (0.05 mole) is added to the reaction mixture. The mixture is then heated at reflux for 18 hours, cooled to room temperature and poured into 300 ml of water. The aqueous mixture is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined, washed with 200 ml of water and 200 ml of saturated NaCl solution. The CHCl3 layer is then dried over anhydrous NaSO4, evaporated in vacuo to yield 15.4 g (90%) of crude product as a pale yellow oil. The oil is chromatographed on 300 g of neutral Alumina III to give 11.8 g (69%) of wet product (eluted with 650 ml of chloroform and 200 ml of 2% methanolic chloroform). 11.8 g of wet product is dried in vacuo to give the desired product as a clear colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1([F:9])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.N(CC)(CC)CC.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH3:22][O:21][C:19](=[O:20])[CH2:18][N:6]1[CH2:7][CH2:8][C:3]([F:9])([F:2])[CH2:4][CH2:5]1
Reactant: COC(=O)CBr
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)CN1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.1 %

Procedure:
Treat a ° C. solution of 4,4-difluoropiperidin HCl (17.91 g, 0.113 mol) and (CH3CH2)3N (28.75 g, 0.284 mol) in CH2Cl2 (250 mL) with methyl bromoacetate (17.37 g, 0.113 mol), warm to room temperature, and stir 16 hours at room temperature under N2. Dilute the reaction with saturated NaHCO3 and water and extract twice with 3:1 chloroform:isopropanol. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with 0 to 5% methanol in CH2Cl2 to afford 14.22 g (65%) of the titled product. Rf=0.77 (9/1 CH2Cl2/methanol). ES MS (m/z): 194 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
17.64 g (128 mmol) of 4-hydroxybenzoic acid (Aldrich, purity 99%) and 14.32 g (255 mmol) of potassium hydroxide are dissolved in 30 ml of distilled water and added to 260 ml of ethanol. After addition of 33.0 g (29.7 ml, 0.17 mol) of 1-bromooctane (Aldrich, purity 99%), the solution is heated at the boil for 24 hours with stirring. A further 14.32 g (255 mmol) of potassium hydroxide are then added, and the mixture is refluxed with stirring for a further two hours. After the reaction batch has been cooled, the solvent is substantially removed under reduced pressure, and the residue is taken up in distilled water and strongly acidified using 2 M hydrochloric acid solution. The residue is extracted with chloroform, dried over magnesium sulfate, evaporated and recrystallized from acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:46][C:47]([F:61])([F:60])[C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]([C:51]2[CH:50]=[CH:49][C:48]([C:47]([F:60])([F:61])[F:46])=[CH:53][CH:52]=2)[CH2:59][CH2:58]1)=[O:6]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 2-Chloro-5-methanesulfonyl-benzoic acid (102 mg, 0.43 mmol) in dimethylformamide (20 ml) were successively added TBTU (153 mg, 0.48 mmol), N-ethyldiisopropylamine (0.28 ml, 2.17 mmol) and 1-(4-trifluoromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7], 100 mg, 0.43 mmol). The reaction was then stirred at room temperature for two hours, then concentrated in vacuo and purified by column chromatography (SiO2, 50 g, heptane/ethylacetate=0 to 100%), to give the title compound as a colorless gum (170 mg, 0.38 mmol). MS (m/e): 464.3 (M+NH4+, 100%)
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[O:12](C1C=C(C=CC=1)N)C1C=CC(N)=CC=1.NC1C=C(C=CC=1)OC1C=CC=C(OC2C=CC=C(N)C=2)C=1.C1(=O)OC(=O)C2=CC=CC=C12>CN1CCCC1=O>[CH:8]1[CH:7]=[C:3]([C:4]([NH2:5])=[O:6])[C:2]([C:1]([OH:11])=[O:12])=[CH:10][CH:9]=1
Reactant: Nc1ccc(Oc2cccc(N)c2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Nc1cccc(Oc2cccc(Oc3cccc(N)c3)c2)c1
Agent: O=C1OC(=O)c2ccccc21
Solvent: CN1CCCC1=O
Product: NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The following example illustrates the synthesis of a phthalimide-terminated imide oligomer with theoretical number average molecular weight of 11,600 g/mole. 3,4'-Oxydianiline (ODA) (25.0 mmole, 5.0062 g) and 1,3-bis(3-aminophenoxy)benzene (APB) (25.0 mmole, 7.3084 g) were dissolved in N-methylpyrrolidinone (NMP) (~35 mL) in a flask equipped with a mechanical stirrer, condenser and nitrogen inlet. 3,3',4,4'-Biphenyl tetracarboxylic dianhydride (BPDA) (47.87 mmole, 14.0845 g) and phthalic anhydride (PA) (4.260 mmole, 0.6310 g) were slurried in NMP (~35 mL) and were added to the solution. After washing with ~38 mL of NMP to provide a 20% solids content reaction, an exotherm of 10-15° C. was observed. The exotherm quickly subsided and the reaction was stirred at 25° C. for 16 h to form the phthalamide acid-terminated polyamide acid. The inherent viscosity (ηinh) of the phthalamide acid-terminated polyamide acid was 0.49 dL/g in NMP at 25° C. To imidize, toluene (30 mL) was added and the reaction was heated at 160° C. for 24 h. After cooling to 25° C., the polymer was still soluble. The solution was poured into water to precipitate a powder which was washed twice in water and dried at ~230° C. in a vacuum to afford a yellow solid in high yield. The resulting phthalimide-terminated polyimide was soluble in NMP and had a glass transition temperature 219° C. A film cast from the polyamide acid solution and dried 1 hour each at 100, 225, and 371° C. had a Tg of 223° C. and was tough and creasible.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([Cl:7])[N:6]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Cl:7][C:5]1[N:6]=[C:2]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:3][CH:4]=1
Reactant: C1COCCN1
Reactant: Clc1csc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Clc1csc(N2CCOCC2)n1
Temperature: 110 °C
Yield: 91.2 %

Procedure:
In a 75 mL dry pressure vessel, 2,4-dichloro-thiazole (500 mg, 3.2 mmol) and morpholine (560 μL, 6.4 mmol) are dissolved in dry THF (2.0 mL). Cs2CO3 (1.56 g, 4.8 mmol) is added, and the reaction vessel is sealed. The reaction mixture is heated to 110° C. overnight. Solvent is removed via reduced pressure, and the crude reaction mixture is purified via silica gel chromatography to give the title compound (597 mg, 2.92 mmol, 91%). 1H-NMR (CDCl3), δ 3.45 (m, 4H), 3.79 (m, 4H), 6.31 (s, 1H) ppm. ES-MS (m/z): calcd for C7H9ClN2OS (M+H)+: 204.68; found: 205.2.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH:13]=[N:14][NH:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([N+]([O-])=O)[CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][C:13]1[C:28]([CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:15]([CH:16]([CH3:17])[CH3:18])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C(=Cc1ccc(F)cc1)CC1OCCO1
Reactant: CC(C)NN=CCCNC(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of [3-(isopropyl-hydrazono)-propyl]-carbamic acid benzyl ester (0.5 g, 1.9 mmol) and 2-[3-(4-fluoro-phenyl)-2-nitro-allyl]-[1,3]dioxolane (0.48 g, 1.9 mmol) in pyridine (20 mL) was stirred at rt for 2 days. The mixture was cooled to rt, concentrated, and the residue purified by FCC to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[CH3:20]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:26]3[CH:27]=[CH:28][C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:30])=[CH:24][CH:25]=3)=[CH:9][C:8]=2[C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-tert-butylbenzene (Intermediate 112, 70.0 mg, 0.30 mmol) and ethyl-4-iodo benzoate (Reagent A, 85.0 mg, 0.30 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (19.0 mg, 0.01 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (70 mg, 0.01 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc-hexanes) afforded 70.0 mg (73%) of the title compound.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13](C3CCCCO3)[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([NH:27][C:28]2[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]([F:47])([CH3:46])[C:43](O)=O.CN(C)C=O.C(N(CC)C(C)C)(C)C.C(O)(=O)C>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:27]2[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]=[C:43]2[C:42]([F:47])([F:41])[CH3:46])[N:15]=3)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(F)(F)C(=O)O
Reactant: CC(C)(C)N1CCN(Cc2nc3c(N4CCOCC4)nc(Nc4ccccc4N)nc3n2C2CCCCO2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(F)(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)[nH]c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
N1-(8-((4-tert-butylpiperazin-1-yl)methyl)-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl)benzene-1,2-diamine (0.085 g, 0.15 mmol) and 2,2-difluoropropanoic acid (0.019 g, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL, 0.02 mol). N,N-Diisopropylethylamine (0.054 mL, 0.31 mmol) was added. The resulting solution was cooled at 0° C. for 20 minutes. N,N,N′N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.070 g, 0.00018 mol) was added and the reaction stirred overnight at room temperature. The reaction mixture was concentrated to dryness. Acetic acid (3.0 mL, 0.053 mol) was added to the crude residue and the reaction mixture was heated at 90° C. for 18 hours. The reaction mixture was cooled, filtered and concentrated to dryness. The crude was purified by reverse phase HPLC to give 457 (15.3 mg, 18%). [M+H]+=540.3
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH:9]3[CH2:13][CH:12]([CH2:14][OH:15])[O:11][CH:10]3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.[OH2:40]>C(Cl)Cl>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH:9]3[CH2:13][CH:12]([CH2:14][OH:15])[O:11][CH:10]3[C:4]=2[CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O-:38])(=[O:37])=[O:40])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O
Agent: OCC1CC2c3ccccc3Cc3ccc(F)cc3C2O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[2R-(2α, 3aα, 12bβ)]-11-fluoro-2-hydroxymethyl-3,3a,8,12b-tetrahydro-2H-dibenzo [3,4:6,7]cyclohepta[1,2-b]furan (4.1 g, 0.0144 mol) was dissolved in DCM (20 ml). Triethylamine (0.0173 mol) was added and the mixture was cooled on an ice-bath. A solution of 4-methyl-benzenesulfonyl chloride (0.0159 mol) in DCM (10 ml) was added over ±5 min. The mixture was stirred for 2 hours at 0° C. then allowed to warm to room temperature. The reaction mixture was stirred overnight at room temperature. Water (20 ml) was added. The layers were separated. The organic phase was stirred in a 10% aqueous potassium carbonate solution for one hour. The layers were separated. The organic layer was dried (MgSO4), filtered and the solvent evaporated. The residue was stirred in toluene (30 ml). A 10% aqueous potassium carbonate solution (30 ml) was added. The layers were separated. The organic layer was dried (MgSO4), filtered and the solvent evaporated, yielding 5.8 g (92%) of [2R-(2α, 3aα, 12bβ)]11-fluoro-3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-methanol-4-methylbenzenesulfonate, intermediate 1. An alternative method of preparing this intermediate is described in W003/048146 [CAS number=543741-40-8].
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>C(O)C>[CH3:11][N:12]1[CH2:17][CH2:16][C:15]2[NH:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:14]=2[CH2:13]1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CN1CCc2[nH]c3ccccc3c2C1
Temperature: 85 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Phenyl hydrazine hydrochloride (5 g, 34.57 mmol) and 1-methylpiperidin-4-one hydrochloride (4.5 g, 30.1 mmol, 1 eq.) was dissolved in of ethanol (150 mL) and stirred at 80-90° C. for overnight. The reaction was monitored by TLC. The mixture was cooled to RT, solvent was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated sodium bicarbonate solution. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 3.0 g of 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm) 8.0 (bs, 1H), 7.4 (d, 1H), 7.35 (d, 1H), 7.20-7.0 (m, 2H), 3.7 (s, 2H), 2.9 (s, 4H), 2.6 (s, 3H).
Reaction SMILES: [OH-].[Na+].O.Cl.[C:5]([NH2:13])(=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]([CH2:22][C:23](OCC)=[O:24])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C>O>[C:6]1([C:5]2[N:13]=[C:23]([OH:24])[CH:22]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a ice cooled solution of sodium hydroxide (2.4 g, 60 mmol) in water (30 ml) was added benzamidine hydrochloride hydrate (9.4 g, 60 mmol) and ethyl benzoylacetate (12.1 g, 63 mmol). Ethanol (ca 30 ml) was added and the mixture was stirred at room temperature overnight. The solid was filtered off, washed with water and diethyl ether and dried which gave the title compound (9.0 g, 60%), (M+H)+1 249.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.C(O)(=O)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([F:15])[C:12]=3[CH3:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 88.3 %

Procedure:
A mixture of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylate (1.97 g), concentrated sulfuric acid (1.6 ml) and acetic acid (12.8 ml) in water (9.6 ml) was refluxed for 1.5 hours. The reacting mixture was poured into ice-water (100 ml), the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (1.58 g) as white powder, mp 243°-245° C.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].P.[C:23]1([CH2:29][SH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[Pd]>[CH2:29]([S:30][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: P
Product: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1F

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate in appropriate solvent is added base under nitrogen atmosphere, followed by Pd catalyst, phosphine ligand and phenylmethanethiol. The reaction is generally carried out at high temperature (80-130° C., prefer 90-110° C.) and normally complete within several hours (8-24 h, prefer 12-18 h). Methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate is obtained after conventional workup.
Reaction SMILES: [Na].[CH3:2][C:3]1[O:9][CH:8]=[CH:7][C:5](=[O:6])[C:4]=1[OH:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO.O>[CH3:2][C:3]1[O:9][CH:8]=[CH:7][C:5](=[O:6])[C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1occc(=O)c1O
Reactant: BrCc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: Cc1occc(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.5 g of sodium were dissolved in 300 ml CH3OH and 63g of maltol were added and stirred at room temperature for one hour. 200 ml CH3OH were added and then 102 g benzylbromide were dropped in (30 minutes). Refluxing for 3 hours and distilling off the CH3OH then yielded a residue which was dissolved in 300 ml H2O/300 ml ethyl acetate. The organic phase was washed with water and evaporated. The remaining oil was distilled in vacuo. B.P. (43 mm) =148°-150° C., 81.5 g colorless oil of the title compound was isolated.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31](O)=[O:32])(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:31](=[O:32])[CH2:30][C@H:29]([O:28][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CI
Product: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Yield: 89.4 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-dodecanoyloxytetradecanoic acid (935 mg, 2.2 mmol) in the presence of EDC MeI (745 mg, 2.5 mmol) in CH2Cl2 to afford 1.08 g (90%) of N-[(R)-3-dodecanoyloxytetradecanoyl]-L-serine benzyl ester: mp 53-54° C. 1H NMR (CDCl3) δ 0.88 (t, 6 H, J=6.5 Hz), 1.1-1.6 (m, 46 H), 2.30 (t, 2 H, J=7.7 Hz), 2.50 (d, 2 H, 5.6 Hz), 2.62 (t, 1 H, J=6.2 Hz), 3.97 (m, 2 H), 4.65 (m, 1 H), 5.19 (m, 3 H), 6.63 (d, 1 H, J=6.8 Hz), 7.35 (br s, 5 H).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:18][C:19]1[O:20][CH2:21][CH2:22][CH:23]=1.P([O-])([O-])([O-])=O>ClCCl.O.C(OCC)(=O)C>[C:3]([CH2:2][S:1][C:19]1([CH3:18])[CH2:23][CH2:22][CH2:21][O:20]1)([OH:5])=[O:4]
Reactant: CC1=CCCO1
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(SCC(=O)O)CCCO1

Procedure:
A solution of mercaptoacetic acid (10 mmol) in 5 mL of dichloromethane containing p-toluenesulfonic acid mono-hydrate (100 mg) is cooled with stirring to -10° to -25° C. 2-Methyl-4,5-dihydrofuran (10 mmol) in 10 mL of dichloromethane is added dropwise to the cold solution while the temperature is maintained between -10° C. to -25° C. Then 5 mL of phosphate buffer is added and the solution is allowed to come to room temperature. The mixture is poured into a 30 mL of ethyl acetate and 10 mL of water. Organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined ethyl acetate layer is dried and evaporated to give 26 as a colorless oil.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=O)=[O:8].C(Cl)(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.P([O-])(OCC1C=CC=CC=1)OCC1C=CC=CC=1>CC#N.CN(C1C=CN=CC=1)C>[CH:1]1[CH:2]=[CH:3][C:4]2[N:12]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=c1[nH]cnc2ccccc12
Reaction time: 0.17 h
Yield: 185.4 %

Procedure:
The quinazoline 1 (0.2 g, 0.62 mmol) was dissolved in CH3CN (5 mL). After cooling to −10° C. (ice/NaCl), CCl4, DIEA and DMAP were added. After stirring for 10 min, a solution of dibenzyl phosphite in CH3CN (2 mL) was slowly added over 10 min. Stirring was continued at −10° C. for 2 h, then at RT for 24 h. Quenched by addition of 0.5 M K2HPO4, diluted with water (15 mL), extracted with DCM (30 mL), dried, concentrated, purified by flash chromatography (100% DCM) to obtain 2 (168 mg, 47% yield) as a colorless oil. LC/MS (10-99%) M/Z 586.0 retention time 2.54 min.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[CH2:13]([OH:16])[C:14]#[CH:15]>C1C=CC=CC=1>[OH:16][CH2:13][C:14]1[CH:15]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: C#CCO
Solvent: c1ccccc1
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Yield: 23 %

Procedure:
4.8 g (0.03 mole) of 3-diazooxindole is suspended in 500 ml of benzene and 1.96 g (0.033 mole) of propargyl alcohol added. The reaction mixture is refluxed overnight under nitrogen, after which 19.6 g (0.33 mole) of propargyl alcohol is added and the reaction continued under reflux for a total of 48 hours. The tan solid which precipitates is filtered off (1.5 g, 23% yield), m.p. 272°-275° (sl. dec.). Recrystallization from methanol gives crystals of the title compound, m.p. 286°-288° (sl. dec.).