Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCC1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9][CH2:10][CH:11]=[CH2:12])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: C=CCCC(=O)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: C=CCCC(=C1C(=O)Nc2cc(Cl)ccc21)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of 1-(3-chlorophenyl)pent-4-en-1-one (Example 62, Step A) (14.86 g, 76 mmol) and 6-chloroindolin-2-one (12.79 g, 76 mmol) in toluene (50 mL) at room temperature was added pyrrolidine (6.31 mL, 76 mmol). The slurry was heated at reflux with a Dean Stark trap for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 10 to 20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:20])[CH:17]=2)[C:12]1=[O:21])(=[O:3])[CH3:2].[CH3:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][Br:26]>>[Br-:26].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:22][C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[CH3:25])[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:20])[CH:17]=2)[C:12]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnccc1CC1Cc2cc(C)ccc2C1=O
Reactant: Cc1ccccc1CBr
Product: CC(=O)c1c[n+](Cc2ccccc2C)ccc1CC1Cc2cc(C)ccc2C1=O
Product: [Br-]

Procedure:
The title compound 137 is prepared according to the procedure reported in Example 38.1 with compound 114 (55.8 mg, 02 mmol) and 2-methylbenzyl bromide (45 μL, 0.34 mmol) as reactants. White solid. (Yield 78.9 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[NH:9][CH:10]2[CH3:13])=[CH:5][C:4]=1[OH:16].[K].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([O:16][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:13])=[N:9][C:8]([CH3:15])([CH3:14])[CH2:7]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1O)CC(C)(C)NC2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)CC(C)(C)N=C2C
Temperature: 55 °C
Yield: 64.8 %

Procedure:
To a solution of 239 (970 mg, 4.4 mmol) in acetone (10 ml) was added potassium C(Ar)bonate (3.06 g, 22.0 mmol), benzyl bromide (1.05 ml, 8.8 mmol) and tetrabutyl ammonium iodide (163 mg, 0.44 mmol). The reaction mixture was heated at 55° C. for 60 h. The reaction mixture was cooled to rt, water (20 ml) was added and the aqueous layer was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography eluting with EtOAc then EtOAc:MeOH:TEA; 10:1:0.1 afforded the title compound (882 mg, 64%) as a pale orange solid. mp=87.9-90° C. 1H NMR (270 MHz; CDCl3) 1.16 (6H, s, 2×CH3), 2.22 (3H, s, CH3), 2.59 (2H, s, CH2), 3.90 (3H, s, OCH3), 5.13 (2H, s, CH2Ph), 6.63 (1H, s, CH), 7.0 (1H, s, CH), 7.27-7.46 (5H, m, 5×CH, phenyl). 13C NMR (67.5 MHz; CDCl3) 23.54 (CH3), 28.15 (2×CH3), 38.70 (CH2), 53.65 (C(CH3)), 56.07 (OCH3), 71.87 (CH2Ph), 111.40 (CH), 112.57 (CH), 121.49 (C), 127.58 (CH), 128.08 (CH), 128.68 (CH), 130.78 (C), 137.15 (C), 146.33 (C), 151.79 (C), 160.65 (C). LC/MS (ES+) tr=2.5 min, m/z 310.05 (M++H). HRMS (ES+) calcd. for C20H24NO2 (M++H) 310.1802, found 310.1801.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:23])[CH2:20][CH2:19][O:18][C:17]([CH3:22])([CH3:21])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]I>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([O:23][CH3:24])[CH2:20][CH2:19][O:18][C:17]([CH3:21])([CH3:22])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1(C)CC(O)(c2cccc(OCc3ccccc3)c2)CCO1
Product: COC1(c2cccc(OCc3ccccc3)c2)CCOC(C)(C)C1
Yield: 89 %

Procedure:
Using the procedure described in Example 3, 4-(3-benzyloxyphenyl)-4-hydroxy-2,2-dimethyltetrahydropyran (1.14 g) was reacted with methyl iodide (0.25 ml) to give 4-(3-benzyloxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran (1.06 g, 89%), as an oil.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1F)[C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>>[Cl:14][C:15]1[CH:16]=[C:17]([C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2Cl)CC1
Yield: 78.6 %

Procedure:
Tert-Butyl piperazine-1-carboxylate (0.931 g, 5 mmol) and 3-chloro-4-fluorobenzonitrile (0.785 g, 5.00 mmol) were combined, K2CO3 (0.898 g, 6.50 mmol) was added and the reaction mixture was stirred at 90° C. for 1d. The mixture was triturated with ethyl acetate (3×5 mL) and the combined organic extracts were filtered. This was concentrated down to about 5-10 mL and subjected to flash column chromatograhy on silica gel (120 g SiO2, hexanes:ethyl acetate 1:0 to 4:1) to afford tert-butyl 4-(2-chloro-4-cyanophenyl)piperazine-1-carboxylate (1.264 g, 3.93 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.42 (s, 9H) 3.00-3.09 (m, 4H) 3.42-3.53 (m, 4H) 7.25 (d, J=8.59 Hz, 1H) 7.77 (dd, J=8.34, 2.02 Hz, 1H) 7.97 (d, J=2.02 Hz, 1H); [M+H] calc'd for C16H20ClN3O2, 322; found, 322.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[S:5][C:6]=1[C:7](=[O:9])[CH3:8].[NH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[C:7]([C:6]1[S:5][C:4]([NH:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[N:3][C:2]=1[NH2:1])(=[O:9])[CH3:8]
Reactant: CC(=O)c1sc(S(C)(=O)=O)nc1N
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)c1sc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1N
Temperature: 120 °C

Procedure:
390 mg (1.77 mmol) of 1-[4-amino-2-(methylsulfonyl)-1,3-thiazol-5-yl]ethanone (Example 48A) were dissolved in 5 ml of DMSO, and 209.6 mg (0.89 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate and 0.585 ml (3.54 mmol) of N,N-diisopropylethylamine were added. The mixture was heated in a microwave at 120° C. for 45 min. This gave, after purification by preparative HPLC, 162 mg (52% of theory) of the product as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:4]=1[Cl:13].C(N(CC)CC)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCOC(C)=O>C1COCC1>[Cl:9][C:8]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:13])[C:3]=1[CH2:2][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Reactant: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)c(CN2CCCCC2)c1Cl
Temperature: 25 °C

Procedure:
To a solution of 2-bromomethyl-1,3-dichloro-4-nitro-benzene (20) (8.79 g, 30.8 mmol) and triethylamine (6.06 g, 60 mmol) in anhydrous THF (50 mL), piperidine (2.72 g, 32 mmol) was added at 0° C. under stirring. The reaction mixture was allowed to warm to room temperature gradually, and the reaction was monitored by TLC (SiO2, Hexanes:EtOAc, 1:1). After stirring for about 14 hours, the reaction mixture was evaporated to dryness, and the product was extracted in EtOAc (250 mL) and washed with water (2×100 mL) and dried (MgSO4). The product was purified by column chromatography (SiO2, hexanes:EtOAc 95:5 to 8:2) and was obtained as a yellow solid, yield: 7.38 g, 83%, mp 67-68° C. 1H-NMR (CDCl3) δ 1.37 (m, 2H), 1.46-1.49 (m, 4H), 2.45 (m, 4H), 3.7 (s, 2H); MS (CI) m/z 290 (M+H), 291 (M+2H). Anal Calc for C12H14Cl2N2O2 : C, 49.85; H, 4.88; N, 9.69. Found: C, 49.86; H, 4.88; N, 9.73.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:29]=[C:14]3[N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH:16]=[N:17][C:18](Cl)=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].[F:31][C:32]1[C:40]([OH:41])=[CH:39][CH:38]=[C:37]2[C:33]=1[CH:34]=[C:35]([CH3:42])[NH:36]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:29]=[C:14]3[N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH:16]=[N:17][C:18]([O:41][C:40]4[C:32]([F:31])=[C:33]5[C:37](=[CH:38][CH:39]=4)[NH:36][C:35]([CH3:42])=[CH:34]5)=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncn(Cc4ccc(OC)cc4)c-3n2)cc1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc3c(Oc4ccc5[nH]c(C)cc5c4F)ncn(Cc4ccc(OC)cc4)c-3n2)cc1
Temperature: 95 °C

Procedure:
A mixture of 3.96 g (9.4 mMol) of 4-[4-chloro-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid ethyl ester, 2.14 g (13 mMol) of 4-fluoro-5-hydroxy-2-methyl-1H-indole (preparation see WO 00/47212; Ex. 237) and 2.44 (17.7 mMol) of K2CO3 In 90 ml of DMF is heated for 9 h at 95° C. The reaction mixture is concentrated in vacuuo, the residue dissolved in EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2, EtOAc/hexane 1:1) gives the title compound; TLC (EtOAc/hexane 1:1) Rf=0.24; MS-ES+: (M+H)+=551.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][NH:15][C:14]3=[N:28][C:29]#[N:30])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[C:34]#[N:35].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([C:34]#[N:35])[C:14]3=[N:28][C:29]#[N:30])=[CH:11][CH:12]=2)=[CH:31][CH:32]=1
Reactant: N#CBr
Reactant: N#CN=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#CN=C1N(C#N)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)—N-(1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)-phenyl)imidazolidin-2-ylidene)cyanamide [prepared from Example 203] (15.0 mg, 0.033 mmol) in 1,4-dioxane (0.5 mL) is treated with excess BrCN and K2CO3. The reaction mixture is heated at 100° C. for 2 h, cooled, then quenched with H2O (5 mL) and extracted with EtOAc (3×3 mL). The combined organics are evaporated en vacuo and purified by preparatory LC/MS followed by preparatory TLC to provide the title compound; HPLC-MS calculated for C24H15ClF3N5O (M+H+) 482.1, found 482.1.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3([C:29]([OH:31])=[O:30])[O:18][N:17]=[C:16]([C:19]4[CH:28]=[CH:27][C:22]5[NH:23][C:24](=[O:26])[O:25][C:21]=5[CH:20]=4)[CH2:15]3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O.[C:35]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(O)(C(F)(F)F)=O>[CH3:35][O:30][C:29]([C:14]1([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[O:18][N:17]=[C:16]([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24](=[O:26])[O:25][C:21]=3[CH:20]=2)[CH2:15]1)=[O:31]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(CN2CCC(Cc3ccc(F)cc3)CC2)CC(c2ccc3[nH]c(=O)oc3c2)=NO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: COC(=O)C1(CN2CCC(Cc3ccc(F)cc3)CC2)CC(c2ccc3[nH]c(=O)oc3c2)=NO1
Yield: 31.3 %

Procedure:
To a solution of 5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydroisoxazole-5-carboxylic acid (687 mg, 0.909 mmol) in MeOH (20 mL) and TFA (1.5 mL) was added p-toluenesulfonic acid monohydrate (190 mg, 0.999 mmol). The reaction mixture was heated to reflux overnight, then concentrated and purified by flash chromatography (silica gel, 5% MeOH in CH2Cl2) to give 5-[4-(4-fluorobenzyl)piperidin-1-ylmethyl]-3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydroisoxazole-5-carboxylic acid methyl ester (133 mg, 31%), as an off white solid:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])=[CH:23][C:22]=1[OH:28]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: COc1cccc(CCCCCCBr)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCCc2cccc(OC)c2OC)cc1O
Yield: 93.6 %

Procedure:
A mixture of 1.0 g (3.3 mmol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene, 0.55 g (3.3 mmol) of 2,4-dihydroxybenzoic acid methyl ester, 1.2 g (9 mmol) of potassium carbonate and 0.75 g (4.5 mmol) of potassium iodide in 25 mL of acetone was stirred at reflux for 20 hours. Workup as in Example 16 gave 1.2 g of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-2-hydroxybenzoic acid methyl ester as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[CH:5]2.[O:14]1CCCC1.[OH-].[Na+].OO>CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[CH2:6][CH:5]2[OH:14]
Reactant: CC1(C)C=Cc2cc(Br)ccc2N1
Reactant: C1CCOC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CC(O)c2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-2,2-dimethyl-1,2-dihydroquinoline (4.50 g, 18.9 mmol) in tetrahydrofuran (37.8 ml, 18.9 mmol) was added BH3DMS (3.58 ml, 37.8 mmol) dropwise at 0 deg C. The resulting solution was allowed to warm to RT and stirred for 1 hour. The temperature was returned to 0 deg C. and sodium hydroxide (6N) (30.0 ml, 18.9 mmol) followed by Hydrogen peroxide (30.0 ml, 18.9 mmol) was slowly added to the reaction mixture. The resulting solution was stirred for 45 minutes and then transferred to a sep. funnel containing water and EtOAc. The layer were separated and the aqueous layer was subsequently washed 3× with DCM. The organic layers were dried with MgSO4, filtered and concentrated. The crude mixture was then purified with the MPLC (100% DCM to 10% 90:10:1 DCM:MeOH:NH4OH) to provide the desired product. MS m/z: 257 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[CH:12]([CH:14]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:15]([O-:17])=[O:16])=O.Cl.[C:27]1(C)C=CC=C[CH:28]=1>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH:5]/[CH:12]=[C:14](/[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)\[C:15]([O:17][CH2:27][CH3:28])=[O:16]
Reactant: COc1ccc(OC)c(N)c1
Reactant: Cc1ccccc1
Reactant: COc1ccc(C(C=O)C(=O)[O-])cc1
Agent: Cl
Product: CCOC(=O)/C(=C\Nc1cc(OC)ccc1OC)c1ccc(OC)cc1
Yield: 52 %

Procedure:
A solution of 2,5-dimethoxyaniline (1.07 g, 7.00 mmol) and ethyl ∀-formyl-4-methoxyphenylacetate (1.71 g, 1.1 eq) in toluene (15 ml) is refluxed for 18 hours. After cooling, the reaction mixture is diluted with toluene (15 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO4 and then evaporated under reduced pressure. The isolated residue is crystallized from methanol and then filtered on a sinter funnel to give 1.30 g (52%) of compound 28.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:48]=[CH:47][C:19]([C:20]([NH:22][C@@H:23]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([Br:46])[CH:40]=3)[CH2:24][N:25]([CH3:38])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)=[O:21])=[C:18]([F:49])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.SC1C=CC(C(O)=O)=CC=1.O[Li].O>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:16]2[CH:48]=[CH:47][C:19]([C:20]([NH:22][C@@H:23]([C:39]3[CH:44]=[C:43]([F:45])[CH:42]=[C:41]([Br:46])[CH:40]=3)[CH2:24][NH:25][CH3:38])=[O:21])=[C:18]([F:49])[CH:17]=2)=[N:4][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:14])[C@@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CN(C[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(O)c1ccc(S)cc1
Agent: [Li]O
Solvent: CN(C)C=O
Solvent: O
Product: CNC[C@@H](NC(=O)c1ccc(-c2nc([C@H]3CC[C@H](O)[C@@H](F)C3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)-pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(N-methyl-2-nitrophenyl-sulfonamido)ethyl)-2-fluorobenzamide (500 g crude product from previous step) in DMF (2.0 kg) was added 4-mercaptobenzoic acid (161.5 g, 1047.7 mmol). The reaction mixture became a solution after 5 minutes and then was cooled to 10° C. After addition of LiOH.H2O (137.3 g, 3274.0 mmol) in one portion, the mixture was stirred at 25° C. for 3 hours before the temperature was cooled to 10° C. The reaction mixture was diluted with water (3.0 kg) and extracted with IPAC (3*2.5 kg). The IPAC layers was first washed with 15% aqueous Na2CO3 (2*3.0 kg) followed by water (2*3.0 kg), and then concentrated under vacuum (<100 mbar) at 40-45° C. To the resulting residue was added MeCN (1.8 kg) to give a clear solution, which was heated to 50° C. and stirred for 30 minutes. The mixture was further cooled to 10° C. in 2 hours and stirred at this temperature for a further 1 hour. After filtration of the resulting suspension, the solid cake was washed with pre-cooled MeCN (400 g, 5° C.). The wet cake was dried under vacuum (<100 mbar) at 80° C. for 18 hours to give 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide as a crystalline solid (245 g, overall yield for 2 steps is 66%, HPLC purity=98.3%, chiral purity=99.0%). Mp 115-117° C. ESI-MS (m/z): 578.1381, 580.1381 ([M+H]+, 100). HPLC (method A), retention time=7.24 min. 1H NMR (400 MHz, DMSO-D6): 8.82 (d, J=8 Hz, 1H), 8.0 (s, 1H), 8.82 (t, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.53 (s, 1H), 7.48 (d, J=8 Hz, 1H), 7.34 (d, J=8 Hz, 1H), 6.21 (br. s, 2H), 5.18 (m, 2H), 4.46-4.52, 4.32-4.37 (m, 1H), 3.52-3.60 (m, 1H), 2.80-2.94 (m, 3H), 2.36 (s, 3H), 2.23-2.25 (m, 1H), 1.95-1.98 (m, 1H), 1.76-1.86 (m, 3H), 1.51-1.62 (m, 1H), 1.39-1.48 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:5][C:4](=O)[CH:3]=1.Cl.[NH2:17][OH:18].NC1C=CC=CN=1>>[OH:18][N:17]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: NO
Reactant: Cc1ccc(-c2cc(C)cc(=O)o2)cc1
Agent: Cl
Agent: Nc1ccccn1
Product: Cc1ccc(-c2cc(C)cc(=O)n2O)cc1
Yield: 16.1 %

Procedure:
1 g of 4-methyl-6-(4-tolyl)-2-pyrone, 0.6 g of hydroxylamine hydrochloride and 4 g of 2-aminopyridine were heated for 1 hour to 80° C. After the usual working up, 0.173 g (16.1 %) of 1-hydroxy-4-methyl-6-(4-tolyl)-2-pyridone melting at 125° C (calc.: 6.5 % N, found: 6,6 % N) were isolated. When using pyridine instead of aminopyridine under otherwise equal reaction conditions, the yield was 0.012 g (1.1 %) only.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH:19]1[C:50](=[O:51])[NH:49][CH:48]([CH:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[CH:41]([CH2:42][CH:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][CH:37]([CH:56]([OH:66])[CH:57]([OH:65])[C:58]2[CH:63]=[CH:62][C:61]([OH:64])=[CH:60][CH:59]=2)[C:35](=[O:36])[NH:34][CH:33]([CH:67]([OH:69])[CH3:68])[C:31](=[O:32])[N:30]2[CH:26]([CH:27]([OH:71])[CH:28]([CH3:70])[CH2:29]2)[C:24](=[O:25])[NH:23][CH:22]([OH:72])[CH:21]([OH:73])[CH2:20]1)=[O:17].C(O)CCC.O>C(OCC)(=O)C.C(O)CCC>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C@@H:19]1[C:50](=[O:51])[NH:49][C@@H:48]([C@H:52]([OH:54])[CH3:53])[C:46](=[O:47])[N:45]2[C@@H:41]([CH2:42][C@@H:43]([OH:55])[CH2:44]2)[C:39](=[O:40])[NH:38][C@@H:37]([C@H:56]([OH:66])[C@@H:57]([OH:65])[C:58]2[CH:59]=[CH:60][C:61]([OH:64])=[CH:62][CH:63]=2)[C:35](=[O:36])[NH:34][C@@H:33]([C@H:67]([OH:69])[CH3:68])[C:31](=[O:32])[N:30]2[C@@H:26]([C@@H:27]([OH:71])[C@@H:28]([CH3:70])[CH2:29]2)[C:24](=[O:25])[NH:23][C@H:22]([OH:72])[C@H:21]([OH:73])[CH2:20]1)=[O:17]
Reactant: CCCCCCCCCCCCCCCC(=O)NC1CC(O)C(O)NC(=O)C2C(O)C(C)CN2C(=O)C(C(C)O)NC(=O)C(C(O)C(O)c2ccc(O)cc2)NC(=O)C2CC(O)CN2C(=O)C(C(C)O)NC1=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)[C@@H](C)CN2C(=O)[C@H]([C@@H](C)O)NC(=O)[C@H]([C@H](O)[C@@H](O)c2ccc(O)cc2)NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@H]([C@@H](C)O)NC1=O

Procedure:
1.7 g. of crude aculeacins obtained in Example 2 dissolved in 5 ml. of n-butanol was charged on a silica gel column packed with a water-saturated solvent of ethyl acetate-n-butanol (4 : 1). The column was eluted with the same solvent and 10 g. fractions were collected. Each fraction was assayed by bio-assay and thin layer chromatograph to find the activity of Nos. 33 to 55 fractions. Vacuum drying gave 629 mg. of white powder. The powder was further purified by dissolving in n-butanol (50 ml.), and was washed three times with distilled water (each 10 ml.) and dried in vacuo. 577 mg. of purified aculeacin-A was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[O:12].[NH2:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26].[C:31]1(N)C=CC=C[C:32]=1N>>[NH2:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]([C:2]1[CH:1]=[CH:10][C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:32][CH:31]=2)=[CH:4][CH:3]=1)=[O:12]
Reactant: O=C(O)CCCCCCC(=O)c1ccc2ccccc2c1
Reactant: Nc1ccccc1N
Reactant: NCc1ccccc1N
Product: Nc1ccccc1CNC(=O)CCCCCCC(=O)c1ccc(-c2ccccc2)cc1
Yield: 32 %

Procedure:
Following the procedure described in Example 22, but substituting carboxylic acid 50h for carboxylic acid 50g and 2-aminobenzylamine for 1,2-phenylenediamine respectively, the title compound 75 was obtained in 32% yield. 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=8.4 Hz, 2H), 7.71-7.61 (m, 4H), 7.37-7.51 (m, 3H), 7.12-7.01 (m, 2H), 6.70-6.62 (m, 2H), 5.76 (br s, 1H), 4.38 (d, J=6.3 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.19 (t, J=7.5 Hz, 2H), 1.80-1.58 (m, 4H), 1.45-1.32 (m, 4H).