Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]2[N:10]=[C:11]([SH:13])[S:12][C:8]=2[C:7]([F:14])=[CH:6][C:5]=1[F:15].Br[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>CN(C=O)C.O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][S:13][C:11]1[S:12][C:8]2[C:7]([F:14])=[CH:6][C:5]([F:15])=[C:4]([F:3])[C:9]=2[N:10]=1)[CH3:25]
Reactant: Fc1cc(F)c2sc(S)nc2c1F
Reactant: CCOC(=O)CCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCSc1nc2c(F)c(F)cc(F)c2s1
Yield: 63 %

Procedure:
Sodium hydride (60% in oil, 220 mg, 5.5 mmol) was suspended in DMF (2 ml) and the suspension was stirred on a water bath. To the suspension was added dropwise a solution of 4,5,7-trifluoro-2-mercaptobenzothiazole (1.1 g, 5 mmol) in DMF (5 ml) under ice cooling and the mixture was stirred for 30 min. at room temperature and then cooled on a water bath. To the cooled mixture was added dropwise a solution of ethyl 5-bromopentanoate (1.05 g, 5 mmol) in DMF (3 ml) and the mixture was stirred for 2 hours at room temperature. The resultant mixture was diluted with water, then acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with an aqueous saturated saline solution, dried and then evaporated. The resulting residue was purified on a silica gel column to give 5-(4,5,7-trifluorobenzothiazol-2-ylthio)pentanoic acid ethyl ester (1.1 g, 64%) as an oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH3:12])[CH2:8][CH:7]([NH2:9])[CH2:6][C:5]([CH3:11])([CH3:10])[CH2:4]1.[C:13]([NH:16][NH:17][C:18](N)=[O:19])(N)=[O:14]>CN1CCCC1=O>[O:14]=[C:13]1[N:1]([CH2:2][C:3]2([CH3:12])[CH2:8][CH:7]([N:9]3[C:18](=[O:19])[NH:17][NH:16][C:13]3=[O:14])[CH2:6][C:5]([CH3:11])([CH3:10])[CH2:4]2)[C:18](=[O:19])[NH:17][NH:16]1
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Reactant: NC(=O)NNC(N)=O
Solvent: CN1CCCC1=O
Product: CC1(C)CC(n2c(=O)[nH][nH]c2=O)CC(C)(Cn2c(=O)[nH][nH]c2=O)C1

Procedure:
765 g of 1-aminomethyl-5-amino-1,3,3-trimethyl cyclohexane and 708 g of hydrazodicarbonamide are stirred in 1 liter of N-methyl pyrrolidone for 4 hours at 175° C., for 5 hours at 200° C. and for 15 hours at 220° C. The solvent is then distilled off in vacuo and the residue is dried in vacuo, giving 1473 g (97% of the theoretical) of 1-(3,5-dioxo-1,2,4-triazolidin-4-yl-methyl)-1,3,3-trimethyl-5-(3,5-dioxo-1,2,4-triazolidin-4-yl)-cyclohexane in the form of colourless crystals melting at 213 C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.S(Cl)([Cl:19])=O.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][Cl:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: ClCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 25.0 grams (0.141 mole) of 3,5-dichlorophenylmethanol and 11.4 mL (0.141 mole) of pyridine in 200 mL of chloroform was cooled to 5° C., and 15.9 mL (0.218 mole) of thionyl chloride was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for about 18 hours. After this time, the reaction mixture was poured into 300 mL of water, and the mixture was extracted with 600 mL of diethyl ether. The ether solution was washed with 70 mL of an aqueous 6N hydrochloric acid solution, and then it was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure, yielding 25.6 grams of 3,5-dichlorophenylmethyl chloride, bp 95°-100° C./0.1 mm Hg.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]C(Br)(Br)Br.O[CH:26]([C:28]1[O:29][C:30](=[O:45])[C:31]2[C:36]([C:37]=1[C:38]1[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27]>C(Cl)Cl>[Br:20][CH:26]([C:28]1[O:29][C:30](=[O:45])[C:31]2[C:36]([C:37]=1[C:38]1[CH:39]=[C:40]([CH3:44])[CH:41]=[CH:42][CH:43]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27]
Reactant: Cc1cccc(-c2c(C(C)O)oc(=O)c3ccccc23)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(-c2c(C(C)Br)oc(=O)c3ccccc23)c1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
Triphenylphosphine (365 mg, 1.39 mmol) and perbromomethane (461 mg, 1.39 mmol) were was added to a solution of 3-(1-hydroxyethyl)-4-m-tolyl-1H-isochromen-1-one (intermediate B6, 300 mg, 1.07 mmol) in DCM (2.2 ml), and the resulting mixture was stirred at RT. The reaction product was then purified on the silica Biotage SNAP 50 g, eluting with a gradient of hexane and EtOAc to give the title compound (67 mg, 18.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH2:18]([NH:23][C:24]([CH:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27])=[O:25])[CH2:19][CH2:20][CH2:21][CH3:22]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:31]1[CH2:30][CH2:29][N:28]([CH:26]([C:24]([NH:23][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:25])[CH3:27])[CH2:33][CH2:32]1)=[O:9]
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Reactant: CCCCCNC(=O)C(C)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCCCNC(=O)C(C)N1CCN(C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5.62 g of 3,4,5-trimethoxycinnamoyl chloride is added with stirring at room temperature to a solution of 4.15 g of 1-[1-(pentylaminocarbonyl)ethyl]piperazine in 60 ml of chloroform, and the resulting solution is stirred at room temperature for 20 minutes.
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:21](Cl)(=[O:23])=[O:22])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3].[NH3:25]>>[CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([S:21](=[O:23])(=[O:22])[NH2:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCSc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1Oc1ccccc1
Reactant: N
Product: C=CCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
3-Allylthio-5-chlorosulfonyl-4-phenoxybenzoic acid (1 g) is dissolved in cooled concentrated aqueous ammonia (20 ml) while stirring. After 1 hour the reaction mixture is heated on a steam bath for 5 minutes, cooled, and 3-allylthio-4-phenoxy-5-sulfamylbenzoic acid precipitated by addition of 4 N hydrochloric acid. After collection by filtration, recrystallisation from aqueous ethanol, and drying, the compound is obtained with a melting point of 218°-219°C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[CH:31][C:32](OC)=[O:33])[CH:27]([CH3:36])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)C>O1CCCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[CH:31][CH2:32][OH:33])[CH:27]([CH3:36])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1CN(C(=O)OC(C)(C)C)CCC1=CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of 1 M diisobutylaluminum hydride in toluene (13.9 mL, 13.9 mmol) was slowly dropped into a cooled (-78° C.) solution of 4-methoxycarbonylmethylene-3-methylpiperidine-1-carboxylic acid t-butyl ester (1.5 g, 5.6 mmol) obtained in the above 1) in tetrahydrofuran (30 mL) under an atmosphere of argon. After dropping, it was stirred for 2 hours at the same temperature. After the reaction was completed, ethanol (8 mL) was added thereto at 0° C. and allowed to warm to room temperature gradually. The reaction mixture was then concentrated under a reduced pressure, treated with an aqueous solution of 20% sodium potassium tartrate (20 mL), and stirred for 30 minutes. After stirring, the solution was extracted with ether, dried over anhydrous sodium sulfate. After drying, it was filtered, and the filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=2:1) to obtain 1.2 g (yield 89.6%) of 4-(2-hydroxyethylidene)-3-methylpiperidine-1-carboxylic acid t-butyl ester. Its physical property is shown below.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[O:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:23])[CH2:19][C:20](=O)[CH3:21])[CH:15]=2)[CH:10]=[CH:9]1)#[N:2].[NH3:27]>CO>[NH2:27]/[C:20](/[CH3:21])=[CH:19]\[C:18]([NH:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][O:6][C:5]2[CH:24]=[CH:25][CH:26]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:12][CH:13]=1)=[O:23]
Reactant: CC(=O)CC(=O)Nc1ccc2ccn(COc3cccc(C#N)c3)c2c1
Reactant: N
Solvent: CO
Product: C/C(N)=C/C(=O)Nc1ccc2ccn(COc3cccc(C#N)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(1-((3-cyanophenoxy)methyl)-1H-indol-6-yl)-3-oxobutanamide (1.04 g, 2.99 mmol), MeOH (20 mL) and ammonia (20 mL) was stirred at rt overnight. The mixture was concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [CH3:1][C@@H:2]([NH:12][CH2:13][C@H:14]([OH:25])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([NH:22][CH:23]=[O:24])[CH:16]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C@H:26]([OH:35])([C:32]([OH:34])=[O:33])[C@@H:27]([OH:31])[C:28]([OH:30])=[O:29].[C:36](#[N:38])[CH3:37]>CO>[CH3:1][C@@H:2]([NH:12][CH2:13][C@H:14]([OH:25])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([NH:22][CH:23]=[O:24])[CH:16]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:28]([C@@H:27]([C@H:26]([C:32]([O-:34])=[O:33])[OH:35])[OH:31])([O-:30])=[O:29].[C:36](#[N:38])[CH3:37]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COc1ccc(C[C@@H](C)NC[C@H](O)c2ccc(O)c(NC=O)c2)cc1
Solvent: CO
Solvent: CC#N
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
A suspension of 348.8 mg (0.70 mmol) of (R,R)-arformoterol tartrate Form B in 15 mL of methanol was heated to the reflux temperature of the solvent for 15 minutes or until a clear yellow solution was obtained. Afterwards, it was cooled to about 60-50° C. and followed by addition of 5 mL aliquots of acetonitrile (total of 45 mL) at the same temperature until a suspension was obtained. The suspension was further cooled to 10-40° C. and stirred at this temperature for 10 minutes. The product was collected by filtration, washed with acetonitrile and dried under vacuum (2 mbar, equivalent to 1.5 mm Hg) at 40° C. for 12 hours to provide 262.4 mg (75% yield) of acetonitrile solvate of (R,R)-Formoterol-L-tartrate, which contained acetonitrile in a range between 2 and 4% (w/w), as determined by 1H-NMR or TGA analysis.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:18][O:17][CH:16]([O:19][CH3:20])[C:14]1([CH3:13])[CH2:2][C:1](=[O:3])[C:4]2[CH:5]=[C:6]([C:7]#[N:8])[CH:9]=[CH:10][C:11]=2[O:12]1
Reactant: COC(OC)C(C)=O
Reactant: CC(=O)c1cc(C#N)ccc1O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: COC(OC)C1(C)CC(=O)c2cc(C#N)ccc2O1
Yield: 85.7 %

Procedure:
In 100 ml of toluene were dissolved 8.06 g (50 mmole) of 3-acetyl-4-hydroxybenzonitrile and 7.68 g (65 mmole) of pyruvic aldehyde dimethyl acetal; and, 1.67 ml (20 mmole) of pyrrolidine was added at room temperature thereto. 30 Minutes thereafter, the reactants were heated to reflux for 8 hours using Dean-Stark apparatus. The solvent was removed under reduced pressure; and, 50 ml of 2N HCl solution was added to the residue so obtained. The resultant solution was stirred for 30 minutes at room temperature, extracted with ethyl acetate (100 ml×2), washed with 50 ml of water and then with 50 ml of saturated sodium chloride aqueous solution and purified by silica gel column chromatography using as an eluent a mixture of hexane and ethyl acetate (4:1) to obtain 11.19 g (yield 86%) of the title compound as a white solid.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.C(N(CC)C(C)C)(C)C.[C:21](Br)(=[O:23])[CH3:22].[CH:25](=[O:30])[CH2:26][CH:27]([CH3:29])[CH3:28]>C(Cl)Cl.FC(F)(F)S(N[C@@H](C(C)C)CN(CC1C=CC=C(CN(C[C@H](C(C)C)NS(C(F)(F)F)(=O)=O)C[C@H](C(C)C)NS(C(F)(F)F)(=O)=O)C=1)C[C@H](C(C)C)NS(C(F)(F)F)(=O)=O)(=O)=O>[CH2:26]([C@@H:25]1[O:30][C:21](=[O:23])[CH2:22]1)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CC=O
Reactant: CC(=O)Br
Agent: CC(C)[C@@H](CN(Cc1cccc(CN(C[C@@H](NS(=O)(=O)C(F)(F)F)C(C)C)C[C@@H](NS(=O)(=O)C(F)(F)F)C(C)C)c1)C[C@@H](NS(=O)(=O)C(F)(F)F)C(C)C)NS(=O)(=O)C(F)(F)F
Agent: C[Al](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)C[C@H]1CC(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
In an atmosphere of argon, the ligand (6) obtained in Example 6 (0.10 g, 0.10 mmol) was suspended in methylene chloride (5 ml) in a Schlenk glassware, and to this suspension was added trimethylaluminum in toluene (0.20 ml of 1M solution, 0.20 mmol) via a syringe. Then, the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture changed from a white suspension into a colorless solution. After completion of the stirring, the solvent was removed by evaporation under reduced pressure. Hexane (5 ml) was added to the residue, and the mixture was further stirred for one hour. After that, the mixture was allowed to stand for a while, and the supernatant liquid was removed by means of a syringe. The precipitate was dried under reduced pressure to give a catalyst. To the catalyst obtained was added methylene chloride (16 ml), followed by the addition of N,N-diisopropylethylamine (0.59 ml, 3.4 mmol). The mixture was cooled to −78° C. in a dry ice-ethanol bath. To this were added acetyl bromide (0.28 ml, 3.8 mmol) and isovaleraldehyde (0.21 ml, 2.0 mmol) via a syringe, and the mixture was stirred at −50° C. for 24 hours, during which time the reaction solution turned pale yellow. After completion of the reaction, the reaction mixture changed to orange when it was warmed up to room temperature. The reaction mixture was filtered through a glass filter packed with silica gel, and the solvent of the filtrate was evaporated off to give (S)-4-isobutyl-2-oxetanone (0.20 g, 77% yield). The asymmetric yield of the product was measured by means of GLC using a capillary column Chirasil-DEX CB (0.25 mm×25 m, membrane thickness 0.25 μm, GL Science) and was found to be 93% e.e.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].Cl[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1>C1COCC1>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: CN(C)CCO
Reactant: Clc1cnccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cnccn1
Reaction time: 0.08 h

Procedure:
A solution of 2-dimethylaminoethanol (1 mL) in THF (20 mL) was treated with potassium tert-butoxide (1.2 g). After 5 min, chloropyrazine (2 g) was added and the reaction stirred 2 h. The solvent was evaporated, the residue suspended in cold water, the mixture acidified, and the mixture extracted with ether. The aqueous fraction was made basic and extracted with EtOAc. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 10%-EtOH-1%-NH4OH--CHCl3 to give 2-(2-dimethylaminoethoxy)pyrazine (1.3 g). The HCl salt crystallized from 2-propanol as a white solid, m.p. 151°-153° C. (Compound 26).
Reaction SMILES: C([O:14][C:15]([C:17]1[O:18][C@@H:19]([C:45](=[O:51])[N:46]([CH3:50])[CH2:47][CH2:48][CH3:49])[C@H:20]([NH:41][C:42](=[O:44])[CH3:43])[C@@H:21]([NH:23][C:24]([NH:33]C(OC(C)(C)C)=O)=[N:25]C(OC(C)(C)C)=O)[CH:22]=1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>ClCCl>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[C:42]([NH:41][C@H:20]1[C@H:19]([C:45](=[O:51])[N:46]([CH3:50])[CH2:47][CH2:48][CH3:49])[O:18][C:17]([C:15]([OH:16])=[O:14])=[CH:22][C@@H:21]1[NH:23][C:24]([NH2:33])=[NH:25])(=[O:44])[CH3:43]
Reactant: CCCN(C)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]1NC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](NC(=N)N)[C@H]1NC(C)=O
Reaction time: 3 h

Procedure:
(4S,5R,6R)-5-Acetylamino-4-[2,3-bis(tert-butoxycarbonyl)-guanidino]-6-(methylpropylcarbamoyl)-5,6-dihydro-4H-pyran-2-carboxylic acid benzhydryl ester (0.11 g) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and left to stand for 3 hours. The solvent was removed in vacuo and the residue was triturated using diethyl ether. The solid was collected by filtration and dried to give the title compound as a white solid. (0.061 g) 1H NMR (250 MHz, D2O) 6.00 (1H, d, J=4Hz), 5.34 (1H, d, J=6.3Hz), 4.43-4.29 (2H, m) 3.56-3.13 (2H, m), 3.13,2.93 (3H, 2xs), 2.00 (3H, s), 1.79-1.44 (2H, m), 0.88 (3H, m); Mass analysis:C16H24F3N5O7. Required C, 42.20; H, 5.31; N15.38. Found C, 42.24; H, 5.45; N, 15.09; Mass Spec (Low resolution):MH+ =342.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][N:12]([CH2:20][CH3:21])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1.I.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](SC)=[NH:31]>C(O)C.C(OCC)(=O)C>[CH2:20]([N:12]([CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][S:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[NH:31])=[CH:3][C:4]1=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:21]
Reactant: CSC(=N)c1cccs1
Reactant: CCN(CCN1CCSc2ccc(N)cc21)C(=O)OC(C)(C)C
Agent: I
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CCN1CCSc2ccc(NC(=N)c3cccs3)cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of tert-butyl 2-(6-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl(ethyl)carbamate (800 mg, 2.371 mmol) in ethanol (8 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (1.014 g, 3.56 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, concentrated, and then chromatographed in 1:1 hexanes:ethyl acetate giving the desired product (415 mg, 39.2%). 1H NMR (DMSO-d6) δ 7.70 (d, J=3.0 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.49-7.44 (m, 1H), 7.07 (t, J=4.4 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.35-6.26 (m, 2H), 6.08 (d, J=7.5 Hz, 1H), 3.64-3.49 (m, 2H), 3.45-3.25 (m, 4H), 3.24-3.12 (m, 2H), 3.01-2.85 (m, 2H), 1.39-1.29 (m, 9H), 1.02 (t, J=6.9 Hz, 3H); ESI-MS (m/z, %): 447 (MH+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21].NCCC(O)=O.C(O)(=O)C>O>[CH3:18][O:17][C:16]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH:11]=[C:25]2[NH:19][C:20](=[O:21])[NH:22][C:23]2=[O:24])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1cccc(C=O)c1OCc1ccccc1
Agent: NCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C=C2NC(=O)NC2=O)c1OCc1ccccc1
Yield: 84 %

Procedure:
A solution of 96.90 g (0.40 mole) of 2-benzyloxy-3-methoxybenzaldehyde, 48.04 g (0.48 mole) of hydantoin, 8.02 g (0.09 mole) of β-alanine, and 200 mL of glacial acetic acid is stirred at reflux for 6 hours. Water (500 mL) is added and the separated solid is filtered, washed well with water, methanol, and then ether; wt 109.00 g (84% yield); mp 210°-212° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH:26]=[O:27])[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].CC(=CC)C.Cl([O-])=[O:40].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][C:26]([OH:40])=[O:27])[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC=O)CC4)cc3)oc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC(=O)O)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension (partially dissolved) of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-oxoethyl)cyclohexyl]methyl}benzamide (50 mg, 0.113 mmol, EXAMPLE 43, Step B) in t-butanol (4 ml) was added 2-methyl-2-butene (0.060 ml, 0.570 mmol), and then a solution of sodium chlorite (25 mg, 0.276 mmol) and sodium dihydrogen phosphate (27 mg, 0.225 mmol) in water (1 ml). The mixture was stirred overnight at room temperature (the mixture remained a finely divided suspension), at which point LC/MS analysis showed no starting material. The mixture was diluted with 10 ml of water and 10 ml of ethyl acetate. The phases were separated and the aqueous phase was acidified to pH 4 and extracted with 2×10 ml of ethyl acetate. The combined organics were washed with 10 ml of brine, dried (sodium sulfate), and concentrated to provide the title compound (52 mg, 0.113 mmol, 100% yield). Mass spectrum (ESI) 459.8 (M+1).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]1([S:21][C:22]2[CH2:28][CH:27]3[CH:24]([C:25](=[O:29])[CH2:26]3)[C:23]=2[C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:46](=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>O1CCCC1.C(O)(=O)C>[C:15]1([S:21][C:22]2[CH2:28][CH:27]3[CH:24]([C:25](=[O:29])[CH:26]3[CH:46]([OH:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:23]=2[C:30]([O:32][CH:33]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2C1C(=O)C2C(O)c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 235 μL of hexamethyldisilazane in 30 mL of dry tetrahydrofuran under argon at 0° was added 735 μL of butyllithium (1.37M in hexane) over a 2 min period. After addition was complete, the solution was cooled to -78°. A solution of 425 mg of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, in 3 mL of dry tetrahydrofuran was added over a 3 min period. After addition was complete, the solution was stirred for 10 min at -78° and then 120 μL of freshly distilled benzaldehyde was added. After an additional 5 min, 150 μL of acetic acid was added and the reaction mixture was evaporated to a small volume on the rotary evaporator. The residue was partitioned between water and methylene chloride and water, and the organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness. The crude reaction product was subjected to preparative thin layer chromatography on four 20×20×0.2 cm silica gel plates eluted with ether-petroleum ether (1:1) to afford two diastereomers of 3-phenylthio-6-(α-hydroxybenzyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, as glasses. Isomer A (153 mg, 28.8%) was the less polar compound; Isomer B (278 mg, 52.4%) was more polar. Material prepared by essentially the same procedure had the following spectral characteristics: