Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[NH2:20][C:18]1[S:19][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:3]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][CH:2]=2)[N:17]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1-c1ccc(Cl)cc1
Yield: 75.2 %

Procedure:
To a cold (5° C.) vigorously stirred mixture of 121.87 g (0.936 mole) of ethyl acetoacetate, 314 ml. of benzene and 626 ml. of water was added 41.25 ml. of 33% sodium hydroxide. To the above mixture was added simultaneously in two dropping funnels 177.0 g (1.01 mole) of p-chlorobenzoyl chloride and 188.8 ml. of 33% sodium hydroxide in 2 hours. The reaction mixture became pasty. The reaction mixture was heated at 35° C. for 1 hour, cooled and filtered to give 170.0 g of sodium salt of ethyl 2-benzoylacetoacetate. Part (150 g) of this salt was added to a mixture of 39.0 g (0.729 mole) of ammonium chloride and 78 ml. of concentrated ammonium hydroxide in 780 ml. of water. The mixture was stirred at 40°-50° C. for 3 hours and cooled in an ice bath. The precipitate was filtered to give 115.5 g of yellow solid which was Kugelrohr distilled to give 76.0 g (38% based on ethyl acetoacetate) of crude ethyl p-chlorobenzoylacetate. A mixture of 40.0 g (0.175 mole) of crude ethyl p-chlorobenzoylacetate, 24.2 g (0.18 mole) of sulfuryl chloride and some chloroform was held at reflux for 6 hours, cooled and concentrated to give 49.0 g of crude ethyl 2-chloro-p-chlorobenzoylacetate. A mixture of 46.0 g (0.174 mole) of crude ethyl 2-chloro-p-chlorobenzoylacetate, 13.25 g (0.174 mole) of thiourea, and 174 ml. of ethanol was held at reflux for 2 hours and cooled. The precipitate was filtered and neutralized with saturated sodium bicarbonate. The insoluble material was filtered to give 37.0 g (80%) of ethyl 2-amino-4-p-chlorophenyl-5-thiazolecarboxylate, m.p. 198°-200° C. To a cold (-5° C.) mixture of 11.3 g (0.04 mole) of ethyl 2-amino-4-p-chlorophenyl-5-thiazolecarboxylate and 80 ml. of 85% phosphonic acid was added 40 ml. of 70% nitric acid. To the above mixture was added with vigorous stirring, 4.0 g (0.0434 mole) of sodium nitrite in 20 minutes at -5°-0° C. The reaction mixture was stirred at -5°-0° C. for 10 minutes and poured into a mixture of 4.0 g (0.04 mole) of cuprous chloride, 20 ml. of concentrated hydrochloric acid and 20 ml. of water. The reaction mixture was stirred at room temperature for 30 minutes, after which time evolution had subsided. The precipitate was filtered to give 10.5 g of solid which was Kugelrohr distilled (145° C. at 0.05 mm Hg) to give 6.0 g of solid, m.p. 113°-120° C., which was recrystallized from hot ethanol to give 4.4 g (37%) of ethyl 2-chloro-4-p-chlorophenyl-5-thiazolecarboxylate as a white solid, m.p. 119°-120° C.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[Cl:14][SiH:15]([Cl:17])[Cl:16]>[Pt].C1(C)C=CC=CC=1>[Cl:14][Si:15]([Cl:17])([Cl:16])[CH2:3][CH2:2][CH2:1][C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1
Reactant: C=CCc1ccc(-c2cccs2)s1
Reactant: Cl[SiH](Cl)Cl
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cl[Si](Cl)(Cl)CCCc1ccc(-c2cccs2)s1

Procedure:
The hydrosilylation reaction of Example 1 was repeated using 18.7 g of 5-allyl-2,2′-bithiophene in place of 2-allylthiophene, 10 g of anhydrous toluene, 20 g of trichlorosilane, and 150 mg of Platinum Catalyst. 5-(3-Trichlorosilylpropyl)-2,2′-bithiophene was obtained as a colorless liquid: 1H NMR (CDCl3) δ 7.20 (dd, 1H, J=5.1, 1.2 Hz); 7.14 (dd, 1H, J=3.6, 0.9 Hz); 7.02 (m, 2H); 6.74 (d, 1H, J=3.6 Hz); 2.93 (t, 2H, J=7.2 Hz); 1.99 (m, 2H); 1.49 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8][CH3:9])[CH:7]=1.BrC1C=CC(S(C)=[O:18])=NC=1>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8]([CH3:9])=[O:18])[CH:7]=1
Reactant: CS(=O)c1ccc(Br)cn1
Reactant: CSc1cncc(Br)c1
Product: CS(=O)c1cncc(Br)c1

Procedure:
The title compound was prepared from 3-bromo-5-methylsulfanyl-pyridine following a procedure analogous to that described for 5-bromo-2-methanesulfinyl-pyridine in Example 182.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2Cl.O>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: N#CCc1ccc(Br)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nccc(C(C#N)c3ccc(Br)cc3)c2cc1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
Commercially available 4-bromophenylacetonitrile (4.3 g) was dissolved in toluene (10 ml) and the temperature was lowered to 0° C., after which sodium hydride (1.0 g) was added, the temperature was raised to 50° C., and the admixture was then stirred for 1 hour. Next, 6,7-dimethoxy-4-chloroquinoline (2.2 g) was added, and the admixture was stirred for 15 hours, after which water was poured and the mixture was extracted with ethyl acetate. After drying with anhydrous sodium sulfate and removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (2/1) to obtain 850 mg of the title compound (yield: 22%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11](O)[CH2:10][CH2:9]2.C(=O)([O-])O.[Na+]>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([Cl:3])[CH2:10][CH2:9]2
Reactant: OC1CCc2cc(Br)ccc21
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3.09 mL (37.45 mmol) of thionyl chloride, dissolved in cooled dichloromethane, are added dropwise at −10° C. to a solution of 3.8 g (17.83 mmol) of 5-bromoindan-1-ol in 200 mL dichloromethane. The reaction mixture is allowed to come up slowly to ambient temperature and stirred for 14 hours at ambient temperature. Then ice and 100 mL of dilute sodium hydrogen carbonate solution are added successively. The organic phase is extracted twice with 50 mL of water. The combined organic phases are dried over magnesium sulfate, filtered and the solvent is distilled off. Yield: 3.7 g (90% of theory); C9H8BrCl (M=231.52); Rf value: 0.91 (silica gel, petroleum ether/ethyl acetate (6:4)).
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:13]4[N:14]=[N:15][N:16]([C:19]5[C:20](F)=[N:21][CH:22]=[CH:23][CH:24]=5)[C:17]=4[CH3:18])[CH:10]=3)[C:5]2=[O:26])[CH2:3][CH2:2]1.C(O)=[O:28]>>[CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:13]4[N:14]=[N:15][N:16]([C:19]5[C:20]([OH:28])=[N:21][CH:22]=[CH:23][CH:24]=5)[C:17]=4[CH3:18])[CH:10]=3)[C:5]2=[O:26])[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: Cc1c(-c2ccc3c(c2)CN(C2CC2)C3=O)nnn1-c1cccnc1F
Product: Cc1c(-c2ccc3c(c2)CN(C2CC2)C3=O)nnn1-c1cccnc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
180 mg of 4-(2-cyclopropyl-1-oxo-isoindoline-5-yl)-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole obtained in Example 49 was dissolved in 10 ml of formic acid, and the mixture was stirred for 5 hours. After cooling down to room temperature, the residues obtained by distilling out the solvents under reduced pressure were purified by silicagel column chromatography (chloroform:methanol=90:10) to obtain 112 mg of the above compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>CO>[C:1]1([CH2:7][N:8]2[CH2:9][CH:10]=[C:11]([CH2:14][OH:15])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1=CC(Cl)N(Cc2ccccc2)C=C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCC1=CCN(Cc2ccccc2)CC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
1-(Phenylmethyl)-4-(hydroxymethyl)-pyridinyl chloride (0.87 mol) was dissolved in methanol (2200 ml) and cooled to −20° C. Sodium borohydride (1.75 mol) was added portionwise under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes and water (200 ml) was added dropwise. The reaction mixture was partially evaporated, water was added and the reaction mixture was extracted with DCM. The organic layer was separated, dried, filtered and evaporated. The residue was purified over silica gel (eluent: DCM), yielding 155 g of 1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C=O)C>[CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:16][CH:15]=[CH2:14])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
3.3 g (0.11 mol) of sodium hydride (80% in oil) and 100 ml of DMF are introduced under a stream of nitrogen into a round-bottomed flask. 15 g (0.1 mol) of 4-formylbenzoic acid, dissolved in 200 ml of DMF are added dropwise and the mixture is stirred at room temperature until gaseous evolution has ceased. 9.5 ml (0.11 mol) of allyl bromide are then introduced and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. 19 g (100%) of allyl ester are collected in the form of a slightly yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([Br:15])[C:11]2=[O:14])=[CH:7][CH:6]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.CCOC(C)=O>[Br:15][C:10]1[C:11](=[O:14])[C:12]2[C:8]([C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:7][CH:6]=[C:5]([OH:4])[CH:13]=2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
2-Bromo-1-oxo-3-phenyl-1H-inden-6-yl acetate (24 g, 70.0 mmol) obtained in Step 4 was placed into a flask and dissolved in MeOH (350 mL). The solution was charged with K2CO3(11.64 g, 1.2 eq) and stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with a brine solution. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired product (19.5 g, 93%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[CH:35]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:41][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:27])#[N:2]
Reactant: NC1CCCCC1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)NC3CCCCC3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of cyclohexylamine (0.185 ml, 1.62 mmol), triethylamine (0.451 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give the objective product as a solid material.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CCCCC.O1CCCC1>[C:7]([O:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:3][CH2:1][CH3:4]
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCC(OC(=O)CCCCCCCCCCC)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.21 ml, 0.36 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (124.5 mg, 0.37 mmol) in tetrahydrofuran (5 ml) at 0 degrees under argon. After 5 minutes, the cooling bath was removed and lauroyl chloride (88 microliter) was added. The mixture was stirred at room temperature for 16 hours and quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 1000u silica plate; developed with 5% ethyl ether/hexane). The title ester was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]([CH3:28])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5]CC)[CH3:2].[Li+].[OH-].CO.Cl>[Cl-].[Na+].O.O>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][C:11]([CH3:28])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:5])[OH:8])[CH3:2]
Reactant: CCOP(=O)(CCC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CCOP(=O)(O)CCC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 27.6 %

Procedure:
A mixture of [5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonic acid diethyl ester 158C (27 mg, 0.066 mmol), LiOH (200 mg), MeOH (3 mL) and water (1 mL) was stirred at 70° C. for 4 hours. After cooling, the reaction solution was acidified with 2 N HCl, mixed with brine, and extracted with ethyl acetate/acetonitrile. The organic extract was concentrated and the residue was purified by preparative reverse-phase HPLC (acetonitrile and 0.1% aqueous CF3COOH), affording [5-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-3-methyl-pent-3-enyl]-phosphonic acid monoethyl ester 158D (7 mg, 28%); 1H NMR (300 MHz, CD3OD) δ 1.28 (t, J=6.9 Hz, 3H), 1.7-1.9 (m, 5H), 2.20 (s, 3H), 2.2-2.3 (m, 2H), 3.41 (d, J=6.6 Hz, 2H), 3.80 (s, 3H), 4.02 (m, 2H), 5.2-5.3 (m, 3H) ppm.
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CC(C2N=C(C3CCC3)N3C=CN=C(N)C=23)=CC=1.[NH2:29][C:30]1[C:31]2[N:32]([C:36]([CH:56]3[CH2:59][CH2:58][CH2:57]3)=[N:37][C:38]=2[C:39]2[CH:44]=[CH:43][C:42]([C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:46])=[C:41]([N+:53]([O-])=O)[CH:40]=2)[CH:33]=[CH:34][N:35]=1>>[NH2:53][C:41]1[CH:40]=[C:39]([C:38]2[N:37]=[C:36]([CH:56]3[CH2:57][CH2:58][CH2:59]3)[N:32]3[CH:33]=[CH:34][N:35]=[C:30]([NH2:29])[C:31]=23)[CH:44]=[CH:43][C:42]=1[C:45]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:46]
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(C(=O)c4ccccc4)c([N+](=O)[O-])c3)c12
Agent: Nc1cccc(Oc2ccc(-c3nc(C4CCC4)n4ccnc(N)c34)cc2)c1
Product: Nc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1C(=O)c1ccccc1

Procedure:
Prepared according to a procedure analogous to that described for 1-[4-(3-aminophenoxy)-phenyl]-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine, except using [4-(8-amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-2-nitro-phenyl]-phenyl-methanone.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)[OH:8])[CH3:2].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([CH3:28])[CH3:27].C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([N:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=1)[OH:8])[CH3:2]
Reactant: CC(C)(F)CCCCCBr
Reactant: CCNCCCC(O)c1ccc(NS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCN(CCCCCC(C)(C)F)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
(Procedure B) A stirred mixture of the product from Example 7, Step II, (0.37 g, 0.00128 mol), the product from Step III above (0.298 g, 0.0141 mol), sodium bicarbonate (0.21 g, 0.0026 mol) and acetonitrile (11 ml) was refluxed for 5 hours and kept at ambient temperature for 18 hours. It was filtered and the solid was washed with acetonitrile. The filtrate was concentrated and the residue was chromatographed on silica gel with 10% MeOH--CH2Cl2 to give 0.332 g of the titled product, a compound of Formula I'. The mass spectrum had m/z 416 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:16][NH:17][O:18][CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:19][O:18][N:17]([CH3:16])[C:12]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]1)=[O:14]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (11.00 g, 54.7 mmol, 1.0 eq) in methylene chloride at 0° C. was added N,O-dimethyl hydroxylamine HCl (5.9 g, 60.4 mmol, 1.1 eq), TEA (13.82 g, 13.6 mmol, 2.5 eq) and HATU (22.90 g, 60.2 mmol, 1.1 eq). The resulting reaction mixture was stirred at room temperature under an N2 atmosphere overnight. After TLC showed reaction was completed, the reaction mixture was concentrated, diluted with water and extracted with diethyl ether. The organic layer was washed with brine, dried over Na2SO4 and concentrated to get the desired product as a white solid. Yield: 13.00 g (97.52%).
Reaction SMILES: [CH:1]1[C:10]2[C:9]([NH2:11])=[N:8][C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[NH:5][C:4]=2[S:3][CH:2]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20][C@H:21]1[CH2:26]N[CH2:24][CH2:23][NH:22]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:16][O:17][CH2:18][CH2:19][CH2:20][C@@H:21]1[NH:22][CH2:23][CH2:24][N:11]([C:9]2[C:10]3[CH:1]=[CH:2][S:3][C:4]=3[NH:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[N:8]=2)[CH2:26]1
Reactant: NC1=Nc2ccccc2Nc2sccc21
Reactant: COCCC[C@H]1CNCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 45 h
Yield: 16.2 %

Procedure:
Combine 4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (1.10 g, 5.11 mmol), (S)-2-(3-methoxy-propyl)-piperazine (1.62 g, 10.22 mmol), DMSO (4.0 ml), and toluene (16.0 ml). Stir and heat the mixture at 105° C. After 45 hours, cool the mixture to ambient temperature. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (85:15) to give 296.0 mg (16%) of the title compound: mass spectrum (ion spray): m/z=357.2 (M+1).
Reaction SMILES: C[C@H]1[C@@H]2CCC3(C)OO[C@]42[C@H]([C@@H](C)[C@@H](O)O[C@@H]4O3)CC1.[CH3:21][C@@H:22]1[C@H:31]2[CH2:32][CH2:33][C@@:34]3([CH3:38])[O:36][O:37][C@@:30]42[C@H:25]([C@H:26]([CH3:50])[C@H:27]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]([OH:49])=[O:48])=[CH:45][CH:46]=2)[O:28][C@@H:29]4[O:35]3)[CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)(C)C)C>C(#N)C>[CH3:21][C@H:22]1[C@@H:31]2[CH2:32][CH2:33][C:34]3([CH3:38])[O:36][O:37][C@:30]42[C@H:25]([C@@H:26]([CH3:50])[C@@H:27]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([OH:49])=[O:48])=[CH:43][CH:42]=2)[O:28][C@@H:29]4[O:35]3)[CH2:24][CH2:23]1
Reactant: C[C@@H]1[C@H](OCc2ccc(C(=O)O)cc2)O[C@@H]2O[C@@]3(C)CC[C@@H]4[C@@H](C)CC[C@@H]1[C@]24OO3
Agent: CCN=C=NC(C)(C)C
Agent: 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: On1nnc2ccccc21
Solvent: CC#N
Product: C[C@H]1[C@@H](OCc2ccc(C(=O)O)cc2)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C

Procedure:
Attempts to prepare an hydrazide derivative of artesunate were unsuccessful and resulted in the formation of dihydroartemisinin due to the cyclization reaction. Artelinate was synthesized from dihydroartemisinin as previously described (Shrimali et al. (1998) Indian J. Chem. 37B:1161-1163). Artelinic acid (0.1 g, 0.24 mmol) was dissolved in anhydrous acetonitrile (0.48 mL). To this solution, 1-hydroxybenztriazole (HOBt) (0.038 g, 0.29 mmol) was added, followed by addition of ethyl dimethylethylcarbodiimide (0.055 g, 0.29 mmol). The reaction mixture was stirred at room temperature and monitored by thin-layer chromatography (TLC) until all the acid was converted to the HOBt ester.
Reaction SMILES: [CH:1]([N:3]([O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[C@@H:4]([CH2:13][CH2:14][CH3:15])[C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)=[O:2].C(P(=O)(OCC)OCC)#N.CN1CCOCC1.Cl.[S:41]1[CH:45]=[CH:44][N:43]=[C:42]1[NH:46][C:47](=[O:60])[C@@H:48]([NH2:59])[CH2:49][CH2:50][CH2:51][NH:52][CH2:53][N:54]=[N:55][N+:56]([O-:58])=[O:57].[Cl-].[Na+]>CN(C=O)C>[N+:56]([N:55]=[N:54][CH2:53][NH:52][CH2:51][CH2:50][CH2:49][C@H:48]([NH:59][C:6](=[O:8])[C@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@@H:4]([N:3]([CH:1]=[O:2])[O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH2:13][CH2:14][CH3:15])[C:47](=[O:60])[NH:46][C:42]1[S:41][CH:45]=[CH:44][N:43]=1)([O-:58])=[O:57]
Reactant: N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1
Reactant: CCC[C@@H]([C@@H](CC(C)C)C(=O)O)N(C=O)OC1CCCCO1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC[C@@H]([C@@H](CC(C)C)C(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1)N(C=O)OC1CCCCO1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a 0° C. solution of (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)hexanoic acid (172 mg, 0.546 mmol) in 1 mL DMF is added diethyl cyanophosphonate (98 mg, 0.60 mmol) followed by NMM (61 mg, 0.60 mmol). Stirring is continued for 30 min at 0° C. (2S)-2-Amino-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide hydrochloride (203 mg, 0.60 mmol) is added followed by additional NMM (122 mg, 1.20 mmol). The mixture is heated at 40° C. for 16 h then allowed to cool to 25° C. The reaction mixture is added to half-saturated aqueous sodium chloride and extracted with 1:1 EtOAc-diethyl ether. The combined organic layers are washed with pH 4.3 phosphate buffer, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and dried over magnesium sulfate. Concentration and chromatography on silica gel (5% methanol-dichloromethane) provides 166 mg of (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)hexanoic Acid [(1S)-4-(nitroimino-amino)methylamino-1-(1,3-thiazol-2-ylcarbamoyl)-1-butyl]amide as a foam.