Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl([O-])=[O:13].[Na+].O.O.P([O-])([O-])(O)=O.[Na+].[Na+].Cl>C(O)(C)(C)C.O>[C:4]([C:3]1[CH:6]=[C:7]([CH:8]=[CH:9][C:2]=1[F:1])[C:10]([OH:13])=[O:11])#[N:5]
Reactant: [O-][Cl+][O-]
Reactant: N#Cc1cc(C=O)ccc1F
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: N#Cc1cc(C(=O)O)ccc1F
Yield: 90 %

Procedure:
To a stirred solution of 15.0 g (97.6 mmol) 2-fluoro-5-formyl-benzonitrile (Aldrich), 150 ml dest. water and 630 ml t-butanol were added 40.8 g (361 mmol) sodium chlorite and 35.9 g (230 mmol) sodium hydrogen phosphate dihydrate. The reaction mixture was stirred over night and poured into a diluted aqueous hydrogen chloride solution (pH=3.5). The pH value was readjusted to pH=3.5 by aqueous hydrogen chloride. The aqueous solution was extracted trice with dichloromethane/isopropanol (10:1). The combined organic phases were dried (sodium sulphate) and concentrated. The residue was purified by extraction with sodium hydrogen carbonate solution and dichloromethane, acidification with aqueous solution and subsequent filtering. The solid crude product 2a was obtained in 90% yield (14.5 g, 87.8 mmol) and was used for the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:11])[C:8]([O-:10])=[O:9])[N:6]=1.[K+].[CH2:13](O)[CH:14]([CH3:16])[CH3:15].Cl.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:11])[C:8]([O:10][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)[O-])cs1
Reactant: CC(C)CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)COC(=O)C(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture comprising 10 g of potassium 2-aminothiazol-4-ylglyoxylate, 15 g of isobutyl alcohol and 50 ml of a 4N dioxane solution of hydrogen chloride was stirred at room temperature for 2 days. The reaction mixture was poured into water and neutralized with potassium carbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the ethyl acetate was evaporated off under reduced pressure, giving the desired compound as a pale yellow powder.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:10]Br)[CH:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2].[S-:12][C:13]#[N:14].[K+].O>CN(C)C=O>[C:1]([O:4][CH2:5][CH:6]([CH2:10][S:12][C:13]#[N:14])[CH:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2]
Reactant: N#C[S-]
Reactant: CC(=O)OCC(CBr)C(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC(CSC#N)C(C)C

Procedure:
A mixture of 2-bromomethyl-3-methylbutyl acetate (6 g) and potassium thiocyanate (7.3 g) in dry dimethylformamide (50 ml) was heated at 140° for 2 hours. After cooling, the reaction mixture was poured into water (150 ml) and then extracted with diethylether (3×50 ml). The combined ethereal extracts were washed with water (3×50 ml) before drying over anhydrous magnesium sulphate and evaporation in vacuo. 2-Thiocyanatomethyl-3methylbutyl acetate was obtained and was used without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[C:18]2[N:27]([CH3:28])[CH:26]=[CH:25][C:19]2=[N:20][C:21]=1[C@@H:22]([NH2:24])[CH3:23].CC([O-])(C)C.[K+].C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[NH2:24][C@H:22]([C:21]1[N:20]=[C:19]2[CH:25]=[CH:26][N:27]([CH3:28])[C:18]2=[CH:17][C:16]=1[N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@H:2]([CH3:1])[CH2:7]1)[CH3:23]
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 90 °C
Yield: 32.6 %

Procedure:
To a 50 mL pear flask were added (R)-tert-butyl 2-methylpiperazine-1-carboxylate (156 mg, 0.777 mmol) and (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (94 mg, 0.370 mmol) in 1,4-dioxane (0.92 mL). Potassium 2-methylpropan-2-olate (1 M in THF, 0.81 mL, 0.81 mmol) was added, and the mixture was heated to 90° C. for 45 minutes. After cooling for 10 minutes, the red mixture was poured into saturated NaHCO3 and the pH was adjusted to ˜10 by adding K2CO3. The mixture was extracted with EtOAc (3×). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to give crude product, which was purified by preparative HPLC (basic mode, 30-55% ACN/water gradient). The product-containing fractions were combined, concentrated in vacuo, and then partitioned between saturated NaHCO3 and EtOAc. The organic phase was dried over MgSO4, filtered, and concentrated to give the title compound as a colorless oil (45 mg, 33%). ESI-MS m/z [M+H]+ calc'd for C20H31N5O2, 374. found 374.
Reaction SMILES: C1COCC1.[NH:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.C1C=CC2N(O)N=NC=2C=1.[N:32]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34](O)=[O:35]>CN(C=O)C>[N:32]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
THF (180 ml), H-Pro-OBzl.HCl (43.5 g, 0.18 M) and HOBT (24.3 g, 0.18 M) were added to BOC-Pro-OH (36.6 g, 0.17 M); DMF (100 ml) was added, and WSCI (33.0 ml, 0.18 M) was added dropwise at 0° C. After stirring at 0° C. for one hour and at room temperature overnight, the solvent was distilled off in vacuo. Benzene (500 ml) was added to the residue, which was washed three times with 5% sodium bicarbonate, three times with 1 N HCl and three times with water, in that order. After drying with anhydrous sodium sulfate, the solution was concentrated in vacuo to obtain the oily material [23] (74 g, yield: 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[CH:6][CH:7]=1.C[O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1>>[C:19]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C:29]([OH:39])=[O:28])=[CH:36][CH:35]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])(=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc2c(-c3cccc(N)c3)c(C(=O)c3ccccc3)cnc12
Reactant: COC(=O)Cc1ccc(C=O)cc1
Product: Cc1cccc2c(-c3cccc(NCc4ccc(CC(=O)O)cc4)c3)c(C(=O)c3ccccc3)cnc12

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-methyl-quinolin-3-yl]-phenyl-methanone and (4-formyl-phenyl)-acetic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 487; MS (ESI) m/z 485.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[N:12]1([C:10]2([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:11][NH:8][CH2:9]2)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC1(N2CCOCC2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1(N2CCOCC2)CNC1

Procedure:
[1-(diphenylmethyl)-3-morpholin-4-ylazetidin-3-yl]methyl}amine (1.00 g, 3.0 mmol) was dissolved in dichloromethane (10 ml) and di-tert-butyldicarbonate (0.71 g, 3.3 mmol) was added. This was followed by the dropwise addition of triethylamine (0.62 ml, 4.4 mmol). The reaction was stirred at room temperature overnight. The organics were washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness to give tert-butyl {[1-(diphenylmethyl)-3-morpholin-4-ylazetidin-3-yl]methyl}carbamate. tert-butyl {[1-(diphenylmethyl)-3-morpholin-4-ylazetidin-3-yl]methyl}carbamate (1.20 g, 2.7 mmol) and 20% palladium hydroxide on carbon (0.12 g) in methanol (20 ml) was hydrogenated on a parr at 45 psi for 2 days (complete conversion to product by 1c-ms). The resulting mixture was filtered and the filtercake washed with methanol. The methanol was evaporated to give tert-butyl [(3-morpholin-4-ylazetidin-3-yl)methyl]carbamate which was used without further purification. m/z (M++H) 272.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].[CH2:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6][CH2:7][OH:8])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCNCCO
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: OCCCN(CCO)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
6 g of 2-hydroxyethyl-3-hydroxypropylamine and 18.9 g of 1-benzyl-4-piperidone are taken up in 250 ml methylene chloride and at 0° C. combined with 21.2 g of sodium triacetoxyborohydride. The mixture is stirred overnight at ambient temperature, then acidified with 2 N hydrochloric acid and made alkaline with concentrated sodium hydroxide solution. It is extracted with methylene chloride, the extract is dried over sodium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed over silica gel with ethyl acetate/methanol/conc. ammonia solution 20:80:1. The uniform fractions according to TLC are combined and freed from solvent in vacuo. 2.3 g of 1-benzyl-4-[(2-hydroxy-ethyl)-(3-hydroxy-propyl)-amino]-piperidine are obtained as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:36]C(=O)OCC2C=CC=CC=2)[C@H:18]([OH:35])[CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=2[CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34])[CH:12]=[C:13]([F:15])[CH:14]=1.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[NH2:36][C@@H:17]([CH2:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([F:8])[CH:10]=1)[C@H:18]([OH:35])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[CH2:30][CH2:31][CH2:32][CH:33]=[CH2:34]
Reactant: C=CCCCc1ccc(OC)cc1CNC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: C=CCCCc1ccc(OC)cc1CNC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
Step AH (6): To a solution of benzyl (2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(5-methoxy-2-(pent-4-enyl)benzylamino)butan-2-ylcarbamate trifluoroacetate salt (91.3 mg, 0.140 mmol) in DME (9.0 mL) and water (6.0 mL) was added barium hydroxide monohydrate (831.2 mg, 4.389 mmol). The reaction mixture was stirred at 110° C. in a high-pressure vial for 18 h. The reaction was filtered through a pad of celite and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography to give (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-(5-methoxy-2-(pent-4-enyl)benzylamino)butan-2-ol double trifluoroacetate salt (45.8 mg, 52%) as colorless oil. LC-MS (M+H)+=405.42. 1H NMR (CD3OD, 500 MHz) δ 7.30-6.75 (m, 6H) 5.86 (m, 1H) 5.02 (m, 2H) 4.33 (m, 1H) 3.81 (s, 3H) 3.72 (m, 2H) 3.37 (m, 1H) 3.12-2.92 (m, 2H) 2.75-2.60 (m, 2H) 2.14 (m, 2H) 1.65 (m, 2H) 1.53 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[N+:32]([C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=4)(=[O:42])=[O:43])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc([N+](=O)[O-])c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-nitro-benzenesulfonyl chloride. Purity (ELSD, based on MW=606.6)=75%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[C:9]([NH2:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[O:18]=[C:19](Cl)OC(Cl)(Cl)Cl>C1COCC1.ClCCl>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]2[CH2:13][CH2:14][O:15][C:19](=[O:18])[NH:16][C:9]=2[CH:8]=1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(CCO)c(N)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc2c(c1)NC(=O)OCC2
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a stirring solution of 3-amino-4-(2-hydroxy-ethyl)-benzoic acid tert-butyl ester (2.1 g, 8.86 mmol) in THF (150 mL) and dichloromethane (50 mL) at 0° C. was added diphosgene (0.65 mL, 5.38 mmol) all at once. The reaction turned milky and became clear after 1 minute. The reaction was warmed to room temperature and stirred for 150 minutes. The solvent evaporated to provide 6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid tert-butyl ester: MS (m/e) 264 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.B([O-])([O-])O[CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH:14]1([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15]1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: [O-]B([O-])OC1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccnc(C2CC2)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 53.4 %

Procedure:
To 21 ml of toluene were added 1.9 g of 2-chloro-4-trifluoromethylpyridine, 1 g of cyclopropyl borate, 2.92 g of potassium carbonate and 0.26 g of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (1:1), and the mixture was stirred at 100° C. for 10 hours. After allowing to cool, the reaction solution was poured into an aqueous saturated ammonium chloride solution, and the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1 g of 2-cyclopropyl-4-trifluoromethylpyridine.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.CO.[OH-].[Na+]>O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]2)=[O:8])[CH:3]=1
Reactant: COC(=O)CC1CCN(C(=O)c2cc(C)on2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)N2CCC(CC(=O)O)CC2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.9 %

Procedure:
Into the reaction flask was added methyl {1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}acetate (2.8 g, 10.0 mmol) and methanol (10 mL) and 3 M of sodium hydroxide in water (10 mL). The mixture was stirred at rt for 2 h. After concentration, the residue was neutralized to pH=7. The mixture was extracted with EtOAc twice. The combined organic layers were dried and concentrated to give the desired product (0.30 g, 11%). LCMS for C12H17N2O4 (M+H)+: m/z=253.1
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:33]2[N:32]=[CH:31][C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:39])[NH:19][C:9]5[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:35][CH:34]=2)[CH2:38][CH2:37]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C4CC4)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M149) (310 mg, 0.56 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (192 mg, 79%).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:17][CH:18]([CH2:21][CH3:22])[CH2:19][NH2:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH3:6][CH:4]([CH3:5])[CH2:3][C@H:2]([NH:1][C:10](=[O:11])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([NH:20][CH2:19][CH:18]([CH3:17])[CH2:21][CH3:22])=[O:9]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCC(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of Boc-Leu-OH (61.3 mg, 0.26 mmol), 2-methylbutylamine (0.046 ml, 0.40 mmol) and 3 ml of MeCN in a round bottom flask equipped with a magnetic stirring bar was added DIEA (0.092 ml, 0.53 mmol) followed by HBTU (120 mg, 0.32 mmol). The reaction mixture was stirred at room temperature for 16 hours at which point TLC analysis showed that the reaction was complete. The mixture was concentrated under reduced pressure. 10 ml of DCM was added and this mixture was washed with water (×3), citric acid (1M, ×3), and brine (×1), dried over Na2SO4 and concentrated under reduced pressure. The crude 1H NMR showed that the product was pure enough to carry over to the next step. 1H NMR (CDCl3, 300 MHz): δ 6.75 (b, 1H), 5.21 (b, 1H), 4.18 (b, 1H), 3.17 (m, 2H), 1.77-1.07 (m, 16H), 0.98 (m, 12H) ppm; 13C NMR (CDCl3, 75 MHz): δ 172.9, 156.0, 53.3, 45.1, 41.4, 35.0, 28.4, 27.1, 27.1, 27.0, 24.9, 23.0, 22.3, 17.2, 17.1, 11.4, 11.3 ppm. HRMS (ESI+) [M+H]+ calcd. for C16H33N2O3 301.2485, found 301.2489.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.CO.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C@:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:8][C@@H:9]4[O:15]3)=[O:19])[CH2:4][CH2:3]1
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of the crude dihydroartemisinin in chloroform (40 mL) and methanol (1 mL, 24.8 mmol) was added boron trifluoride etherate (0.16 mL, 1.24 mmol) at 0° C. The reaction was stirred at 0° C. for 15 minutes, slowly warmed up to room temperature and stirred at room temperature for 3 hours. The reaction was monitored by TLC until all starting material was consumed. The reaction mixture was quenched with water (50 mL) and diluted with chloroform (25 mL). The two phases were separated, and the aqueous layer was extracted with chloroform (30×2 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford crude product which was further purified by column chromatography on Florisil (1%-10% EtOAc/hexanes) to give two artemisinin isomers as white solids: β-isomer (0.29 g, 0.98 mmol, 79%) mp 73°-74.5° C.; α-isomer (0.05 g, 0.17 mmol, 14%), with each having a 1H NMR spectrum identical to that reported in the literature. ##STR33##
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6]1.[CH3:13][CH2:14]O>>[NH:5]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1
Reactant: O=C(O)C1CCNC1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CCNC1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
Thionyl chloride (5 mL) was added to a cold (0° C.) stirred solution of pyrrolidine-3-carboxylicacid (500 mg, 4.34 mmol) in EtOH (25 mL) and continued stirring at 80° C. for 12-16 h. The reaction mixture was concentrated under reduced pressure to afford 600 mg (crude) of ethyl pyrrolidine-3-carboxylate, which was used as such in the next step without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:3][CH2:2]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24](=[O:27])[CH2:25]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[C:9]([C:8]1[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:25][C:24]([NH:23][C:17]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=3[CH3:15])=[O:27])[CH2:6][CH2:5]2)=[N:14][CH:13]=[CH:12][CH:11]=1)#[N:10]
Reactant: N#Cc1cccnc1C1CCNCC1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CN1CCC(c2ncccc2C#N)CC1
Yield: 20.1 %

Procedure:
The product from Example 58D (trifluoroacetic acid salt, 30 mg, 0.1 mmol), N-(2,6-dimethylphenyl)-2-chloroacetamide (23 mg, 0.15 mmol, Aldrich) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure. The residue was purified by preparative HPLC to provide 7 mg (28%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 1.82 (m, 2H), 2.05 (m, 2H), 2.12 (s, 6H), 2.35 (m, 2H), 3.05 (m, 3H), 3.15 (s, 2H), 7.05 (m, 3H), 7.45 (dd, J=6 Hz, 1H), 8.25 (d, J=6 Hz, 1H), 8.79 (dd, J=6 Hz, 1H), 9.21 (s, 1H); MS (ESI/APCI+) m/e 349 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH2:26][O:27][C:28]4[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=4[CH:30]=3)(=[O:24])=[O:23])[CH2:18][C:17]2=[O:36])([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[Cl:35][C:33]1[CH:32]=[CH:31][C:29]2[CH:30]=[C:25]([S:22]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][C:11]4([OH:14])[CH2:12][CH2:13][N:8]([C:11]5[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=5)[CH2:9][CH2:10]4)[C:17](=[O:36])[CH2:18]3)(=[O:23])=[O:24])[CH2:26][O:27][C:28]=2[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1CC1(O)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (150 mg) were added 4N hydrochloric acid in ethyl acetate (8 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and to the residue were added 4-chloropyridine hydrochloride (81 mg), triethylamine (81 mg) and ethanol (20 ml). The mixture was allowed to react in a sealed tube at 150° C. for 15 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (dichloromethane: methanol containing 10% ammonia solution=10: 1) to give colorless solid of the title compound (63 mg).