Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:18].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]3)=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: COC(=O)CC1CCc2ccc(O)cc2C1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CC1CCc2ccc(OCc3ccc(C#N)cc3)cc2C1
Yield: 93 %

Procedure:
In 50 ml of 2-butanone, 1.2 g of methyl 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-acetate and 1.60 g of 4-cyanobenzyl bromide were dissolved, 1.51 g of potassium carbonate was added, and the mixture was refluxed by heating for 12 hours. Most of the solvent was distilled off under reduced pressure. The concentrated residue was mixed with water and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography using a mixture, ethyl acetate:n-hexane=1:3, as a developer to yield 1.7 g of the entitled compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl-].[Mg+2].[Cl-].[CH2:14]=[O:15].Cl>C1COCC1.C(N(CC)CC)C>[CH:14]([C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([CH3:10])[C:2]=1[OH:1])=[O:15]
Reactant: Cc1c(O)cccc1C#N
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C#N)ccc(C=O)c1O
Yield: 15.3 %

Procedure:
To a solution of 3-hydroxy-2-methylbenzonitrile (7.00 g) in THF (100 mL) were added triethylamine (13.1 g), magnesium chloride (12.4 g) and paraformaldehyde (6.60 g), and the mixture was heated with reflux for 16 hr under nitrogen atmosphere. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (1.30 g).
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]2[CH2:23][CH:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=3)[CH2:25][N:12]([CH2:13][CH2:14][CH2:15][N:16]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:17][CH2:18]2)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:37]([CH2:36][N:16]1[CH2:15][CH2:14][CH2:13][N:12]2[CH2:25][CH:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=3)[CH2:23][N:19]([CH2:20][CH2:21][CH2:22][N:9]([CH2:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:10][CH2:11]2)[CH2:18][CH2:17]1)([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38]
Reactant: CC(C)(C)OC(=O)CN1CCCN2CCN(CC(=O)OC(C)(C)C)CCCN(CC1)CC(Cc1ccc([N+](=O)[O-])cc1)C2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1CCCN2CCN(CC(=O)OC(C)(C)C)CCCN(CC1)CC(Cc1ccc(N)cc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a solution of compound 26 (4.26 g, 7.06 mmol) in ethanol (100 mL) was added 10% Pd/C (1.28 g). The resulting mixture was stirred under H2 (g) atmosphere at room temperature for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 mL). The combined filtrate was evaporated in vacuo to give an oily residue which was triturated with Et2O to provide an off-white solid 27 (3.93 g, 97% yield).
Reaction SMILES: C[N-]C.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][C:14](=[O:18])[C:15]([OH:17])=O)=[CH:5]1.[CH:19]1[CH:20]=[CH:21][C:22]2N(O)N=[N:25][C:23]=2[CH:24]=1.C1(N)CCCCC1.CN1CCOCC1>CCN=C=NCCCN(C)C.Cl>[CH:23]1([NH:25][C:15](=[O:17])[C:14]([CH2:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)=[O:18])[CH2:24][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: C[N-]C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: NC1CCCCC1
Product: O=C(Cc1c[nH]c2ccccc12)C(=O)NC1CCCCC1

Procedure:
The same method as described in Example 7 was followed for the preparation of N,N-dimethylamide. 500 mg 3-indolepyruvic acid were reacted with 400 ml HOBt and 570 ml EDC.HCl. 340 microliters of freshly distilled cyclohexylamine and 325 microliters NMM were added to the solution, which was reacted for 5 hours.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:16][C@@H:17]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]1.C(P(=O)(OCC)OCC)#N.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:16][C@@H:17]2[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:18]2)=[O:15])=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1nc(C(=O)O)c2ccccc21
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Reaction time: 14 h
Yield: 97.7 %

Procedure:
To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (300 mg, 1.47 mmol) and 1-tert-butyl 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (396 mg, 1.62 mmol, Bioorg. Med. Chem., 2002, 10, 1399-1415) in N,N-dimethylformamide (15 mL) were added diethyl cyanophosphonate (0.27 mL, 1.76 mmol) and N,N-diisopropylethylamine (0.31 mL, 1.76 mmol) at room temperature. The resulting mixture was stirred for 14 h at the same temperature and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (200 mL), and the solution was washed with water (50 mL×2), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (3:1) to give 618 mg (98%) of the title compound as a white amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[CH2:19]([CH:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)[CH2:20][CH2:21][CH2:22][CH3:23].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH:27]4[CH2:26][CH2:25][CH:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:29][CH2:28]4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: CCCCCC1CCC(O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
(R)-4-(6-Hydroxnaphthalen-2-yl)-4-methyl-oxazolidin-2-one (Example 4, 0.3303 g, 0.001358 mol) was added to a capped 40 mL vial equipped with a magnetic stir bar. 4-Pentyl-cyclohexanol (0.277 g, 0.00163 mol) was added, followed by tetrahydrofuran (6.00 mL, 0.0740 mol). Triphenylphosphine polymer-bound (1.17 g, 0.00217 mol) was then added and the mixture was stirred for 5 minutes. Diisopropyl azodicarboxylate (0.428 mL, 0.00217 mol) was then added and the mixture was stirred for 48 hours at room temperature. The mixture was diluted in ethyl acetate, filtered through CELITE™, concentrated under vacuum and purified by flash chromatography (0-5% MeOH in dichloromethane) to give 0.3672 g of the title compound (68% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:33][C@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([NH:33][C@H:34]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(N)nc3sc(CCc4ccc(F)cc4)nc23)C1
Yield: 42.1 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4-d]pyrimidine (150 mg, 0.42 mmol) in dichloromethane (10 ml) was added diisopropylethylamine (3.0 mmol, 492 μL) and tert-butyl 3-(S)-aminopyrrolidine-1-carboxylate (2.1 mmol). The reaction mixture was refluxed for 40 hours whereupon the mixture was extracted with a saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (81 mg) which was characterized by its mass spectrum: MS m/z (%): 459 ([M+H]+, 100).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][NH2:38])=[CH:31][CH:30]=2)[CH:22]=1)(=O)C.[N+]([O-])(O)=O.CC1C=C(C)[N:46]([C:50](=N)[NH2:51])N=1.CCN(C(C)C)C(C)C.C([O-])=O>CC#N>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:6]2[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([S:19][CH3:20])[O:7]2)=[CH:22][C:23]=1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][NH:38][C:50]([NH2:51])=[NH:46])=[CH:33][CH:34]=1
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCN)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1cc(C)n(C(=N)N)n1
Agent: O=C[O-]
Solvent: O=[N+]([O-])O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCNC(=N)N)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Yield: 34.2 %

Procedure:
To a solution of (2S,3S,4R,5S,6R)-2-(3-(4-(2-aminoethoxy)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (44, 31 mg, 0.057 mmol) and 3,5-dimethyl-1H-pyrazole-1-carboximidamide nitrate (23 mg, 0.11 mmol) in CH3CN was added DIPEA (30 μL, 0.17 mmol). The reaction was heated at 60° C. for 4 hours, then cooled to room temperature and concentrated under vacuum. The residue was dissolved in MeOH and treated with a few drops of NaOMe (25 wt % in MeOH) for 1 hour. The reaction was concentrated under vacuum, and the residue was purified by prep HPLC (C18 30×100 mm column, 5-40% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) to give urea 46 (9 mg, 34% yield) as the formate salt. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.11-7.20 (m, 3 H), 7.07 (d, J=8.6 Hz, 2 H), 6.81-6.89 (m, 2 H), 4.39 (d, J=9.3 Hz, 1 H), 4.12 (d, J=9.1 Hz, 1 H), 4.08 (t, J=4.9 Hz, 2 H), 3.94 (s, 2 H), 3.58 (t, J=5.1 Hz, 2 H), 3.34-3.48 (m, 3 H), 2.20 (s, 3 H), 2.14 (s, 3 H); MS (ES+) [M+H]+=462.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>>[CH:18]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[O:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: C1=CCCCC1
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Product: CC1(C)CC(=O)CC(C)(C)N1OC1C=CCCC1
Temperature: 85.5 °C
Yield: 10.3 %

Procedure:
A mixture of 25.0 g (0.15 mol) of 1-oxyl-4-oxo-2,2,6,6-tetramethylpiperidine and 162.2 g (1.97 mol) of cyclohexene is heated under a nitrogen atmosphere at 85-86° C. for 56 hours. The reaction mixture is filtered to remove the hydroxylamine, and the solvent is removed in vacuo. The residue is dissolved in heptane and washed with 5% ascorbic acid (2×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous magnesium sulfate and the volatiles removed in vacuo. The residue is eluted through a silica gel column with heptane/ethyl acetate (9/1) to give 3.9 g (21% yield) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[NH:6]1)[CH3:2].[CH3:12]I.[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH3:12][N:6]1[C:7](=[O:10])[CH2:8][CH2:9][C@H:5]1[C:4]([O:3][CH2:1][CH3:2])=[O:11]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCC(=O)N1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 6.2 %

Procedure:
D-pyroglutamic acid ethyl ester (4.0 g, 25.5 mmol) was dissolved in tetrahydrofuran (25 ml) and cooled to 0° C. Methyl iodide (1.66 ml, 26.7 mmol) was added and stirring continued for 10 minutes under argon at 0° C. Sodium hydride (60% in oil, 1.6 g, 26.7 mmol) was then added portionwise (allowing each portion to react). After addition of all the sodium hydride the mixture was allowed to warm to room temperature and stirred overnight under argon. The mixture was then treated with saturated aqueous ammonium chloride solution (˜15 ml) and stirred for 4 hrs. The organic layer was separated and the aqueous layer was extracted with more dichloromethane. The combined organic layers were dried over magnesium sulphate and then concentrated to a dark oil. This was purified by flash silica column chromatography, eluting with a 0-75% gradient of ethyl acetate in hexane, to give ethyl 1-methyl-5-oxoprolinate as a colourless oil (0.27 g) which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=O)[NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13].P(=O)(O)(O)O.O>C(OCC)(=O)C>[Br:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH2:6][CH2:5][NH:4][C:3]2=[O:2]
Reactant: COC(=O)NCCc1ccccc1Br
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NCCc2c(Br)cccc21
Yield: 8.8 %

Procedure:
1.36 g of methyl[2-(2-bromophenyl)ethyl]carbamate and 5.2 g of phosphoric acid are stirred under an inert atmosphere at a temperature close to 150° C. The reaction mixture is cooled to a temperature close to 20° C., then it is hydrolysed with a mixture of water and ethyl acetate using ultrasound treatment. After decanting, the organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, water, a saturated aqueous solution of sodium chloride, then concentrated using a rotary evaporator under reduced pressure (5 kPa). 0.105 g of 5-bromo-3,4-dihydroisoquinolin-1(2H)-one is obtained in the form of an amorphous beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][CH2:16][NH:15][N:14]=3)[CH2:10][C@H:9]2[C:19]([O:21]C)=[O:20])=[CH:4][CH:3]=1.ClC1C=CC([C@@H]2CN(C3C=CCNN=3)C[C@H]2C([O-])=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][CH2:16][NH:15][N:14]=3)[CH2:10][C@H:9]2[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(C2=NNCC=C2)C[C@H]1c1ccc(Cl)cc1
Agent: O=C([O-])[C@@H]1CN(C2=NNCC=C2)C[C@H]1c1ccc(Cl)cc1
Product: O=C(O)[C@@H]1CN(C2=NNCC=C2)C[C@H]1c1ccc(Cl)cc1
Yield: 70 %

Procedure:
The title compound (0.48 g, 70%) was prepared from the product of Step A, (3S,4R)-4-(4-chlorophenyl)-1-(1,6-dihydropyridazin-3-yl)pyrrolidine-3-carboxylate (0.72 g, 2.27 mmol) according to the same procedure as in Step C of Preparation 17.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7](Br)[N:6]=1)=[O:4].ClCCl.O.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>CN(C)C=O.CCOC(C)=O>[NH2:11][C:10]1[C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][C:7]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:17])[CH:23]=2)=[CH:8][N:9]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CNC(=O)c1nc(Br)cnc1N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1nc(-c2cccc(N)c2)cnc1N
Temperature: 87.5 °C
Reaction time: 0.07 h
Yield: 53.9 %

Procedure:
To a solution of 3-amino-6-bromo-pyrazine-2-carboxylic acid methylamide (1.234 g, 5.30 mmol, 1.00 equiv.) in N,N-dimethylformamide (DMF, 30 mL) was added [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1), (Aldrich Chemical Company, 433 mg, 0.530 mmol, 0.100 equiv.), 3-aminophenylboronic acid monohydrate (Aldrich Chemical Company, 1.149 g, 7.41 mmol, 1.40 equiv.), and triethylamine (TEA, 1.073 g, 10.6 mmol, 2.00 equiv.). Nitrogen was passed through the solution for 3-5 min. The reaction mixture was heated at 85-90° C. for 15 h with stirring. The reaction was allowed to cool to room temperature and diluted with 400 mL of EtOAc. The mixture was washed with saturated aqueous NaHCO3 (2×50.0 mL), saturated aqueous NaCl (1×50.0 mL), dried over magnesium sulfate (MgSO4), and filtered. The filtrate was concentrated on a rotary evaporator under reduced pressure. To the crude product was added 30 mL of a 4.0M solution of anhydrous HCl in dioxane. The resulting solid was filtered and rinsed with 20% methanol in diethyl ether to remove impurities. The solid was dissolved in methanol and neutralized with sufficient AG 1-X8 Resin (hydroxide form) that the pH of the solution became basic. The mixture was filtered, and the filtrate was concentrated on a rotary evaporator at reduced pressure to afford the title compound (0.695 g, 54% yield).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]2[CH:12]3[CH2:14][CH:15]([NH:18][C:19](=[O:21])[CH3:20])[CH2:16][CH2:17][CH:11]3[CH2:10][O:9][C:8]=2[CH:7]=[C:6]([CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH3:27])[CH:5]=1.[C:28](Br)(=[O:31])[CH2:29][CH3:30]>>[C:28]([O:3][C:4]1[C:13]2[CH:12]3[CH2:14][CH:15]([N:18]([C:4](=[O:3])[CH2:5][CH3:6])[C:19](=[O:21])[CH3:20])[CH2:16][CH2:17][CH:11]3[CH2:10][O:9][C:8]=2[CH:7]=[C:6]([CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH3:27])[CH:5]=1)(=[O:31])[CH2:29][CH3:30]
Reactant: CCC/C=C\Cc1cc(O)c2c(c1)OCC1CCC(NC(C)=O)CC21
Reactant: CCC(=O)Br
Agent: [H-]
Agent: [Na+]
Product: CCC/C=C\Cc1cc2c(c(OC(=O)CC)c1)C1CC(N(C(C)=O)C(=O)CC)CCC1CO2

Procedure:
Exhaustive acylation of 9-amino and 9-acylaminodibenzo[b,d]pyrans effects peracylation to afford 1-acyloxy-9-diacylamino-hexahydro-dibenzo[b,d]pyrans. Such peracylation can be effected by reacting either a 9-amino or a 9-acylamino-hexahydro-dibenzo[b,d]pyran with an excess of an acylating agent, for example from about 2 to 10 molar excess, as well as carrying out the reaction at an elevated temperature of about 60° to about 150° C. The peracylation is carried out in the presence of a strong base such as sodium hydride. As an illustration of peracylation, a compound such as dl-cis-1-hydroxy-3-(2-hexenyl)-9-acetamido-6a,7,8,9,10,10a-hexahydro-6H-dibenzo[b,d]pyran can be reacted with about a 5 molar excess of propionyl bromide in the presence of sodium hydride at about 100° C. for about seventy-two hours to afford dl-cis-1-propionoxy-3-(2-hexenyl)-9-(N-propionyl)acetamido-6a,7,8,9,10,10a-hexahydro-6H-dibenzo[b,d]pyran.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]([C:10](=[O:24])[NH:11][C@:12]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C@H:13]2[CH:15]=[CH2:16])[CH2:8][CH:7]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:27]=2)[CH:6]=1)=[O:4].[Li+].[OH-]>O1CCOCC1.O>[C:20]([O:19][C:17]([C@@:12]1([NH:11][C:10]([CH:9]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]([O:25][C:26]3[C:35]4[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=4)[N:29]=[C:28]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:27]=3)[CH2:8]2)=[O:24])[CH2:14][C@H:13]1[CH:15]=[CH2:16])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)OC)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C=C1C(=O)O)C(=O)OC(C)(C)C
Yield: 1 %

Procedure:
The methyl ester 30 (35 mg, 59 mmol) was dissolved in dioxane/water (1:1, 4 mL) and LiOH (1.2 mmol) was added. The reaction was stirred over night and then co-concentrated. This gave the title compound (0.32 g, 90%) as a yellow salt.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[O:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 6-amino-3H-benzoxazol-2-one [J. Chem. Soc.,321. (1938)] according to the method described in Example 1c. Melting Point: 224-227° C. (diethylether)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.[OH-].[K+]>C(O)C>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: COc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(Oc2ccc3ccc(N)nc3n2)c1
Temperature: 4 °C
Yield: 66.3 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.95 g), 3-methoxyphenol (49.6 g) and potassium hydroxide pellets (13.2 g; 85% purity). After treatment with caustic soda and washing, the product produced (23.8 g; m.p. 156° C.) is dissolved in boiling ethanol (200 cc). After 18 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). 2-Amino-7-(3-methoxyphenoxy)-1,8-naphthyridine (17.7 g) is produced, m.p. 160° C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1)[CH2:2][CH2:3][CH3:4].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>O>[CH2:1]([N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][O:11]1)[C:26](=[O:27])[CH2:25][Cl:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCCN(CC1OCCO1)C(=O)CCl

Procedure:
N-n-Butyl-N-(1,3-dioxolan-2-ylmethyl)amine (12.5 grams), benzene (100 ml), water (100 ml) and sodium carbonate (10 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (6 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-n-butyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.