Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[S:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:8]=[C:12]=[S:13])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: S=C(Cl)Cl
Reactant: CC(C)Oc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1cccc(N=C=S)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-isopropoxy aniline (6.0 g, 40 mmol) in 150 ml of CHCl3 was added dropwise thiophos-gene (2.81 ml, 44 mmol) at 0° C. After the addition of thiophosgene, triethylamine (7.0 ml, 48 mmol) was added slowly and the reaction mixture was stirred for 2 hours at room temperature. It was then concentrated and diluted with 200 ml of ethyl acetate. The triethylamine hydrochloride salt was filtered off and the filtrate was concentrated to yield crude 3-isopropoxyphenyl isothiocyanate.
Reaction SMILES: [C:1]1([C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[H][H].[OH-].[Na+]>C(O)C>[C:1]1([C@H:7]2[O:13][C:10](=[O:12])[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: [H][H]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CC[C@@H](c2ccccc2)O1
Temperature: 40 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
In a 100 ml autoclave were charged 1.78 g (10 mmole) of 4-phenyl-4oxobutyric acid and 14 ml of ethanol. A solution separately prepared from 44.9 mg (0.05 mmole) of ##STR13## double the molar quantity of concentrated hydrochloric acid, and 5 ml of ethanol was added to the above-prepared solution in a nitrogen atmosphere to conduct hydrogenation at 35° C. and at a hydrogen pressure of 70 kg/cm2 for 230 hours. To the reaction mixture was added 8 ml of a 10% sodium hydroxide aqueous solution, followed by stirring at 40° C. for 3 hours. After cooling to room temperature, the resulting solution was extracted twice with 30 ml portions of methylene chloride. The organic layer was removed, and the aqueous layer was adjusted to a pH of 4 with a 10% hydrochloric acid aqueous solution and then again extracted thrice with 20 ml portions of methylene chloride. The combined extract was concentrated, and the residue was purified by silica gel column chromatography using hexanediethyl ether as a developing solvent to obtain 1.02 g (percent yield: 63%) of (S)-4-phenyl-γ-butyrolactone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:14]3[C@H:9]([CH2:10][CH2:11][NH:12][CH2:13]3)[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([N:12]1[CH2:11][CH2:10][C@H:9]2[C@H:14]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:16][C:6]=3[C:7](=[O:15])[CH2:8]2)[CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1C[C@H]2CCNC[C@H]2c2ccc(F)cc21
Reactant: BrCc1ccccc1
Product: O=C1C[C@H]2CCN(Cc3ccccc3)C[C@H]2c2ccc(F)cc21

Procedure:
In an analogous manner to that described in Example 49 b), from cis-8-fluoro-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one by alkylation with benzyl bromide there was obtained cis-2-benzyl-8-fluoro-1,3,4,4a,5,10b-hexahydro-2H-benzo[h]isoquinolin-6-one, which was converted with MeOH/HCl into the hydrochloride with m.p. >220°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[CH:11]#[C:12][CH:13](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:14].[OH-].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:9][C:5]1[C:6]([O:8][CH:13]([CH3:14])[C:12]#[CH:11])=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C#CC(C)Oc1cc(N)c(F)cc1Cl
Temperature: 60 °C
Yield: 56.2 %

Procedure:
A round-bottomed flask (50 cc) was charged with 5-amino-2-chloro-4-fluorophenol (1.40 g, 8.67 mmol), (1-butyn-3-yl)tosylate (2.03 g, 9.00 mmol) and tetrabutylammonium bromide (71 mg, 0.22 mmol) to prepare a solution in toluene (25 mL). Subsequently, 48% sodium hydroxide in aqueous solution (6 mL) was added slowly and the mixture was stirred under heating at 60° C. for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (15 mL) was added, followed by extraction with toluene (10 mL×2). The organic layers were combined and washed with water (10 mL×2). The solvent was distilled off under vacuum from the resulting toluene solution, thereby giving 4-chloro-2-fluoro-5-{(1-butyn-3-yl)oxy}aniline (1.04 g, 4.87 mmol; yield=56.1%). MP: 74.5°-75.5° C. 1H-NMR(CDCl3,TMS,ppm): δ1.60(3H,d,J=6.3Hz), 2.48(1H, d,J=1.5Hz), 3.46(2H,brs), 4.72(1H,d&q,J=6.3 and 1.5Hz), 6.62(1H,d,JHF =7.5Hz), 7.01(1H, d,JHF =10.0Hz).
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[N:7]([CH:18]([CH3:20])[CH3:19])[CH:6]=1)=[O:4].[OH-:23].[Na+]>>[CH:18]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:23])=[CH:6]1)([CH3:20])[CH3:19]
Reactant: [OH-]
Reactant: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(C(F)(F)F)cc21
Agent: [Na+]
Product: CC(C)n1cc(C(=O)O)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1-isopropyl-6-trifluoromethyl-1H-indol-3-yl)-ethanone (800 mg, 2.48 mmol) in a 20% aqueous sodium hydroxide solution (12 mL) was heated at 110° C. for 3 h. At this time, the reaction was cooled to 25° C., partitioned between water (100 mL) and ethyl acetate (100 mL), and treated with a 1N aqueous hydrochloric acid solution (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-isopropyl-6-trifluoromethyl-1H-indole-3-carboxylic acid (704 mg, 99%) as a yellow solid: mp 177-178° C.; EI-HRMS m/e calcd for C13H12F3NO2 (M+) 271.0820, found 271.0807.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:29][O:30][C:31]([C:33]1[C:34]([Cl:40])=[N:35][C:36](Cl)=[CH:37][CH:38]=1)=[O:32].C1N2CCN(CC2)C1>>[CH3:29][O:30][C:31](=[O:32])[C:33]1[CH:38]=[CH:37][C:36]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:35][C:34]=1[Cl:40]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: C1CN2CCN1CC2
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1Cl

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was reacted with methyl-2,6-dichloro-pyridine-3-carboxylate and DABCO (21 h, r.t.) to give the title compound as a white solid. MS (m/e)=585.2 [M+H+]
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([C:13]2[C:14]([CH2:27][CH2:28][CH3:29])=[N:15][CH:16]=[CH:17][C:18]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:11][OH:12])=[C:4](F)[C:3]=1[Si](C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]2[C:10]([C:13]3[C:14]([CH2:27][CH2:28][CH3:29])=[N:15][CH:16]=[CH:17][C:18]=3[O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[N:11][O:12][C:4]=2[CH:3]=1
Reactant: CCCc1nccc(Oc2ccc(Cl)cc2)c1C(=NO)c1cc(OC)c(Cl)c([Si](C)(C)C)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nccc(Oc2ccc(Cl)cc2)c1-c1noc2cc(Cl)c(OC)cc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of the oxime from Step 8 (12.0 g, 27 mmol) and cesium carbonate (17 g, 54 mmol) in DMF (200 mL) was stirred at 80° C. for 18 h. The reaction was diluted with ethyl acetate and washed with water. The crude product was purified by chromatography on silica gel to give the title product.
Reaction SMILES: [OH-].[K+].[C:3]([OH:6])(=[S:5])[CH3:4].Cl[CH:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[C:9]([OH:11])=[O:10]>C(O)C>[C:3]([S:5][CH:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[C:9]([OH:11])=[O:10])(=[O:6])[CH3:4]
Reactant: CC(O)=S
Reactant: COc1ccc2cc(C(Cl)C(=O)O)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2cc(C(SC(C)=O)C(=O)O)ccc2c1
Reaction time: 15 h

Procedure:
To a solution of 600 ml. of anhydrous ethanol and 21 g. (0.317 moles) of potassium hydroxide is added 45 ml. of thioacetic acid dropwise. To this mixture is then added 0.244 moles of α-chloro-6-methoxy-2-naphthylacetic acid and stirring is continued for 15 hours. The solid which forms is filtered off and washed with ethanol. The filtrate is evaporated to dryness and the residue is dissolved in 500 ml. of ether and washed several times with water. Drying the ether and evaporation to dryness results in α-acetylthio-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:21][C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]3[C:14]=2[C@:5]2([C@@H:11]([O:12]3)[CH2:10][C:8](=[O:9])[CH:7]=[CH:6]2)[CH2:4][CH2:3]1.CN1CC2C=CC(OC)=C3C=2[C@]2([C@@H](O3)C[C@@H](O)C=C2)CC1.CN1CC2=C3C(=C(OC)C=C2)OC2C3(C=CC(O)C2)CC1.CN1CC2=C3C(=C(OC)C=C2)O[C@H]2[C@@]3(C=C[C@@H](O)C2)CC1>>[CH3:1][N:2]1[CH2:21][C:15]2=[C:14]3[C:13](=[C:18]([O:19][CH3:20])[CH:17]=[CH:16]2)[O:12][C@H:11]2[C@@:5]3([CH:6]=[CH:7][C:8]([CH2:10]2)=[O:9])[CH2:4][CH2:3]1
Reactant: COc1ccc2c3c1O[C@H]1CC(=O)C=C[C@@]31CCN(C)C2
Agent: COc1ccc2c3c1OC1CC(O)C=CC31CCN(C)C2
Agent: COc1ccc2c3c1O[C@@H]1C[C@H](O)C=C[C@]31CCN(C)C2
Agent: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCN(C)C2
Product: COc1ccc2c3c1O[C@@H]1CC(=O)C=C[C@]31CCN(C)C2

Procedure:
Once dissolved, the racemic narwedine mixture is maintained at a temperature of 25° C. to 70° C., preferably 40° C. to 60° C., and the crystals of enantiomeric narwedine, enantiomeric galanthamine, or enantiomeric epigalanthamine in an amount of from 0.1% to 2%, preferably 0.2% to 1% by weight relative to the amount of narwedine to be resolved are added. If (-)-narwedine is to be produced, the crystals added here are either (-)-narwedine, (+)-galanthamine, or (+)-epigalanthamine. If the reaction is to produce (+)-narwedine, the crystal used here are (+)-narwedine, (-)-galanthamine or (-)-epigalanthamine. Since the end result of the next step (the reduction to (-)-galanthamine) is intended to be as free as possible of epigalanthamine and (+)-galanthamine, (-)-narwedine is the most preferred crystal to use to generate additional (-)-narwedine so long as it is available. The temperature is then dropped to 25° to 70° C., preferably 40° C. to 60° C. and held there for 5-24 hours, preferably 12-18 hours, most preferably about 16 hours.
Reaction SMILES: [OH-].[Na+:2].[N:3]1[S:4][N:5]=[C:6]2[CH:11]=[C:10]([C:12]3[C:13](=[O:33])[O:14][C:15]([OH:32])([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[C:16]=3[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=[CH:8][C:7]=12>CO>[N:3]1[S:4][N:5]=[C:6]2[CH:11]=[C:10]([C:12](=[C:16]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[O:32])[C:13]([O-:33])=[O:14])[CH:9]=[CH:8][C:7]=12.[Na+:2]
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4nsnc4c3)=C2Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)C(Cc2ccccc2)=C(C(=O)[O-])c2ccc3nsnc3c2)cc1
Temperature: 25 °C

Procedure:
0.7 ml of 0.1 N NaOH is added to a suspension of 30 mg of 3-(2,1,3-benzothiadiazol-5-yl)-4-benzyl-5-hydroxy-5-(4-methoxyphenyl)-5H-furan-2-one in 1 ml of methanol and the mixture is stirred at room temperature. The solvent is removed, the residue is partitioned between water and diethyl ether, and the agueous phase is then lyophilized. Sodium 2-(2,1,3-benzothiadiazol-5-yl)-3-benzyl-4-(4-methoxyphenyl)-4-oxo-2-butenoate, FAB 453, is obtained.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C@@H:6]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:37][C:2]([F:1])([F:36])[CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C@@H:6]([NH:15][C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:5]1
Reactant: O=C1[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CCc2ccccc2N1CC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: FC(F)(F)CN1C[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)CCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A round-bottom flask containing the product of Step 1 (1.94 g, 3.88 mmol) was fitted with a condenser, stirbar and septa and flushed with nitrogen. Tetrahydrofuran (40 mL) was added, giving a solution that was cooled to 0° C. Lithium aluminum hydride (0.77 g, 20 mmol) was added, and the reaction was then removed from the cooling bath and allowed to warm to room temperature. After one hour, the reaction was warmed to 60° C., then stirred an additional 17 hours. The reaction mixture was then cooled to room temperature and quenched via the sequential additions of H2O (0.77 mL), 10% aqueous sodium hydroxide solution (0.77 mL), and H2O (3×0.77 mL). The resulting mixture was stirred 10 minutes, diluted with ethyl acetate (100 mL), filtered through celite and concentrated in vacuo to give the desired product.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])(C)(C)C.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])(B(O)O)[NH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.[Pd].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>[Cl:18][C:19]1[CH:20]=[C:21]([C:13]2[CH:12]=[CH:11][C:10]([C@H:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=2)[C:22]([O:28][CH3:29])=[N:23][CH:24]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: COC1(B(O)O)C=CC(Cl)=CN1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ncc(Cl)cc1-c1ccc([C@@H](C)N)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a suspension of (R)-1-(4-bromophenyl)ethylamine (23.89 g, 0.101 mol) in tetrahydrofuran (200 ml) was added triethylamine (21 ml), 4-dimethylaminopyridine (1.5 g) and di-tert-butyldicarbonate (26.5 g, 0.121 mol). The solution was stirred overnight then diluted with diethyl ether and washed with 2M aqueous hydrogen chloride solution, 10% aqueous sodium carbonate solution and brine. The organic phase was dried over anhydrous sodium sulfate and the solution concentrated to low volume. Heptane was added and the resulting white solid filtered off and dried to give (R)-[1-(4-bromophenyl)-ethyl]-carbamic acid tert-butyl ester (17 g). To a solution of (R)-[1-(4-bromophenyl)-ethyl]-carbamic acid tert-butyl ester (2 g, 6.7 mmol) in toluene (40 ml) was added 5-chloro-2-methoxypyridine boronic acid (2.5 g, 13.3 mmol), 2M aqueous sodium carbonate solution (6.8 ml) and tetrakis(triphenylphosphine) palladium (0) (0.4 g). The solution was heated under reflux for 48 h then washed with water, brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue dissolved in dichloromethane (50 ml) and the solution cooled to 0° C. Trifluoroacetic acid (20 ml) was added and the solution stirred for 3 h then evaporated to a gum which was chromatographed on a SCX column eluting with methanol then ammonia/methanol. The solvent was removed and the residue flash chromatographed on silica eluting with 9:1 dichloromethane/methanol then 9:1 dichloromethane/methanol-ammonia. The solvent was evaporated to give (R)-1-[4-(5-chloro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (1.37 g) as a gum.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([OH:7])[CH3:6])([O-])=[O:2].C(=O)CCC.Cl.ClCCCCOCCCCCl.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1CC(O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[N:1](=[C:4]1[CH:5]([CH3:6])[O:7][CH:26]([CH2:27][CH2:28][CH3:29])[S:25]1)[OH:2]
Reactant: O=C(O)Cc1cccs1
Reactant: CC(O)C[N+](=O)[O-]
Agent: Cl
Agent: ClCCCCOCCCCCl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCCC=O
Product: CCCC1OC(C)C(=NO)S1

Procedure:
1-Methyl-2-nitroethyl-1'-acetylthiobutyl ether was prepared using procedures similar to those described in Examples I and II by chloroalkylation of 1-nitro-2-propanol with n-butyraldehyde and hydrogen chloride followed by treatment of the intermediate chlorobutyl ether with thiolacetic acid and then pyridine. Treatment of this nitroalkylacylthio ether in toluene with ethanolic sodium hydroxide as described in Example I afforded crude 4- oximino-2-propyl-5-methyl-1,3-oxathiolane comprised of a mixture of Isomer A (NMR data suggests Trans Isomer) and Isomer B (NMR suggests Cis). Trituration of 26 grams of the crude oxime mixture with 150 ml of hexane and filtration afforded 3.0 grams pure Isomer A, mp 86°-88°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:31])([F:30])[C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:22]1[CH2:23][CH2:24][C:25]([F:29])([F:28])[CH2:26][CH2:27]1)[C:16]1[CH:17]=[N:18][C:13]([C:12]([F:11])([F:30])[F:31])=[CH:14][CH:15]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1ccc(C(F)(F)F)nc1)N1CCC(F)(F)CC1
Product: O=C(NCC(c1ccc(C(F)(F)F)nc1)N1CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(6-(trifluoromethyl)-3-pyridyl)-2-(4,4-difluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.[CH:19]1([NH:22][C:23]([C:25]2[C:34](=[O:35])[C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[N:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[C:38]([Br:43])[CH:37]=3)[CH:26]=2)=[O:24])[CH2:21][CH2:20]1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:43][C:38]1[CH:39]=[C:40]([C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:11][CH:10]3[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=2)[CH:41]=[C:36]([N:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][N:29]=3)[C:34](=[O:35])[C:25]([C:23]([NH:22][CH:19]3[CH2:20][CH2:21]3)=[O:24])=[CH:26]2)[CH:37]=1
Reactant: CCOC(=O)C1CC1c1ccc([Sn](C)(C)C)cc1
Reactant: O=C(NC1CC1)c1cn(-c2cc(Br)cc(Br)c2)c2ncccc2c1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1c1ccc(-c2cc(Br)cc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C

Procedure:
A mixture of ester from step 2 (1.7 eq), dibromo from step 1 (1 eq), Pd2(dba)3 (0.05 eq) and triphenylarsine (0.25 eq) in DMF (0.05M) was heated at 80° C. for 2 h. The mixture was cooled to rt, diluted with EtOAc and water, the organic was washed with brine, dried and solvent evaporated. The residue was purified by flash chromatography (CH2Cl2:MeOH; 99:1 to 90:10) to afford the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(N(CC)CC)C.Cl[CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH:43]([S:44]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1)(=[O:46])=[O:45])=[CH2:42]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1
Reaction time: 1 h
Yield: 82 %

Procedure:
To a mixture of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (100 mg, 0.2 mmol) in dry DCM (2 mL) was added triethylamine (60 μL, 0.4 mmol) and the reaction mixture was stirred for 1 hour. The mixture was washed with water followed by brine, dried (Na2SO4) and then treated with triethylamine (30 μL, 0.2 mmol) followed by 2-chloroethane-sulfonyl chloride (42 μL, 0.4 mmol) in dry DCM (1 mL). The reaction mixture was stirred at RT for 18 hours then diluted with DCM and washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo to give 8-(1-Ethenesulfonyl-azetidin-3-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as a light brown oil (75 mg, 82%). 1H NMR δ (ppm) (CDCl3): 8.39 (1H, d, J=8.22 Hz), 7.93 (1H, s), 7.16 (1H, dd, J=8.22, 1.98 Hz), 7.02 (1H, d, J=1.91 Hz), 6.61 (1H, dd, J=16.50, 9.95 Hz), 6.39 (1H, d, J=16.66 Hz), 6.18 (1H, d, J=9.95 Hz), 5.93-5.87 (1H, m), 4.45-4.39 (2H, m), 4.28-4.22 (2H, m), 4.07-3.97 (2H, m), 3.81 (1H, t, J=7.81 Hz), 3.46-3.40 (2H, m), 1.64 (6H, d, J=6.65 Hz)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[CH:5](C)C.BrC1C=C2C(CN([C@@H](C)C(OC)=O)C2=O)=CC=1.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>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].C(Cl)Cl>[O:37]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)[CH:11]=2)[CH2:16][N:8]1[C@@H:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:38]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O

Procedure:
The compound of example 336 was prepared analogous to compound of example 330 by reaction of the compound of example 335, compound of example 327 and Pd(dppf)Cl2: CH2Cl2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[C:16]1[N:12]([CH:13]=[C:14]([C:20]3[N:24]([CH2:25][CH2:26][OH:27])[N:23]=[CH:22][N:21]=3)[N:15]=1)[CH2:11][CH2:10][O:9]2)=[CH2:5])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[OH:27][CH2:26][CH2:25][N:24]1[C:20]([C:14]2[N:15]=[C:16]3[N:12]([CH:13]=2)[CH2:11][CH2:10][O:9][C:8]2[C:17]3=[CH:18][CH:19]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=2)=[N:21][CH:22]=[N:23]1
Reactant: C=C(OCC)c1ccc2c(c1)OCCn1cc(-c3ncnn3CCO)nc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CCO)nc1-2
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 80.4 %

Procedure:
A mixture of 2-{5-[12-(1-ethoxyethenyl)-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-4-yl]-1H-1,2,4-triazol-1-yl}ethan-1-ol (160 mg, 0.440 mmol) and p-toluenesulfonic acid (7.5 mg, 0.044 mmol) in acetone (10 mL) was stirred at 60° C. for 75 minute. The solid was filtered off, the filtrate was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.3% NH4HCO3 to give 1-{4-[1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}ethan-1-one (120 mg, 81% yield). LCMS (ESI) m/z: 340.3 [M+H+].