Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:2]=1.[CH2:13]([S:17][CH2:18][C:19](O)=[O:20])[CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:19](=[O:20])[CH2:18][S:17][CH2:13][CH2:14][CH2:15][CH3:16])[CH:2]=1
Reactant: CCCCSCC(=O)O
Reactant: CC(C)(C)NCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSCC(=O)N(Cc1cccnc1)C(C)(C)C

Procedure:
N-[(3-pyridyl)methyl]-N-(1,1-dimethylethyl)-α-(n-butylthio)acetamide was prepared by the method of Example 2 by reacting 8.2 g. of N-[(3-pyridyl)methyl]-(1,1-dimethylethyl)amine with 7.4 g. of α-(n-butylthio)acetic acid and 10.3 g. of N,N'-dicyclohexylcarbodiimide in 150 ml. of dichloromethane. Weight 1.6 g. M.P. 55°-56° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][CH:11]=1>C(=O)(O)[O-].[Na+]>[NH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 190 °C
Yield: 61.6 %

Procedure:
This provides an example of a benzoxazole instead of a benzothiazole. In accordance with synthetic Route A, a mixture of 2-aminophenol (1.5 g, 0.0136 mol) and 4-aminobenzoic acid (1.885 g, 0.0136 mol) in polyphosphoric acid (20 g) was heated at about 190° C. for 4 hours, then cooled and poured into 10% aqueous sodium bicarbonate (400 ml). The product was collected by filtration, washed with water and recrystallised from methanol-H2O (10:1) to give small pale yellow crystals (1.76 g, 62%), m.p. 176°-178° C. (lit 185° C.); vmax /cm-1 3472, 3322, 3186, 1614, 1500, 1454, 1312, 1242, 1170, 1066, 830, 742; δH (DMSO-d6) 7.87(2H, d, J8.6, 2',6'-H), 7.69-7.64(2H, m, 5, 6-H), 7.36-7.28(2H, m, 4, 7-H), 6.70(2H, d, J8.6, 3', 5'-H), 6.02 (2H, s, NH2).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:32][CH3:33])=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:22]([CH:24]=3)[NH2:23])[O:15][N:14]=2)[CH:12]=1>N1C=CC=CC=1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([O:32][CH3:33])=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]4[CH3:31])=[C:22]([NH:23][S:2]([CH3:1])(=[O:4])=[O:3])[CH:24]=3)[O:15][N:14]=2)[CH:12]=1
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(N)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(NS(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (20 μL; 0.26 mmol; 1.2 eq.) was added to a solution of Example 69 (83 mg; 0.22 mmol; 1 eq.) in pyridine (1 mL) and the resulting solution was stirred at room temperature for 16 hours. The solution was then partitioned between water and ethyl acetate. The two phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed (3×) with 0.1M HCl, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (c-hexane/ethyl acetate, 60/40) afforded the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]2=[N:8][N:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1.[CH2:26]([NH:28][C:29]1([C:35]([NH2:37])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:27].C(N(CC)CC)C>C(O)C>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:8]=[C:7]3[C:6]=2[CH:5]=[CH:4][N:3]=[C:2]3[N:32]2[CH2:31][CH2:30][C:29]([NH:28][CH2:26][CH3:27])([C:35]([NH2:37])=[O:36])[CH2:34][CH2:33]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(-c2c3ccnc(Cl)c3nn2-c2ccc(Cl)cc2Cl)cc1
Reactant: CCNC1(C(N)=O)CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNC1(C(N)=O)CCN(c2nccc3c(-c4ccc(Cl)cc4)n(-c4ccc(Cl)cc4Cl)nc23)CC1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
7-Chloro-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridine (I-1A-1c; 71 mg, 0.17 mmol), 4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1f; 62 mg, 0.36 mmol) and triethylamine (52 microliters, 0.52 mmol) were combined in ethanol (1.2 ml) and the heterogeneous mixture was stirred and heated to 60° C. After 3 days, the reaction was cooled to room temperature and purified on a Biotage™ Flash 12M column using a solvent gradient of 0-2-4-6% methanol in methylene chloride as eluant to afford title compound I-1A-1 (73 mg, 78%) as a glass: +ESI MS (M+1) 543.1; 1H NMR (500 MHz, CD3OD) δ 7.63 (d, J=2.1 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.57 (d, J=6.2 Hz, 1H), 7.49 (dd, J=8.3, 2.1 Hz, 1H), 7.38 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 6.84 (d, J=6.2 Hz, 1H), 4.35-4.28 (m, 2H), 4.10 (ddd, J=13.3, 9.1, 3.3 Hz, 2H), 2.51 (q, J=7.1 Hz, 2H), 2.12 (ddd, J=13.7, 9.1, 3.7 Hz, 2H), 1.73 (dq, J=13.3, 3.3 Hz, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:11])([CH2:9][CH3:10])[C:4](=[O:8])[CH:5]([Cl:7])[Cl:6].O.C(=O)(O)[O-].[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:29])[C:27]=1[CH3:28])[C:22](Cl)=[O:23]>C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([Cl:29])[C:27]=1[CH3:28])[C:22]([NH:2][C:3]([CH2:9][CH3:10])([CH3:11])[C:4](=[O:8])[CH:5]([Cl:7])[Cl:6])=[O:23]
Reactant: CCC(C)(N)C(=O)C(Cl)Cl
Reactant: Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(C)(NC(=O)c1cc(Cl)c(C)c(Cl)c1)C(=O)C(Cl)Cl
Yield: 85.9 %

Procedure:
In a 100 mL three-necked round bottomed flask was placed 0.93 g of 3-amino-1,1-dichloro-3-methyl-2-pentanone hydrochloride and 5 mL of water. To the resulting solution was added 0.76 g of sodium bicarbonate followed by 20 mL of ethyl acetate. To the resulting well-stirred mixture was added 0.94 g of 3,5-dichloro-4-methylbenzoyl chloride dissolved in 20 mL of ethyl acetate at room temperature over a period of 5 minutes. After the addition was complete the reaction mixture was stirred at room temperature for 1 hour. The two phases were separated and the organic layer was washed with water (2×25 mL), brine (1×25 mL), dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator yielding 1.34 g (84% yield) of 3,5-dichloro-N-(3,3-dichloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide as a white solid. This solid was used as such in the following step.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)(OCC)=[O:2].C(CCCCC1C(=O)CCC=1)(OCC)=O.[CH:31]1[C:32](/[CH:47]=[N:48]/[OH:49])=[CH:33][CH:34]=[N+:35]([CH2:37][N+:38]2[CH:43]=[CH:42][C:41](/[CH:44]=[N:45]/[OH:46])=[CH:40][CH:39]=2)[CH:36]=1.[Br-:50].[Br-].[H-].C([Al+]CC(C)C)C(C)C.[K+].[Br-]>CO>[OH:2][CH2:1][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1.[CH:33]1[C:32](/[CH:47]=[N:48]/[OH:49])=[CH:31][CH:36]=[N+:35]([CH2:37][N+:38]2[CH:39]=[CH:40][C:41](/[CH:44]=[N:45]/[OH:46])=[CH:42][CH:43]=2)[CH:34]=1.[Br-:50].[Br-:50]
Reactant: CCOC(=O)CCCCC1=CCCC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Solvent: CO
Product: O=C1CCC=C1CCCCCO

Procedure:
Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenone as methoxime (Example 24) with diisobutyl aluminum hydride in the manner described in Example 17 gives crystals, m.p. 33°-35° C. IR (KBr) 3420, 1630, 1050, 886 cm-1. λ MeOH/max 243 (12,020).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:9]([OH:11])=[N:10][C:5]2=[N:4][CH:3]=1.[CH:17](/B(O)O)=[CH:18]/[CH3:19]>>[CH3:14][CH2:13][CH:12]([N:8]1[C:6]2=[N:7][C:2](/[CH:17]=[CH:18]\[CH3:19])=[CH:3][N:4]=[C:5]2[N:10]=[C:9]1[OH:11])[CH2:15][CH3:16]
Reactant: C/C=C\B(O)O
Reactant: CCC(CC)n1c(O)nc2ncc(Br)nc21
Product: C/C=C\c1cnc2nc(O)n(C(CC)CC)c2n1

Procedure:
The title compound was prepared by reacting 6-bromo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyrazin-2-ol (1.0 equiv), (Z)-prop-1-enyl boronic acid (1.5 equiv) and (DPPF)PdCl2 (0.15 equiv) in a manner analagous to Example 1(d). LCMS m/z (APCI)=247.0 (M+H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[C:6]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[CH3:7]>O>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:6](=[O:8])/[CH:7]=[CH:2]/[C:1]([OH:5])=[O:4]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1cccs1
Solvent: O
Product: O=C(O)/C=C/C(=O)c1cccs1
Temperature: 125 °C
Yield: 52.5 %

Procedure:
A two phase mixture of 18 grams glyoxylic acid (an 80% solution of glyoxylic acid in water) and 25.2 grams of 2-acetylthiophene is heated to 125° C. with stirring, and heating and stirring are maintained for about 5 hours. A clear solution forms at 115° C. and the water formed is removed by means of a Dean-Stark apparatus. On cooling the residue solidifies. It is dissolved in 100 cc ether and extracted with 150 cc of a 20% solution of Na2CO3. This aqueous solution is treated with activated charcoal, filtered and made strongly acid with 20% HCl. The solid is filtered and dissolved in about 1 L ether. The ether is dried over MgSO4 and removed to yield 19.1 g of the title compound, melting point 139°-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: BrCc1ccccc1Oc1ccccc1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccccc1Oc1ccccc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-2-phenoxybenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 418.01 g/mol.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cs+].[Cs+].[Cs+].[O:7]1[C:11]2([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[C:18]1([Mg]Cl)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([C:14]2([OH:17])[CH2:13][CH2:12][C:11]3([O:10][CH2:9][CH2:8][O:7]3)[CH2:16][CH2:15]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of cesium trichloride (24.9 g) in tetrahydrofuran (45 ml) was stirred at room temperature for 5 hours. 1,4-Dioxa-spiro[4.5]decan-8-one (1.4 g) was added to the solution and stirred at room temperature for 1 hour. To the solution was added dropwise with stirring phenylmagnesium chloride (3.0M solution in dimethyl ether) (33.7 ml) at 0° C. The reaction mixture was quenched with 10% acetic acid aqueous solution. Dimethyl ether was added to the solution. The organic layer was washed with brine, sodium hydrogen carbonate solution and brine and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 hexane-ethyl acetate elution) to give 8-phenyl-1,4-dioxaspiro[4.5]decan-8-ol (5.94 g).
Reaction SMILES: O[CH:2]([CH3:17])[CH2:3][C:4]([CH:6]1[C:15](=[CH2:16])[CH:14]=[CH:13][CH2:12][C:7]21[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:5].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C([O-])(O)=O.[Na+]>[CH2:16]=[C:15]1[CH:14]=[CH:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1[C:4](=[O:5])/[CH:3]=[CH:2]/[CH3:17]
Reactant: C=C1C=CCC2(CCCC2)C1C(=O)CC(C)O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: C=C1C=CCC2(CCCC2)C1C(=O)/C=C/C
Temperature: 80 °C
Reaction time: 7 h
Yield: 56.7 %

Procedure:
A mixture of 3-hydroxy-1-(7-methylenespiro[4.5]dec-8-en-6-yl)butan-1-one (0.65 mg, 2.77 mmol, 3:1 diastereomeric mixture), acetic anhydride (0.55 ml, 5.8 mmol) and sodium acetate (0.25 g, 3.0 mmol) was stirred at 80° C. for 7 h, treated with sodium acetate (0.1 g, 1.2 mmol), stirred at 80° C. for 7 h, cooled to 0° C., poured into cold saturated aqueous NaHCO3 (20 ml), and extracted three times with MTBE (10 ml). The combined organic phases were washed with a saturated aqueous solution of NaCl, dried (MgSO4), and concentrated. FC (30 g SiO2, hexane/MTBE 40:1) of the crude product (0.49 g) gave (E)-1-(7-methylenespiro[4.5]dec-8-en-6-yl)but-2-en-1-one (0.34 g, 57%). Boiling point: 100° C. (0.07 mbar).
Reaction SMILES: [Cl-].[Li+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]1[CH2:27][CH2:26]N2C(=NCCC2)[CH2:19][CH2:18]1.C1(C=O)CCC1>CC#N>[CH:18]1(/[CH:19]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:17][CH2:27][CH2:26]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=CC1CCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: CCOC(=O)/C=C/C1CCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a suspension of lithium chloride (2.22 g, 52.2 mmol) in MeCN (80 mL) were added ethyl 2-(diethoxyphosphoryl)acetate (available from Aldrich) (8.37 mL, 41.8 mmol) and DBU (16.7 mL, 111 mmol) at room temperature. The mixture was cooled to 0° C., and to it was added cyclobutanecarbaldehyde 70.B (2.93 g, 34.8 mmol) dropwise. The resulting cloudy mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford (E)-ethyl 3-cyclobutylacrylate 70.C as a colorless liquid (5.00 g, 94%).
Reaction SMILES: [NH2:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:3]([N:5]1[CH2:8][CH:7]([NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6]1)=[O:4].[O:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=[N:25]1>>[NH2:1][CH:2]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[C:3]([N:5]1[CH2:8][CH:7]([N:9]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:29]([C:28]2[O:24][N:25]=[CH:26][CH:27]=2)=[O:30])[CH2:6]1)=[O:4]
Reactant: NC(Cc1ccc(Cl)cc1)C(=O)N1CC(NC2CCCCC2)C1
Reactant: O=C(Cl)c1ccno1
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CC(N(C(=O)c2ccno2)C2CCCCC2)C1

Procedure:
{1-[2-Amino-3-(4-chloro-phenyl)-propionyl]-azetidin-3-yl}-cyclohexylamine was acylated with isoxazole-5-carbonyl chloride in a manner similar to that described for 6 above and then the Boc protecting group removed by treatment with a solution of HCl in dioxane and MeOH to furnish isoxazole-5-carboxylic acid {1-[2-amino-3-(4-chloro-phenyl)-propionyl]-azetidin-3-yl}-cyclohexyl-amide. 1H NMR (400 MHz, CDCl3) δ 8.33–8.29 (m, 1H), 7.32–7.12 (m, 4H), 6.77–6.71 (m, 1H), 4.54 (br, 2H), 4.34–3.80 (m, 2H), 3.60–3.40 (m, 2H), 3.20–2.70 (m, 2H), 2.60–2.05 (m, 2H), 1.86–1.60 (m, 4H), 1.60–1.00 (m, 4H), 0.90–0.78 (m, 3H); MS Calcd for C22H27ClN4O3 [M+H], 431. Found, 431.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Br:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47](O)=[O:48])=[N:44][CH:45]=1>C1COCC1>[Br:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:48])=[N:44][CH:45]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)Cc1ccc(Br)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(Br)cn1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
Under an inert atmosphere, 0.09 g (0.95 mmol) of 2-aminopyridine, 0.31 g (2.4 mmol) of diisopropylethylamine and 0.35 g (1.1 mmol) of TBTU are successively added to 0.26 g (0.95 mmol) of (5-bromo-2-pyridyl)acetic acid (a synthesis of which is described in Tetrahedron, 1997, 53(24) 8257-8268 Gurnos J. et al.) dissolved in anhydrous THF (4 ml). The reaction mixture is stirred for 3 hours at room temperature. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate (20 ml) and the organic phase thus obtained is then washed with saturated ammonium chloride solution (15 ml) and with saturated sodium hydrogen carbonate solution (15 ml), and then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate, 1% NH4OH), with a gradient of 0% to 20% ethyl acetate, 1% NH4OH. 0.125 g of compound is obtained in the form of a white powder. Yield: 45%. Melting point: 131° C. MH+: 292-294 (tr: 6.1 min., condition 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5]([N:8]([CH2:11][C:12](=O)[CH3:13])[CH:9]=O)=[N:6][CH:7]=1.C([O-])(=O)C.[NH4+:21]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[C:5]([N:8]2[CH:11]=[C:12]([CH3:13])[N:21]=[CH:9]2)=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: COc1cc(Br)cnc1N(C=O)CC(C)=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(Br)cnc1-n1cnc(C)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
A mixture of the crude N-(5-bromo-3-methoxypyridin-2-yl)-N-(2-oxopropyl)formamide (26.4 g), acetic acid (52.8 mL) and ammonium acetate (35.5 g) was stirred at 130° C. for one hour. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. The residue diluted with ice water, ethyl acetate and aqueous ammonia, and the organic layer was separated. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:heptane-ethyl acetate system) to obtain 5.69 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH:33]([CH3:35])[CH3:34])[NH:5][C:6](=[O:32])[C@H:7]([CH:29]([CH3:31])[CH3:30])[NH:8][C:9](=[O:28])[C@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])(O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[C:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH:33]([CH3:34])[CH3:35])=[O:32])[CH:29]([CH3:31])[CH3:30])=[O:28])[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])([CH3:16])([CH3:18])[CH3:17]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C)C(=O)O
Temperature: 0 °C
Yield: 41.9 %

Procedure:
N-tert-butoxycarbonyl O-benzyl L-seryl L-valyl L-valine methyl ester 13 (14.60 g, 28.76 mmol) was dissolved in THF (220 mL) and the solution cooled to 0° C. (icebath). LiOH monohydrate (1.33 g, 31.7 mmol) was dissolved in de-ionized water (110 mL). The solution was cooled to 0° C. (icebath) and added dropwise to the solution of 13 over 25 min. The reaction mixture was stirred for an additional 2 h 35 min before solid NaHCO3 (4.83 g, 57.5 mmol) was added and the bulk of THF evaporated. The solution was diluted with water (220 mL) and washed with Et2O (2×220 mL). The solution was then acidified to pH 2 by addition of 2 M aqueous H2SO4 and extracted with EtOAc (3×350 mL). The combined organic fractions were dried with anhydrous MgSO4 and the solvent evaporated affording a slightly yellowish liquid. The residue was redissolved in EtOAc and precipitated by addition of hexane. The solvent was decanted off and the residue dried affording the title compound as an off-white solid (5.95 g, 42%); δH (200 MHz; d6-DMSO) 12.52 (1H, br s, COOH), 8.03 (1H, d, J 8, NH(Valx)), 7.65 (1H, d, J 9, NH(Valy)), 7.36-7.23 (5H, m, Ph), 7.10 (1H, d, J 8, NH(Ser(Bn)), 4.46 (2H, s, CH2Ph), 4.36 (1H, dd, J 7 and 9, CαH(Valy)), 4.28-4.22 (1H, m, CαH(Ser(Bn))), 4.10 (1H, dd, J 6 and 8, CαH(Valx)), 3.64-3.54 (2H, m, CH2), 2.08-1.91 (2H, m, CH(CH3)2), 1.38 (9H, s, (CH3)2), 0.88-0.80 (12H, m, CH3); δC (75 MHz; d6-DMSO) 172.6, 170.9, 169.4, 155.1, 138.1, 128.0, 127.4, 127.3, 78.3, 71.9, 69.8, 57.2, 56.8, 54.6, 31.1, 29.5, 28.1, 19.0, 18.9, 18.0, 17.7; m/z (ESI) 516.2663 ([M+Na]+; C25H39N3O7Na requires 516.2685)
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]C)=O)(=O)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.[NH2:15][NH2:16]>C(O)C>[CH:2]([C:1]1[CH2:6][C:7](=[O:9])[NH:16][N:15]=1)([CH3:4])[CH3:3]
Reactant: NN
Reactant: COC(=O)CC(=O)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)C1=NNC(=O)C1
Reaction time: 24 h

Procedure:
Methyl isobutyrylacetate (0.5 g, 3.47 mmol) was stirred in ethanol and acetic acid (10:1, 2:0.2 mL) and treated with hydrazine (0.13 mL, 4.16 mmol). After 24 hrs, the resulting solid was filtered off and washed with a minimum amount of ethanol to yield 3-isopropyl-1H-pyrazol-5(4H)-one. Then, the 3-isopropyl-1H-pyrazol-5(4H)-one (0.169 g, 1.34 mmol) and 4-chloroquinoline N-oxide (0.24 g, 1.34 mmol) were stirred in acetic anhydride (1.5 mL) at ambient temperature for 20-30 minutes. The reaction mixture was concentrated and the resulting solid was filtered off and washed with a minimum amount of ether to yield Example 18. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (d, J=6.82 Hz, 6H) 3.98 (bs, 1H) 7.61 (t, J=7.58 Hz, 1H) 7.76-7.82 (m, 1H) 7.93 (d, J=8.34 Hz, 1H) 8.08-8.18 (m, 2H); ESI-MS: m/z calc'd for C15H14ClN3O 287.74. found 288.2 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[CH:11]1[C:24]2[C:23](=O)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O1CCCC1.C1C=CC=CC=1>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([C:23]2[C:24]3[C:15]([N:16]=[C:17]4[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:5]=1)=[CH2:8]
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Reactant: C=Cc1ccc(Br)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Mg]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2c3ccccc3nc3ccccc23)cc1
Reaction time: 8 h
Yield: 42.1 %

Procedure:
Into a four-neck flask equipped with a stirrer, a nitrogen gas inlet tube, a reflux condenser with a calcium chloride tube and a dropping funnel were charged 4.9 g of magnesium cut powder and 50 ml of tetrahydrofuran. 36.6 Grams of p-bromostyrene diluted with tetrahydrofuran to about 4 times the weight was added dropwise under gentle reflux in a dry nitrogen gas stream. After the magnesium had disappeared, a solution consisting of 37.0 g of acridone and 600 ml of tetrahydrofuran was added dropwise over a period of two hours with stirring. After refluxing for further 5 hours, the reaction mixture was allowed to cool and then poured onto hydrochloric acid-ice to effect hydrolysis. The organic layer was extracted with ether and the extract was dried over anhydrous sodium sulfate. The solvent was then distilled off to obtain a yellow semi-solid. Almost the same weight (60 g) of phosphorus pentoxide was added to 500 ml of a solution of the semi-solid in benzene. The mixture was stirred at room temperature for 5 hours and then allowed to stand overnight. The supernatant liquid separated by decantation was washed with water, dried, and then concentrated to dryness. The residue was purified by silica gel chromatography to obtain 22.5 g of 9-(p-vinylphenyl)acridine. Yield 42.1%.