Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(CSC)C(NC1C=CC(Cl)=C(Cl)C=1)=O.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26]O)=[O:25])[CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[C:24]([OH:26])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CSCN(C)C(=O)Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: O=C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 27 g of N-methyl-N-(2-thiapropyl)-N'-(3,4-dichlorophenyl)-urea in 250 ml of methylene chloride was added at 10° C. to a solution of 34.5 g of m-chloroperbenzoic acid in 520 ml of methylene chloride and the mixture was stirred at room temperature for 3 1/2 hours. The precipitate was filtered off and the filtrate was distilled to dryness under reduced pressure. The residue was dissolved in ethyl acetate and the m-chlorobenzoic acid formed was removed by filtration. The organic filtrate was washed with aqueous 5% sodium bicarbonate solution, then with water, dried and concentrated to dryness under reduced pressure. The residue was subjected to chromatography over silica gel and was eluted with ethyl acetate and crystallized from isopropyl ether to obtain 11 g of N-methyl-N-(methylsulfonylmethyl)-N'-(3,4-dichlorophenyl)-urea melting at 159° C. A microanalytical sample was obtained by crystallization from ethyl acetate.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]([OH:19])[CH2:16][CH2:17][CH3:18])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reaction time: 3 h
Yield: 40 %

Procedure:
To 2.37 g (9.05 mmol) of alcohol 19 in 18 mL of CH2Cl2 was added 7.86 g (90.45 mmol) of MnO2. The reaction mixture was stirred for 3 h, then filtered (celite over silica gel pad) and the pad was washed repeatedly with 20 mL aliquots of CH2Cl2. After concentration, ketone 20 was purified by chromatography (SiO2, 3% EtOAc-hexanes) to give 941 mg (3.62 mmol) of 20 (40% yield): TLC (10% EtOAc-90% hexanes) Rf 0.7; 1H-NMR (CDCl3)δ 1.01 (t, 3H, CH2CH3), 1.34 (s, 18H, 6(CH3)), 1.78 (m, 2H, CH2CH3), 2.96 (t, J=7 Hz, 2H, CH2CH2CH3), 7.63 (t, J=1 Hz, 1H, Ar--H), 7.83 (d, J=1 Hz, 2H, Ar--H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][O:6][C:5]2([CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[O:4][CH2:3]1.[BH4-]>CO>[CH3:1][C:2]1([CH3:14])[CH2:3][O:4][C:5]2([CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][CH2:12]2)[O:6][CH2:7]1
Reactant: CC1(C)COC2(CCC(=O)CC2)OC1
Agent: [BH4-]
Solvent: CO
Product: CC1(C)COC2(CCC(O)CC2)OC1

Procedure:
Combine 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-one (Aldrich, 750 mg, 3.78 mmol) with polymer-supported borohydride (Aldrich, 3026 mg, 7.56 mmol) in methanol (30 mL). Shake by rotation the resulting mixture overnight. Filter the reaction mixture and concentrate the filtrate. Wash the residue with hydrochloric acid 0.1M and extract with EtOAc. Dry the organic layer over sodium sulfate, filter and concentrate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[CH:7]=O.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].N1CCCC1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[Na]>C1(C)C=CC=CC=1>[C:9]([C:11](=[CH:7][C:6]1[S:5][N:4]=[N:3][C:2]=1[CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: Cc1nnsc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCOC(=O)C(C#N)=Cc1snnc1C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To 50 ml of toluene were added 1.5 g (12 mmol) of 4-methyl-1,2,3-thiadiazole-5-carbaldehyde, 1.5 g (13 mmol) of ethyl cyanoacetate, 0.40 g (6.0 mmol) of pyrrolidine and 0.20 g (1.2 mmol) of tosylic acid. In a reactor equipped with a Dean-Stark dehydrating apparatus, the mixture obtained above was stirred for 2 hours with heating under reflux. After the reaction was completed, a saturated aqueous solution of sodium Achloride was added to the reaction mixture, the objective product was extracted with ethyl acetate, the organic layer was washed successively with dilute hydrochloric acid, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.73 g of the objective compound was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH:12]=1)=O.Cl>O1CCCC1>[CH2:22]([O:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH:12]=[C:11]([CH2:9][OH:8])[CH:20]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c2cc(F)ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Temperature: 60 °C
Yield: 92.8 %

Procedure:
To the slurry of lithium aluminum hydride (1.4 g, 36.9 mmol) in tetrahydrofuran (30 mL) was added a solution of 4-benzyloxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester (5.8 g, 18.7 mmol) in tetrahydrofuran (30 mL) at 0° C. under a nitrogen atmosphere. After being heated at 60° C. for 1 hour under a nitrogen atmosphere, the resulting mixture was cooled to 0° C. and 1 N hydrochloric acid was added to quench the reaction. The aqueous layer was extracted with diethyl ether (50 mL×4). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give (4-benzyloxy-6-fluoro-naphthalen-2-yl)-methanol (4.9 g, 93%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>C1C=CC=CC=1.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
Aq. 2 M sodium carbonate (3 mL)was added to a suspension of 400 mg (2.0 mmol) of 4-bromopyridine in 2 mL of benzene to give 2 clear phases, and argon was bubbled through the mixture for a few minutes before added 115 mg (0.10 mmol) of palladium tetrakis(triphenylphosphine). To the resulting mixture was added a solution of 200 mg (1.00 mmol) of 4-bromophenylboronic acid in 1 mL of ethanol, and the mixture was heated at reflux for 4 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was dried over sodium sulfate and concentrated. Purification of the residue by silica gel chromatography, eluting with 25% to 50% ethyl acetate in hexane, gave 193 mg (82%) of 4-(4-bromophenyl)pyridine as a white solid: mp 124-126° C.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([N+:15]([O-])=O)[CH:6]=1.O.[OH-].[K+]>Cl>[NH2:15][C:7]1[CH:6]=[C:5]([Br:4])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(Br)cc1N
Reaction time: 24 h
Yield: 84.1 %

Procedure:
Add tin(II) chloride (65.9 g, 292 mmol) to a suspension of methyl 4-bromo-2-nitrobenzoate (15.2 g, 58.4 mmol) in concentrated hydrochloric acid (120 mL) at room temperature and stir for 24 h. Slowly pour the mixture into water (700 mL) and adjust the pH to 9 with solid potassium hydroxide. Filter the white suspension through Celite, then stir the filter cake with ethyl acetate and filter that suspension. Separate the filtrate and extract the aqueous layer with ethyl acetate (200 mL). Combine the organic layers, dry over sodium sulfate, filter and remove the solvent under reduced pressure to afford the title compound as an off-white solid (11.3 g, 84%)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][N:13]1CCCC1=O>>[C:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)#[N:13]
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Product: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
2,6-dichloro-3-nitropyridine (5 g, 26 mmol), Cuprous cyanide (4.64 g, 0.59 mml) and appropriate amount of N-methyl pyrrolidone were mixed to form a solution which was heated to 180° C. to react for 15 min, then cooled to 10° C. and poured into ice-water (200 mL) and stirred for 30 min. The solution was then filtered, washed with water and dried. A mixture of the filter cake and Toluene (50 mL) were stirred and heated under reflux for 10 min, then filtered while still hot. Repeated the above operation 3 times, and combined the filtrate. The filtrate was washed with water for 3 times, then with saturated sodium chloride solution for 1 time. The organic phase was dried with anhydrous magnesium sulfate and kept overnight. After filteration, the solution was evaporated under reduced pressure to dryness, and then filtered with a mixture of petroleum ether/aether (4:1) and air-dried to yield 1.78 g of orange yellow solid product with a recovery rate of 37.55%.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[Br:17][CH2:18][C:19](O)=[O:20].[OH-].[Na+].Cl.C(N=C=NCCCN(C)C)C.Cl>O>[Br:17][CH2:18][C:19]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:11][N:12]=[N:13][N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12)=[O:20]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(O)CBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 70.9 %

Procedure:
To a stirred suspension of 3.0 g (0.0125 mole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 15 ml of water is added 1.74 g (0.0125 mole) of bromoacetic acid dissolved in 5 ml of water. The pH of the mixture is adjusted to 6.0 using 20% sodium hydroxide solution. The resulting clear solution is cooled to 0° C., and then 2.4 g (0.0125 mole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is added. The solution is stirred at 0° C. for a further 2.5 hr, during which time the pH is maintained between 6 and 7 by the addition of 6N hydrochloric acid. At this point, the pH is adjusted to 7.0 and the reaction mixture is extracted with ethyl acetate. The extract is discarded. The pH of the reaction mixture is then lowered to 2.0 (6N hydrochloric acid), and the product is extracted into ethyl acetate. The ethyl acetate is washed with water, dried, and evaporated to give 3.2 g (72% yield) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as a white foam. The infrared spectrum (KBr disc) of the product shows absorption bands at 1795 cm-1 (β-lactam), 1670 cm-1 (amide I) and 1530 cm-1 (amide II). The NMR spectrum (CDCl3) shows absorption bands at 10.6-9.6 ppm (broad singlet, tetrazole hydrogen), 8.8 ppm (doublet, amide hydrogen), 5.8-5.4 ppm (multiplet, C-5 and C-6 hydrogens), 5.35 ppm (singlet, C-3 hydrogen), 4.0 ppm (singlet, methylene hydrogen), 1.90 ppm (singlet, C-2 methyl hydrogens) and 1.15 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: [C:1]1(S(O)(=O)=O)[C:10]2[C:5](=[CH:6][C:7](S(O)(=O)=O)=[CH:8][CH:9]=2)[CH:4]=[C:3](S(O)(=O)=O)[CH:2]=1>S(=O)(=O)(O)O>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)c1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1
Agent: O=S(=O)(O)O
Product: c1ccc2ccccc2c1

Procedure:
If a mixture containing naphthalene-1,3,6-trisulphonic acid, dissolved in sulphuric acid, such as is obtained from the trisulphonation of naphthalene, is employed, then, for example when using a naphthalenetrisulphonic acid solution in about 100% strength sulphuric acid, containing about 33.8% of naphthalene-1,3,6-trisulphonic acid, about 5.8% of naphthalene-1,3,7-trisulphonic acid and about 3.7% of naphthalene-1,3,5-trisulphonic acid, about 96% of theory of nitro-T-acid, about 3% of theory of 1-nitronaphthalene-2,5,7-trisulphonic acid and about 0.5% of theory of 2-nitronaphthalene-3,6,8-trisulphonic acid was obtained as the nitration products of the naphthalene-1,3,6-trisulphonic acid. In that case, about 45% of theory of 1-nitronaphthalene-3,5,7-trisulphonic acid and about 7% of theory of 2-nitronaphthalene-3,5,7-trisulphonic acid are additionally obtained as nitration products of the naphthalene-1,3,7-trisulphonic acid, of which latter compound about 31% of theory remains un-nitrated. Furthermore, about 62% of theory of 1-nitronaphthalene-4,6,8-trisulphonic acid and about 8% of theory of 2-nitronaphthalene-4,6,8-trisulphonic acid are obtained as nitration products of naphthalene-1,3,5-trisulphonic acid, of which latter compound about 19% of theory remains un-nitrated.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[SH:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](S(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([S:8][C:4]2[S:3][CH:7]=[CH:6][N:5]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Sc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2nccs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To sodium hydride (60% wt. suspension in mineral oil, 108 mg) in dry DMF (5 ml) was added 1,3-thiazole-2-thiol (315 mg) at 0° C. After 30 minutes, 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester (500 mg) was added as a solution in DMF (2 ml) and the reaction mixture was warmed up to room temperature overnight, then heated at 50° C. for 3 hours. Aqueous work-up and purification on silica yielded 4-(thiazol-2-ylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester (174 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:24])[NH:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(OC(C(C)(C)COC1C=CC(CC2C(=O)NNC=2C(C)C)=CC=1)=O)C1C=CC=CC=1.CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:34]3[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]3[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[N:18][NH:19][C:20]=2[CH:21]([CH3:22])[CH3:23])=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCC(C)(C)C(=O)OCc2ccccc2)cc1
Product: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 12 using 4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (Kunz, H.; Harreus, A. Liebigs Ann. Chem. 1982, 41-48 Velarde, S.; Urbina, J.; Pena, M. R. J. Org. Chem. 1996, 61, 9541-9545) instead of 4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]-methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
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](O)[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.B(F)(F)F>C(OCC)C>[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:6]([CH3:20])=[CH:7][O:8][C@@H:9]4[O:15]3)[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: CCOCC
Product: CC1=CO[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 172.5 %

Procedure:
To a solution of dihydroartemisinin (10.4 g) in diethyl ether (550 ml) at room temperature under nitrogen was added dropwise boron trifluoride dietherate (1.0 ml). The solution was stirred at room temperature overnight, washed with 5% NaHCO3 solution (3×100 ml); dried (MgSO4) and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2; 10% ethyl acetate/hexanes) to give 9,10-anhydrodehydroartemisinin as a white solid (16.8 g, 97%). δH: 6.20 (1H, q, J=1.41 Hz, H-10), 5.55 (1H, s, H-12), 2.33-3.50 (1H, m), 1.03-2.18 (10H, m), 1.60 (3H, d, J=1.41 Hz, H16), 1.44 (3H, s, H-14), 1.00 (3H, d, J=5.98 Hz, H-15).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2].C(O[C:17](=[O:29])[CH2:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=1)C.N12CCCN=C1CCCCC2.II>C(OCC)(=O)C.CCCCCCC>[CH3:13][S:12][C:6]1[N:7]=[CH:8][C:9]2[CH:10]=[C:18]([C:19]3[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=3)[C:17](=[O:29])[N:3]([CH2:1][CH3:2])[C:4]=2[N:5]=1
Reactant: CCNc1nc(SC)ncc1C=O
Reactant: CCOC(=O)Cc1cc(OC)cc(OC)c1
Agent: II
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Temperature: 80 °C
Yield: 56.6 %

Procedure:
A 5-L round bottomed flask was charged with 516 g (2.62 mol) of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde, 587 g (2.62 mol) of (3,5-dimethoxy-phenyl)-acetic acid ethyl ester, and 391 mL (2.62 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture was heated at 80° C. for one hour. Thin layer chromatography (TLC) (silica, 6:4/heptane:ethyl acetate, developed in an iodine chamber) showed all the 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde was consumed. Ethyl alcohol (absolute, 2.75 L) was added to the reaction vessel, and the reaction mixture was cooled to room temperature. The solid that precipitated was collected by filtration, washed once with ethyl alcohol, and dried in a vacuum oven at 45° C. for 12 hours to provide 530 g (57% yield) of 2-methylsulfanyl-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one. Proton NMR (DMSO) is consistent with the structure: 1H NMR (DMSO): δ 8.86 (s, 1H), 8.10 (s, 1H), 6.83 (d, 2H), 6.51 (s, 1H), 4.36 (q, 2H), 3.75 (s, 1H), 2.58 (s, 3H), 1.22 (t, 3H). The combined mother liquor and washes were allowed to stand at room temperature for seven days. At this time a second crop of precipitate was collected, washed once with ethyl alcohol, and dried in a vacuum oven at 45° C. for 12 hours to provide 79 g (8.5% yield) of 2-methylsulfanyl-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one. Proton NMR (DMSO) is consistent with the structure.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].Cl>[OH-].[Na+]>[CH2:12]([O:11][C:9]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
3-Azetidinecarboxylic acid (4.0 g, 39.6 mmol) was dissolved in 1N sodium hydroxide solution (40 mL) and cooled to 0° C. Benzyl chloroformate (5.9 mL, 41 mmol) was added followed by further 1N sodium hydroxide solution (41 mL) dropwise. The mixture was stirred vigorously for 16 hrs then made acidic with 2N hydrochloric acid. This suspension was extracted with dichloromethane (2×100 mL) and the extracts dried over MgSO4. Concentration yielded the title compound (9.3 g, 39.6 mmol, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[F:20].[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.S(=O)(=O)(O)O.S1(CCCC1)(=O)=O.C(OC)(=O)C.COC(OC)OC>C(OCC)(=O)C.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C.CS(C)=O.CCOCC.C(O)(=O)C.C(O)=O>[F:20][C:3]1[C:2]2[N:1]=[CH:21][O:11][C:10]=2[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]
Reactant: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2F)c1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O=CO
Solvent: O=S1(=O)CCCC1
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1F

Procedure:
4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid can be cyclized in the presence of acid (such as p-toluenesulfonic acid, pyridinium toluene-4-sulphonate, formic acid, acetic acid, sulfuric acid) in appropriate solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer methyl acetate, ethyl acetate and trimethoxymethane) for some time (0.2-12 h, prefer 0.5-10 h). 4-Fluoro-5-((2-fluorophenyl)amino)benzo[d]oxazole-6-carboxylic acid is obtained after conventional workup.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-])=O.ClCCl.CCOCC>C(O)C.[Pd]>[N:11]1([CH2:10][CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(OCCn2ccnc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1ccc(OCCn2ccnc2)cc1
Yield: 75 %

Procedure:
Hydrogenation of the nitro compound (Step A above) in ethanol with 10% palladium on carbon at 2 atmospheres pressure gave, after filtration, evaporation, and crystallization from dichloromethane/ether, 75% yield of 4-(2-imidazol-1-yl-ethoxy)-phenylamine as a light orange solid, mp 93-94° C. Mass spectrum (LR-APCI) MH+=203.