Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB(/[CH:43]=[CH:44]/[CH2:45][CH2:46][OH:47])O1>CC(N(C)C)=O>[NH2:28][C:18]1[N:17]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2](/[CH:43]=[CH:44]/[CH2:45][CH2:46][OH:47])[CH:7]=3)=[CH:10][CH:11]=2)[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=1
Reactant: CC1(C)OB(/C=C/CCO)OC1(C)C
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc(/C=C/CCO)c3)cc2)cc(-c2ccccc2)n1
Temperature: 150 °C
Yield: 14.5 %

Procedure:
N4-{4-[(2-chloropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine (0.10 g, 0.26 mmol, Example 48), K2CO3 (0.089 g, 0.64 mmol), and DMA (2.5 mL) were placed into a small microwave vial. The mixture was degassed for 10 min before (3E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-ol (0.10 g, 0.33 mmol) and Pd(dppf)Cl2 CH2Cl2 complex (0.012 g, 0.020 mmol) were added. The mixture was heated at 150° C. for 20 min in a microwave reactor. The mixture was cooled, filtered, and purified by prep-HPLC. Concentration of the desired fractions gave 0.016 g of the title compound (10%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)O)([CH3:4])([CH3:3])[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[N:24]1[C:20](=[O:30])[C:21]2[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:23]1=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
To a stirred solution of [3-(3-chloro-phenyl)-3-hydroxy-propyl]-carbamic acid tert-butyl ester (12 g, 42 mmol), phthalimide (6.2 g, 42 mmol), and PPh3 (14.3 g, 55 mmol) in THF (150 mL) was added DEAD (9.0 mL, 55 mmol) dropwise at about 5° C. After 1 hour, the mixture was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:8) to afford [3-(3-chloro-phenyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-carbamic acid tert-butyl ester. (Yield 15.65 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[NH:5][C:6](=[O:9])[C:7]=1[NH2:8].[C:20]([O-])(=O)[CH3:21].[Na+].Cl.C(N)(=N)C>C(O)C>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]2[C:7](=[N:8][C:20]([CH3:21])=[N:1]2)[C:6](=[O:9])[N:5]=1)[CH2:18][CH3:19]
Reactant: CC(=O)[O-]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: CC(=N)N
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(C)=NC2=N1

Procedure:
A mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one (1.56 g), anhydrous sodium acetate (114 g) and acetamidine hydrochloride (142 g) was heated in an oil bath at 150°-160° C. for 2 hours. The mixture was digested with ethanol (2 ml), cooled, filtered and the solid washed with ethanol. Recrystallisation from ethanol gave the title compound, 0.72 g, m.p. 264°-265° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:13][CH:12]([OH:14])[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:17](I)[CH3:18]>>[CH2:17]([O:14][CH:12]1[CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:13]1)[CH3:18]
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCOC1CN(c2ccc([N+](=O)[O-])cn2)C1
Yield: 55.5 %

Procedure:
1-(5-Nitro-pyridin-2-yl)-azetidin-3-ol (97.5 mg, 0.5 mmol) was treated with 60% NaH in oil (60 mg, 1.5 mmol) and ethyl iodide (400 uL, 5 mmol) as above to yield 62 mg of product following purification by flash chromatography. ES-MS calcd for C10H13N3O3 (m/e) 223.23, obsd 224.1 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([CH2:16][C:17]2[CH:22]=[C:21](OC)[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)([OH:15])[C:6]1=[O:27])[CH2:2][CH2:3][CH3:4].COC1C=C(C=CC=1)CCl>>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[C:7]([OH:15])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)[C:6]1=[O:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(O)(Cc2cc(OC)cc(OC)c2)c2cc(Cl)ccc21
Agent: COc1cccc(CCl)c1
Product: CCCCN1C(=O)C(O)(Cc2cccc(OC)c2)c2cc(Cl)ccc21

Procedure:
This compound was made in an analogous fashion to 11-ethyl-3-hydroxy-5-methyl-3-(3,4,5-trimethoxybenzyl)indolin-2-one using 1-butyl-5-chloro-3-(3,5-dimethoxybenzyl)-3-hydroxyindolin-2-one and 3-methoxy benzyl chloride (purchased from Fisher Scientific). 1H NMR δ 7.31 (s, 1H), 7.24 (d, 1H), 7.02 (t, 1H), 6.69 (d, 1H), 6.59 (d, 1H), 6.52 (d, 1H), 6.43 (s, 1H), 3.64 (m, 4H), 3.30 (m, 2H), 3.20 (d, 1H), 1.6 (bs, OH), 1.30 (m, 2H), 1.11 (m, 2H), 0.84 (t, 3H). Calculated mass for C20H22ClNO3, 359.13. Observed 382.2 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)=[O:29])=[CH:44][CH:43]=1)(=[O:41])=[O:40]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)cc3)ccc2c1
Yield: 104.7 %

Procedure:
Dissolve trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (555 mg, 1.0 mmol), 4-methansulfonylphenylboronic acid (310 mg, 1.55 mmol), Pd(OAc)2 (23.9 mg, 0.11 mmol), Ph3P (54.2 mg, 0.21 mmol) and Na2CO3 (2.5 mL, 2M in water) in ethyleneglycol dimethyl ether (DME, 30 mL). Reflux the mixture for 2 hours and add additional Pd(OAc)2 (25.2 mg) and Ph3P (58.9 mg). Reflux for 2 hours then dilute the reaction mixture with water and extract with chloroform. Dry the organic phase over Na2SO4, filter and concentrate. Purify the crude material by loading on an SCX column and eluting with 2M NH3/MeOH to afford 569 mg of the title compound (101%). LCMS: m/z=544 (M+H)+
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1ccccc1

Procedure:
Compound 7 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol and methyl 3-(4-hydroxyphenyl)propanoate by following the procedure described in Scheme 5
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][C:11]([CH3:13])=[CH:12][C:5]=12.C([Li])CCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C>C1COCC1.CCCCCC.O>[CH3:13][C:11]1[NH:10][C:6]2=[N:7][CH:8]=[CH:9][C:4]([B:23]([OH:24])[OH:22])=[C:5]2[CH:12]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc2c(Br)ccnc2[nH]1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1cc2c(B(O)O)ccnc2[nH]1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 60% sodium hydride in mineral oil (1.18 g) in THF (25 ml) at 0° C. was added 4-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (5 g) in THF (75 ml) dropwise. The reaction was cooled to −78° C. and 1.6M n-butyl lithium in hexane (30 ml) was added dropwise, keeping the temperature below −60° C. The reaction was stirred at −78° C. for 30 min before the dropwise addition of triisopropylborate (16.4 ml), keeping the temperature below −60° C. The reaction was stirred for 1 h at −78° C., warmed to RT and water (100 ml) was added. The layers were separated and the water washed with ethyl acetate (2×50 ml), before the combined organic layers were washed with 2M sodium hydroxide solution (50 ml). The combined aqueous layers were treated with 2M hydrochloric acid solution to pH 7.2 and the resultant precipitate collected by filtration and dried in vacuo at 40° C. overnight to give title compound (2.64 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[CH:15][C:16](Br)=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:38])[C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>>[C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][N:14]=[CH:15][C:16]([C:23]3[CH:22]=[C:21]([C:20]([O:19][CH3:18])=[O:38])[CH:26]=[CH:25][C:24]=3[C:27]#[N:28])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)cncc21
Reactant: COC(=O)c1ccc(C#N)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)c1ccc(C#N)c(-c2cncc3c2ccn3C(=O)OC(C)(C)C)c1

Procedure:
Using 4-bromo-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (synthesized based on US 2005/0090529 A1, p82) (1 mol. eq.) and 4-cyano-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (2.0 mol. eq.) a starting materials, the reaction was performed using General procedure L (Suzuki) to give 4-(2-cyano-5-methoxycarbonyl-phenyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester. MS(ESI) m/z 378.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:6]2=[O:36].[ClH:37].CCOCC>C(Cl)Cl.C(O)(C)C>[ClH:37].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1)[N:9]=[CH:8][N:7]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34])[C:6]2=[O:36]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 6-methoxy-3-((pivaloyloxy)methyl)-7-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (7.9 g, 16 mmol) in methylene chloride (80 ml) containing 5.5M hydrogen chloride in isopropanol (80 ml) was stirred for 1 hour at ambient temperature. Ether was added and the solid was collected by filtration, washed with ether and dried under vacuum at 60° C. to give 6-methoxy-7-((piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one hydrochloride (6.9 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:15].[Na+]>[C].[Pd].[Pd].CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:15])=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: [OH-]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(-c2ccc(-c3ccc(-c4ccc(O)cc4)cc3)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Into an 1-liter stainless steel autoclave were added 60.0 g of 4-hydroxy-4'-bromobiphenyl, 100 g of methanol, 300 g of a 10% (by weight) aqueous solution of sodium hydroxide, and 13 g of a palladium-carbon containing 5% by weight of palladium and a reaction was carried out at 120° C. for 4 hours under 5 atmospheric pressures. The precipitated disodium salt of 4,4'"-dihydroxy-p-quaterphenyl was filtered and dissolved into N,N-dimethyl-formamide. The catalyst was removed by filtration with heating at 60° C. An addition of dilute sulfuric acid to the filtrate gave white crystalline powder of 4,4'"-dihydroxy-p-quaterphenyl (DHQ), which was purified by washing with methanol. The liquid-crystal transition temperature of the DHQ was 336° C. and the melting point of the DHQ was 420° C. ##STR4##
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH2:8][N:9]=1.[NH2:11][C:12]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15]>CN(C=O)C.O>[CH3:10][CH:6]1[CH2:7][CH2:8][N:9]2[C:3](=[N:11][C:12]3[C:13]([C:14]2=[O:15])=[CH:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[CH:20]=3)[CH2:4][CH2:5]1
Reactant: COC1=NCCC(C)CC1
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCc2nc3cc(C(=O)O)ccc3c(=O)n2CC1
Temperature: 25 °C
Yield: 2.2 %

Procedure:
A solution of (E)-7-methoxy-4-methyl-3,4,5,6-tetrahydro-2H-azepine (1.1 g) and 2-aminoterephthalic acid (1.4 g, 7.7 mmol) in DMF (30 mL) was stirred at 100° C. for 4 h. After it was cooled to room temperature, the reaction was diluted with water (80 mL) and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel chromatography to give 47 mg of desired product.
Reaction SMILES: C(O)CCC.C(O)C.O.N.[CH3:11][C@H:12]1[C@H:41]([CH3:42])[C@@H:40]2[C@@:15]([C:44]([O:46][C@@H:47]3[O:52][C@H:51]([CH2:53][O:54][C@@H:55]4[O:60][C@H:59]([CH2:61][OH:62])[C@@H:58]([O:63][C@@H:64]5[O:69][C@@H:68]([CH3:70])[C@H:67]([OH:71])[C@@H:66]([OH:72])[C@H:65]5[OH:73])[C@H:57]([OH:74])[C@H:56]4[OH:75])[C@@H:50]([OH:76])[C@H:49]([OH:77])[C@H:48]3[OH:78])=[O:45])([CH2:16][CH2:17][C@:18]3([CH3:43])[C@:23]4([CH3:39])[CH2:24][C@@H:25](O)[C@H:26]5[C@@:31]([CH2:33][OH:34])([CH3:32])[C@@H:30]([OH:35])[C@H:29]([OH:36])[CH2:28][C@:27]5([CH3:37])[C@H:22]4[CH2:21][CH:20]=[C:19]32)[CH2:14][CH2:13]1>O>[CH3:11][C@H:12]1[C@H:41]([CH3:42])[C@@H:40]2[C@@:15]([C:44]([O:46][C@@H:47]3[O:52][C@H:51]([CH2:53][O:54][C@@H:55]4[O:60][C@H:59]([CH2:61][OH:62])[C@@H:58]([O:63][C@@H:64]5[O:69][C@H:68]([CH3:70])[C@H:67]([OH:71])[C@@H:66]([OH:72])[C@H:65]5[OH:73])[C@H:57]([OH:74])[C@H:56]4[OH:75])[C@@H:50]([OH:76])[C@H:49]([OH:77])[C@H:48]3[OH:78])=[O:45])([CH2:16][CH2:17][C@@:18]3([CH3:43])[C@:23]4([CH3:39])[CH2:24][CH2:25][C@H:26]5[C@@:31]([CH2:33][OH:34])([CH3:32])[C@@H:30]([OH:35])[C@H:29]([OH:36])[CH2:28][C@:27]5([CH3:37])[C@H:22]4[CH2:21][CH:20]=[C:19]32)[CH2:14][CH2:13]1
Reactant: C[C@H]1[C@H](C)CC[C@]2(C(=O)O[C@@H]3O[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O[C@@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)CC[C@@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5[C@H](O)C[C@]43C)[C@H]12
Agent: N
Solvent: O
Solvent: CCO
Solvent: CCCCO
Product: C[C@H]1[C@H](C)CC[C@]2(C(=O)O[C@@H]3O[C@H](CO[C@@H]4O[C@H](CO)[C@@H](O[C@@H]5O[C@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)CC[C@]3(C)C(=CC[C@@H]4[C@@]5(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]5CC[C@]43C)[C@H]12

Procedure:
A silica gel (70-230 mesh) was filled in a column with a diameter of 6 cm and a length of 26 cm by using a mobile phase (normal butanol:ethanol:ammonia water:water=60:40:5:10). Thereafter, 1 g of WS-TECA was dissolved in as little amount of the mobile phase as possible and loaded thereon. The mobile phase was allowed to flow at a constant rate and fractionated in 25 ml bottles to obtain 400 mg of pure asiaticoside and madecassoside each.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20][OH:21]>>[CH2:1]([N:5]1[C:9]2=[C:10]([O:21][CH2:20][C:19]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:18]=3[F:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: OCc1ccc(F)cc1F
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3F)c21
Yield: 43.1 %

Procedure:
The title compound (cis/trans=18/82) was prepared as a pale yellow powder in 43.1% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=21/79) and 2,4-difluorobenzyl alcohol.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:4]([S:7][CH2:8][C:9]([OH:11])=O)=[N:5][N:6]=1.[NH2:25][OH:26]>>[Br:1][C:2]1[N:3]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:24][CH2:23]3)=[CH:14][CH:13]=2)[C:4]([S:7][CH2:8][C:9]([NH:25][OH:26])=[O:11])=[N:5][N:6]=1
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Reactant: NO
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)NO

Procedure:
2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid can be reacted with hydroxylamine to form 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-N-hydroxyacetamide. Use of an N-substituted hydroxylamine, would provide the N-substituted product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH:10]1([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc(N)cc1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(NC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A solution of p-anisidine (615 mg), cyclopentanone (420 mg) and acetic acid (2 ml) in methanol (30 ml) was cooled to 0° C., and sodium cyanoborohydride (315 mg) was added portionwise. The resulting solution was stirred at ambient temperature for 2 hours. The reaction mixture was then basified with 1N aqueous sodium hydroxide, and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (SiO2 30 g, diethyl ether:n-hexane=1:3) to give N-cyclopentyl-p-anisidine (530 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[C:19]([C:22]1[S:26][C:25](B(O)O)=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[N:11]12[CH2:17][CH:15]3[CH2:14][CH:13]([CH2:18][CH:9]([N:8]([C:4]4[CH:3]=[C:2]([C:25]5[S:26][C:22]([C:19](=[O:21])[CH3:20])=[CH:23][CH:24]=5)[CH:7]=[N:6][CH:5]=4)[CH2:16]3)[CH2:10]1)[CH2:12]2
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: CC(=O)c1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)s1

Procedure:
The title compound was prepared from the product of Example 65A and 5-acetylthiophen-2-ylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 354.0 (M+H)+, retention time 1.26 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:10]=2[N:11]=[C:12]([NH:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31])[N:13]=1
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(S(C)(=O)=O)nc21
Reactant: NC(CO)CO
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NC(CO)CO)nc21

Procedure:
The product of Example 58, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.84 (m, 6H), 1.91 (m, 2H), 2.32 (m, 2H), 3.02 (m, 2H), 3.95 (m, 4H), 4.14 (m, 1H), 5.30 (m, 0.5H), 5.52 (m, 0.5H), 6.28 (br d, 1H, J=9.6), 6.40 (br s, 1H), 7.12 (d, 1H, J=9.6 Hz), 7.30-7.58 (m, 4H). LC MS (m/e)=417 (MH+).
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>C(O)(=O)C.[Pd]>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)[C@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)[C@H](N)Cc1ccc(N)cc1

Procedure:
1.0 g (1.47 mmol) Chas-D-Phe(4-NO2)-Phe(4-NO2)—OMe was dissolved in 200 ml of 90% acetic acid, mixed with 101 mg of Pd—C, purged 3× and hydrogenated overnight with hydrogen. The catalyst was filtered off and the solvent removed in vacuo. The red, viscous oil was dissolved in 8 ml of 25% solvent B, filtered through a 0.2 μm filter and purified by prep. HPLC (start at 10% B). Fractions containing the product were combined, the solvent removed in vacuo, the residue dissolved in 40% t-butanol/water and lyophilized.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.CCCCCC>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[CH:7][C:6]([CH:5]=[CH:4][CH2:3][OH:2])=[CH:11][CH:10]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)C=Cc1ccc(-c2ccc(F)cc2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: OCC=Cc1ccc(-c2ccc(F)cc2)nc1
Temperature: -70 °C
Reaction time: 3 h

Procedure:
520 mg (2 mmol) of 3-(6-(4-fluorophenyl)pyridin-3-yl)acrylic acid methyl ester were dissolved in 40 ml of dichloromethane and cooled to −70° C. Under argon, 4.65 ml of a 1M solution of diisobutylaluminum hydride in hexane were slowly added. The mixture was stirred at −70° C. for 3 h, quenched with a solution of sodium sulfate, and warmed to room temperature. After filtration over Celite, the organic phase was separated and evaporated. Yield: 430 mg (93%)
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:21].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].N>C([O-])(O)=O.[Na+].O>[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][N:14]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13]1)[CH2:11][C:10]2=[O:21]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: N
Solvent: O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A suspension of (±)-(E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester hydrochloride salt (440 mg, 1.36 mmol, Intermediate 1) in aqueous 10% NaHCO3 solution was extracted with DCM (3×10 ml). The organic phase was dried over Na2SO4 and evaporated. The resulting oil was dissolved in DCM (15 ml), treated with benzaldehyde (0.166 ml, 1.63 mmol) and NaBH(OAc)3 (433 mg, 2.04 mmol), and the resulting clear solution was stirred at RT for 2 h. Water was added to the mixture and the pH was brought to basic conditions with NH3. The mixture was extracted with DCM (3×10 ml). The organic layer was dried, evaporated, and the crude residue was purified by column chromatography (eluent: petroleum ether/EtOAc 7:3) to give (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (482 mg) as a light yellow solid.