Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH:25]1[O:29][C:28](=[O:30])[N:27]([CH3:31])[CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH:25]3[O:29][C:28](=[O:30])[N:27]([CH3:31])[CH2:26]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CN1CC(CCl)OC1=O
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CN1CC(CN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)OC1=O
Yield: 24 %

Procedure:
This compound was prepared according to the procedure of Example 1. A mixture of 4.6 g (0.015 mole) of α,α-bis-(p-fluorophenyl)-4-piperidinemethanol, 2.2 g (0.015 mole) of 5-(chloromethyl)-3-methyl-2-oxazolidinone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 50 g of Florisil®. Fractions eluted with 5-20% acetone in benzene were combined and concentrated to give a solid residue. The solid was recrystallized from isopropyl ether-2-propanol to yield 1.5 g (24%) of white solid, m.p. 147°-148° C.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:29]([O:30]C(=O)C)[C@H:28]([O:34]C(=O)C)[C@@H:27]([CH2:38][O:39]C(=O)C)[O:26][C@H:9]1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=O)C>CO>[O:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C@@H:9]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:34])[C@H:29]([OH:30])[C@H:8]1[OH:7]
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
Sodium methoxide (28% methanol solution; 0.12 mL) was added to a solution of 2-(4-methoxybenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.11 g) in methanol (4 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-(4-methoxybenzyl)-phenyl β-D-glucopyranoside (65 mg).
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1>CO>[CH3:1][O:14][C:13](=[O:15])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Br:5])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1cccc(Br)c1
Solvent: CO
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 967 %

Procedure:
Acetyl chloride (0.7 ml, 9.3 mmol) was slowly added to a solution of (3-bromo-phenyl)-acetic acid (20.0 g, 93 mmol) in methanol (500 ml) at 0° C. under nitrogen and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6 g). 1H NMR (400 MHz, CDCl3): δ=7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, s), 3.59 (2H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 253.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[CH3:9])=[CH:4][CH:3]=1.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([O:10][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(O)(c1ccccc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)N1CCN(CCCl)CC1
Product: CCOC(=O)N1CCN(CCOC(C)(c2ccccc2)c2ccc(Cl)cc2)CC1
Yield: 89 %

Procedure:
Following a procedure similar to that described in Preparation 8(a), but using 1-(4-chlorophenyl)-1-phenylethanol and 1-(2-chloroethyl)-4-(ethoxycarbonyl)piperazine, the title compound was obtained in a yield of 89%.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[C:10]([C:13]34[CH2:20][CH:19]5[CH2:21][CH:15]([CH2:16][CH:17]3[CH2:18]5)[CH2:14]4)[NH:9][C:8]=2[C:7](=[O:22])[NH:6][C:5]1=[O:23])[CH:2]=[CH2:3].[H-].[Na+].I[CH2:27][CH2:28][CH3:29].O>CN(C)C=O>[CH2:1]([N:4]1[C:12]2[N:11]=[C:10]([C:13]34[CH2:14][CH:15]5[CH2:21][CH:19]([CH2:18][CH:17]3[CH2:16]5)[CH2:20]4)[NH:9][C:8]=2[C:7](=[O:22])[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)[nH]c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)n(CCC)c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
1.00 g (3.21 mmol) of Compound G was dissolved in 30 ml of dimethylformamide, and 256 mg of sodium hydride (60%, 6.41 mmol) was added slowly to the solution at 0° C. After 30 minutes, 0.33 ml (3.4 mmol) of 1-iodopropane was added dropwise slowly at the same temperature and stirred at room temperature overnight. The resulting reaction mixture was poured into 300 ml of water, neutralized and extracted three times with 100 ml of chloroform. The organic layer was washed with a saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: 30% ethyl acetate/hexane) to give 225 mg (yield 20%) of Compound H as a colorless needle crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[C:15](OCC)(=[O:21])[C:16](OCC)=[O:17]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([NH:9][C:15](=[O:21])[C:16](=[O:17])[NH:8]2)=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(Cl)c(-n2cccc2)cc1N
Product: O=c1[nH]c2cc(Cl)c(-n3cccc3)cc2[nH]c1=O

Procedure:
0.6 g (2.9 mmol) of N-(2-chloro-4,5-diaminophenyl)pyrrole and 32 g (221 mmol) of diethyl oxalate were refluxed for 3 hours. The reaction mixture was cooled and then the crude product was filtered off and washed with petroleum ether.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[O:29][CH2:30][C:31](=[O:34])[NH:32][CH3:33])[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[F:28][C:24]1[CH:23]=[C:22]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[C:14]([CH:15]=2)[O:29][CH2:30][C:31]([NH:32][CH3:33])=[O:34])(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: CNC(=O)COc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)COc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1

Procedure:
3-[4-(3-Fluoro-benzenesulfonyl)-2-methylcarbamoylmethoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was deprotected using HCl in 1,4-dioxane following the procedure described in Example 13, to afford 2-[5-(3-Fluoro-benzenesulfonyl)-2-pyrrolidin-3-yl-phenoxy]-N-methyl-acetamide as a hydrochloride salt. MS (M+H)=393.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[N:9](COCC[Si](C)(C)C)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38](Cl)=[O:39])=[CH:28][CH:27]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:39])=[CH:30][CH:31]=1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: C[Si](C)(C)CCOCn1c(CC2CCCCN2)cc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3[nH]2)c(-c2ccc(F)cc2)s1

Procedure:
(RS)-1-[5-(4-Fluoro-phenyl)2-methyl-thiazol-4-yl]-1-{2-[1-(2-trimethylsilanyl-oxymethyl)-1H-indol-2-ylmethyl]-piperidin-1-yl}-methanone (130 mg) was prepared from (RS)-2-piperidin-2-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole, D68 (520 mg) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (512 mg) according to a procedure similar to that for Example 1. A stirring solution of the above amide (125 mg) in dry THF (5 ml) was treated with a solution of tetrabutylammonium fluoride (2.2 mmol) in THF (5 ml). Once tlc indicated the reaction had gone to completion, the reaction mixture was poured into water and the product extracted with ethyl acetate. The combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-100% pentane-ethyl acetate followed by preparative tlc, 40% ethyl acetate-pentane) afforded the title compound as a white solid (2.5 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](=[S:9])[NH2:8])[CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>CC(C)=O.C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:9][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=2)[CH:3]=1
Reactant: Cc1cc(C(N)=S)no1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1csc(-c2cc(C)on2)n1
Temperature: 55 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
5-Methyl-isoxazole-3-carbothioamide (1.0 g, 7.0 mmol) was dissolved in acetone (16 mL) and treated with ethyl bromopyruvate (1 mL, 1 equivalent) and 3.9 g of powdered 3 A molecular sieves. The reaction was stirred at 55° C. under a nitrogen atmosphere for 18 h. The mixture was filtered and evaporated to give 1.06 g of crude material. This material was dissolved in THF (25 mL), cooled to 0° C., and treated with 2,6-lutidine (1.5 mL, 3 equivalents). Trifluoroactetic acid (0.9 mL, 1.5 equivalents) was added and stirring was continued for 2 hrs under a nitrogen atmosphere. The reaction was poured into a 1 M solution of sodium bicarbonate and extracted twice with ethyl acetate (75 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the solvent was removed by evaporation. The crude material was purified using chloroform:ethyl acetate (1:1) to give 876 mg (53%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([CH3:22])[CH:18]=2)=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1](=[N:26][OH:27])([C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[O:21][N:20]=[C:19]([CH3:22])[CH:18]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCC(=O)c1ccc(OCCCCCCCc2cc(C)no2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC(=NO)c1ccc(OCCCCCCCc2cc(C)no2)cc1
Yield: 59.8 %

Procedure:
To a solution of 1.6 g of 5-[7-(4-propionylphenoxy)heptyl]-3-methylisoxazole (Example 32) in 40 ml of ethanol was added a solution of 368 mg of hydroxylamine hydrochloride and 730 mg of sodium acetate in 8 ml of water. The reaction mixture was heated at reflux overnight and then concentrated in vacuo. The residue was recrystallized from aqueous ethanol to give 1.0 g of 5-[7-(4-propionylphenoxy)heptyl]-3-methylisoxazole oxime, colorless solid, m.p. 88°-89° C.; MIC vs. rhinovirus Type 2 in vitro=2.6 μg/ml; and vs. polio-2 virus at 0.2 μg/ml.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[N:6]=1)=[O:4].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1B(O)O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:26]2[CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=[CH:30][C:25]=2[O:24][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:6]=1)=[O:4]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: COC(=O)c1cccc(C2=C(Br)CCC2)n1
Product: COC(=O)c1cccc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)n1

Procedure:
Prepared by general procedure 3 but using 6-(2-bromocyclopent-1enyl)pyridine-2-carboxylic acid methyl ester instead of 3-(2-bromocyclopent-1-enyl)benzoic acid ethyl ester and 2-benzyloxy-5-trifluoromethylphenylboronic acid instead of 5-chloro-2-methoxyphenylboronic acid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:16]3=[N:17][C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:19]([N+:22]([O-:24])=[O:23])[C:20](=[O:21])[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[N+:22]([C:19]1[C:20](=[O:21])[N:15]2[CH2:14][CH2:13][CH2:12][N:11]([C:9]3[CH:8]=[CH:7][N:6]=[C:5]([NH:39][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:10]=3)[C:16]2=[N:17][C:18]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CS(=O)(=O)c1nccc(N2CCCn3c2nc(-c2ccccc2)c([N+](=O)[O-])c3=O)n1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Product: O=c1c([N+](=O)[O-])c(-c2ccccc2)nc2n1CCCN2c1ccnc(NCCc2ccccc2)n1

Procedure:
A solution of 9-(2-methanesulfonyl-pyrimidin-4-yl) -3-nitro-2-phenyl -6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (220 mg, 0.51 mmol) and phenethylamine (0.13 mL, 1.0 mmol) in dichloromethane (2 mL) was heated to 80° C. for 1 h. Residue purified on silica, and final product isolated as a white solid. M+1=470.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16](O)[C:17]([CH3:20])([CH3:19])[CH3:18].N1C(C)=CC=CC=1C>ClCCl>[CH3:16][C:17]([CH3:20])([CH3:19])[CH2:18][O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)CO
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)COS(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Add trifluoromethanesulphonic anhydride (1.12 mL, 6.8 mmol) to a solution of neopentylalcohol (0.5 g, 5.7 mmol) and 2,6-lutidine (0.7 mL, 6.8 mmol) in dichloromethane (10 mL) at −78° C. and stir for 1 hour. Add water to quench the reaction, separate the organic layer and extract the aqueous layer with dichloromethane. Combine the organic layers, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 1:4 hexane:dichloromethane) to give the desired compound as an oil (0.9 g, 72% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.N1CCCCC1>C(O)C>[OH:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16]
Reactant: O=Cc1ccccc1O
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(-c3cccnc3)ccc2C1=Cc1ccccc1O
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A mixture of 6-pyridin-3-yl-1,3-dihydroindol-2-one (100 mg, 0.5 mmol), 2-hydroxybenzaldehyde (60 mg, 0.5 mmol) and piperidine (0.23 mL) in ethanol (4 mL) was heated to reflux and stirred overnight. The reaction mixture was concentrated and column chromatographed (eluant—isopropanol/dichloromethane) to give 100 mg (64%) of 3-(2-hydroxybenzylidene)-6-pyridin-3-yl-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[NH:5][C:4]1=[O:15]>C(O)C.C(O)(=O)C>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:3]([S:2][CH3:1])[C:4](=[O:15])[NH:5]2
Reactant: CSC1C(=O)Nc2cccc([N+](=O)[O-])c21
Solvent: CC(=O)O
Solvent: CCO
Product: CSC1C(=O)Nc2cccc(N)c21
Temperature: 70 °C

Procedure:
A mixture of compound D1 (1 g), stannous chloride dihydrate (5.03 g) in 36 mL of ethanol and acetic acid (EtOH:AcOH:5:1) was heated at 70° C. under argon. Reaction was monitored using TLC and terminated after 7 hrs on disappearance of the starting material. The reaction mixture was cooled, solvent evaporated to give a sticky solid, water added, then extracted with chloroform. Saturated sodium bicarbonate was added stepwise to water layer, extracted with chloroform. Organic layers were combined, washed with saturated sodium bicarbonate and brine solution, dried over MgSO4, filtered and concentrated to give crude product, which was washed with toluene to give the title compound D2. YD: 95.85%. 1H NMR (DMSO-d6) 400 MHz. δ: 1.888 (s, 3H) 4.303 (s, 1H), 5.121 (s, 2H), 6.050 (d, J=7.6 Hz, 1H), 6.250 (d, J=8.4, 1H), 6.889 (dd, J=7.6 & 8.0 Hz, 1H), 10.231 (s, 1H). MS (ESI): m/z 217.0 [M+Na]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][C@H:17]([CH3:19])[C@@H:16]([CH3:20])[C@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1.CCCC1C2C3OC(C)(C)C=CC=3C3O[C@@H](C)[C@H](C)[C@@H](O)C=3C=2OC(=O)C=1.C([O-])(=O)C.C(=O)([O-])N>CCCCCC.C(O)C>[CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]3[O:18][CH:17]([CH3:19])[CH:16]([CH3:20])[CH:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@H](C)[C@@H](C)[C@@H]3O
Agent: CC(=O)[O-]
Agent: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)O[C@@H](C)[C@H](C)[C@H]3O
Agent: NC(=O)[O-]
Solvent: CCO
Solvent: CCCCCC
Product: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)OC(C)C(C)C3O

Procedure:
The synthetic (±)-1 was resolved into enantiomers, (+)-calanolide A and (−)-calanolide A, by preparative HPLC66. Thus, using a normal phase silica gel HPLC column (250 mm×4.6 mm I.D. Zorbasil, 5 μm particle size, MAC-MOD Analytical, Inc., PA, USA), the synthetic (±)-1 appeared as one peak with a retention time of 10.15 minutes when hexanelethyl acetate (70:30) was used as the mobile phase at a flow rate of 1.5 minutes and a wavelength of 290 nm was used as the uv detector setting. However, on a chiral HPLC column packed with amnylose carbamate (250 mm×4.6 mm I.D. Chiralpak AD, 10 μm particle size, Chiral Technologies, Inc., PA, USA), two peaks with retention times of 6.39 and 7.15 minutes in a ratio of 1:1 were observed at a flow rate of 1.5 mL/min. The mobile phase was hexane/ethanol (95:5) and the uv detector was set at a wavelength of 254 nm. These two components were separated using a semi-preparative chiral HPLC column, providing the pure enantiomers of calanolide A. The chemical structures of the separated enantiomers, which were assigned based on their optical rotations and compared with the reported natural product, were characterized by spectroscopic data. HPLC chromatograms of (±)-calanolide A and its optical forms are shown in FIG. 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]([C:36](=[O:38])[CH3:37])=[C:23]([CH3:39])[CH:22]=2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:26]3[CH:25]=[C:24]([C:36](=[O:38])[CH3:37])[C:23]([CH3:39])=[CH:22][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(OCC2CC2)cc1C
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3cc(C(C)=O)c(C)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 1-[4-cyclopropylmethoxy-2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethanone (example A47) the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].Cl.NC(N)=N.C[O-].[Na+].[NH:13]([CH:20]=[C:21]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[CH:26]=1)[C:22]#N)C1C=CC=CC=1>C(O)C.COCCO>[NH2:3][C:2]1[N:4]=[C:20]([NH2:13])[C:21]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)=[CH:22][N:1]=1
Reactant: N=C(N)N
Reactant: Cn1cc(CC(C#N)=CNc2ccccc2)c2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Solvent: CCO
Product: Cn1cc(Cc2cnc(N)nc2N)c2ccccc21
Yield: 41 %

Procedure:
To 100 mL of an ethanolic guanidine solution prepared from 2.10 g (0.022 mole) of guanidine hydrochloride and 1.20 g (0.022 mole) of sodium methoxide was added 5.00 g (0.017 mole) of 3-anilino-2-(1-methyl-3-indolylmethyl)acrylonitrile. The solution was heated under reflux for 1/2 hour and then 100 mL of 2-methoxyethanol was added. The internal temperature was allowed to gradually increase to 120° by distillation of the ethanol, after which it was heated at this temperature for 4.75 hr. The reaction was cooled and the solvent was removed in vacuo. The residue was recrystallized from 95% ethanol to give two crops of the title compound (total 1.82 g, 41%) mp 253°-256° dec. Anal. Calcd for C14H15N5 : C, 66.38, H, 5.97; N, 27.65. Found: C, 66.05; H, 6.04; N, 27.89.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>O1CCCC1>[C:18]([O:17][C:13]([NH:14][NH:15][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1ccc(C(=O)O)cc1O
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1O

Procedure:
3-Hydroxy-4-methoxybenzoic acid (1.0 g, 5.9 mmol) is coupled to tert-butyl carbazate (0.94 g, 7.1 mmol) using EDC (2.3 g, 12 mmol), HOBT (1.6 g, 15 mmol), and NMM (1.6 mL, 15 mmol) in tetrahydrofuran (30 mL). Following an aqueous work-up, the crude product is purified by reverse-phase high performance liquid chromatography to give N′-(3-hydroxy-4-methoxy-benzoyl)-hydrazinecarboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH:4]1[CH:8]2[CH2:9][C:10](=[O:13])[CH:11]=[CH:12][C:7]2([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)OC1=O)(=[O:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>C(Cl)Cl>[C:23]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:8]([CH2:4][C:1](=[O:3])[CH3:2])[CH:9]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)C1C(=O)OC2(C#Cc3ccccc3)C=CC(=O)CC12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)Cc1cc(OC(C)=O)ccc1C#Cc1ccccc1
Reaction time: 1 h

Procedure:
3-Acetyl-3a,7a-dihydro-7a-(phenylethynyl)benzofuran-2,5(3H,4H)dione, the product of Example 1A, (10.0 g, 34 mmole) and acetic anhydride (25 mL) were placed in a 100 mL flask and heated at reflux overnight under argon. Heating was stopped and the reaction was treated with water (25 mL) and stirred for 1 hr. The reaction was poured into water and extracted with Et2O. The combined ether extracts were washed with water and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to yield 9.4 g of crude product. Chromatography of the crude product over silica gel, using methylene chloride as eluent, gave 4.2 g of pure 1-[5-Acetoxy-2-(phenylethynyl)phenyl]-2-propanone product as a viscous oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][N:17]([CH3:26])[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([N:17]([CH3:26])[CH3:16])=[N:19][CH:20]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(N(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(N(C)C)nc2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, N,N-dimethyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.