Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[NH:4][C:3]1=[O:14].[CH2:16]1[C@H:25]2[C@H:20]([CH2:21][CH2:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=32)[NH:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:16]1[C@H:25]2[C@H:20]([CH2:21][CH2:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=32)[N:19]([C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:14])[C:2]3([CH3:1])[CH3:15])=[O:13])[CH2:18][CH2:17]1
Reactant: CC1(C)C(=O)Nc2ccc(C(=O)O)cc21
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC1(C)C(=O)Nc2ccc(C(=O)N3CCC[C@@H]4c5ccccc5CC[C@@H]43)cc21
Yield: 19 %

Procedure:
The title compound is prepared from 3,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 19% of theory; LC (method 4): tR=1.95 min; Mass spectrum (ESI+): m/z=375 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH2:12].C(N(CC)CC)C.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(Cl)cc1
Yield: 71.4 %

Procedure:
To a solution of 0.21 g of 3,5-dichloro-4-(3-aminopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene and 0.07 g of triethylamine dissolved in 5 ml of dichloromethane was added dropwise a solution of 0.11 g of 4-chlorobenzoyl chloride dissolved in 5 ml of dichloromethane, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was washed with water and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.21 g of 3,5-dichloro-4-(3-(4-chlorobenzamido)propyloxy)-1-(3,3-dichloro-2-propenyl-oxy)benzene (71% yield), m.p., 95.1° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[CH:29]=[CH:30][C:31]([F:37])=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1>O1CCCC1.[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>[F:37][C:31]1[CH:30]=[CH:29][C:28]([C:6]2[N:10]3[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]3=[N:8][CH:7]=2)=[CH:33][C:32]=1[N+:34]([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
To 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (73 ml of a 0.13M solution in tetrahydrofuran, 9.44 mmol) was added 5-bromo-2-fluoronitrobenzene (4.20 g, 19 mmol) followed by tetrakis(triphenylphosphine) palladium(0) (0.62 g). The resulting mixture was heated at reflux for 4 h. The solvent was evaporated at reduced pressure and the residue chromatographed on silica gel eluting with 30% ethyl acetate in dichloromethane to afford 3-(4-fluoro-3-nitrophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, DMSO) 7.59 (1H, d, J 7), 7.83 (1H, dd, J 11 and 9), 8.18 (1H, m), 8.36 (1H, s), 8.53 (1H, dd, J 7 and 2), 9.36 (1H, d, J 7); m/z (ES+) 327 (M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:14][S:15]SC>N1C=CC=CC=1>[CH2:12]([O:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([S:15][CH3:14])[C:9]=1[OH:10])[CH:5]=[O:6])[CH3:13]
Reactant: CSSC
Reactant: CCOc1cc(C=O)cc(Br)c1O
Solvent: c1ccncc1
Product: CCOc1cc(C=O)cc(SC)c1O
Temperature: 90 °C
Yield: 69.3 %

Procedure:
To the solution of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (1.00 g, 4.08 mmol) in pyridine (10 mL) was added Cu powder (0.52 g, 8.1 mmol) and methyl disulfide (0.77 g, 8.2 mmol), the mixture was then heated at 90° C. overnight. The reaction mixture was filtered, and the solvent was removed under reduced pressure, the residue was poured into water, and 6 N HCl (5 mL) was added, then the mixture was extracted with DCM (50 mL×3), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column (PE:EA=5:1) to give Intermediate 50 (600 mg, yield 69%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20]N)=[CH:16][CH:15]=1>CC(O)=O>[Br:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:18][CH:19]=1)[NH:20][C:2]1[CH2:3][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:6][C:7]2=1
Reactant: NNc1ccc(Br)cc1
Reactant: CC(=O)NC1CCCC(=O)C1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)NC1CCc2c([nH]c3ccc(Br)cc23)C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of 0.05 mol of N-(3-oxocyclohexyl) acetamide in 100 ml of glacial HOAc was stirred and heated at 80° C. while adding during 15-30 minutes a warm solution of 0.05 mol of 4-bromophenylhydrazine hydrochloride in 300 ml of glacial HOAc. After an additional 3 hr at 85°, most of the HOAc was evaporated. The residue was triturated with H2O, until solid, the resulting solid was filtered, and recrystallized from ethanol to give the title compound, mp 210°-211°.
Reaction SMILES: [NH2:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH3:8])[C:3](OCC)=[O:4].[BH4-].[Na+]>O.C(O)C>[NH2:1][C:2]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)([CH3:8])[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(N)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(N)(CO)c1cccs1
Yield: 84.2 %

Procedure:
The product of Example 437A (0.497 g, 2.494 mmol) in 1:3 v/v water/ethanol (12 mL) was reacted with sodium borohydride (0.481 g, 12.47 mmol) at reflux for 4 hours. The reaction was concentrated by rotary evaporation partition between water (5 mL), ethyl ether (25 mL), 1N aqueous sodium hydroxide (1.25 mL). Solid sodium chloride was added to saturate separate phases. The aqueous was re-extracted with ethyl ether (25 mL). The combined ethereal extracts were washed with brine (25 mL), dried over potassium carbonate, filtered, and concentrated by rotary evaporation to afford the title compound as an oil (0.330 g, 2.099 mmol, 84%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.35 (s, 3 H) 1.96 (s, 2 H) 3.33-3.42 (m, 2 H) 4.91 (t, J=5.70 Hz, 1 H) 6.89-6.95 (m, 2 H) 7.28 (dd, J=3.49, 2.76 Hz, 1 H). MS (DCI) m/z 158 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:35])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][CH2:20][CH2:19][C:18]([OH:35])=[O:17])=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: COC(=O)CCCc1ccccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2ccccc2CCCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 4, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-[(5-bromopentyl)oxy]benzenebutanoic acid methyl ester from the preceding example, followed by saponification, in 46.5% overall yield. The product was an off-white solid, mp 116°-118° C., recrystallized from acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20]([O:22]CC)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[C:20](=[O:22])[N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: C1CCNC1
Product: O=C(Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)C(=O)N1CCCC1
Yield: 85.6 %

Procedure:
Prepared from ethyl 2-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylamino)-2-oxoacetate (Example 2; 36 mg, 0.10 mmol) and pyrrolidine (36 mg, 0.50 mmol) according to the procedure for Example 3. The product was purified on a pre-packed Isoelute silica gel column (10 g silica), eluting with a gradient of 20% EtOAc/hexanes, 1:1 EtOAc/hexanes, 2:1 EtOAc/hexanes, and then neat EtOAc. The product was obtained as a white powder (33 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 8.52 (d, J=5 Hz, 1H), 7.87 (m, 1H), 7.75 (d, J=6 Hz, 1H), 7.58 (d, J=6 Hz, 1H), 7.37 (m, 1H), 7.26 (m, 1H), 6.52 (d, J=5 Hz, 1H), 4.09 (t, J=7 Hz, 2H), 3.63 (t, J=7 Hz, 2H), 2.02 (m, 2H), 1.91 (m, 2H). LRMS (ESI pos) m/e 386 (M+1). HPLC: 100% purity (220 nm).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)=O)([O-])=O.[H][H].N>[Pd].CCOCCO>[CH:19]1[CH:20]=[C:4]([NH2:1])[CH:5]=[C:6]([CH2:7][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:18]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CCOCCO
Product: Nc1ccc(Cc2cccc(N)c2)cc1

Procedure:
15.3 g (0.05 mol) of 3,4'-dinitro-4-chlorobenzophenone, 0.75 g of 5% Pd/C and 50 ml of ethyl cellosolve were charged in a closed glass vessel equipped with a thermometer and a stirrer. While stirring the mixture at a temperature of 75° to 80° C., hydrogen was introduced thereinto and 10.3 l (0.46 mol) of hydrogen was absorbed in 13 hours. Since no more absorption of hydrogen was observed, the reaction was terminated at this point. The reaction solution was neutralized with 3.6 g (0.06 mol) of 28% aqueous ammonia. The catalyst was removed by filtration. The filtrate was concentrated to obtain 3,4'-diaminodiphenylmethane as a brown oil. A high performance liquid chromatography revealed that the purity was 88.2%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:13]=[N:12][C:11]1=2>C(#N)C>[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21]([NH:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[O:22])[CH:13]=[N:12][C:11]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCc1ccccn1
Solvent: CC#N
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCc1ccccn1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
0.500 g (4.62 mmol) of 2-(aminomethyl)pyridine and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) were heated together with stirring in a 10 ml round bottom flask at 110° C. for 90 minutes. The solution solidified and was cooled to room temperature. 10 ml of acetonitrile was added and the solid was broken up with a spatula until a fine white precipitate was formed. The solid was collected by Buchner vacuum filtration and the solid was washed with acetonitrile and ether to yield 267 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[(2-pyridinyl)methyl]propanamide (AIT-0063) as a white solid. Yield: 84%.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[C:22]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:21]([F:27])[C:20]([F:28])=[CH:19][CH:18]=1.[C:29](=[O:31])=[O:30]>C1COCC1.O>[Br:16][C:17]1[C:22]([Si:23]([CH3:24])([CH3:25])[CH3:26])=[C:21]([F:27])[C:20]([F:28])=[C:19]([CH:18]=1)[C:29]([OH:31])=[O:30]
Reactant: C[Si](C)(C)c1c(Br)ccc(F)c1F
Reactant: O=C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)c1c(Br)cc(C(=O)O)c(F)c1F
Reaction time: 0.25 h

Procedure:
To a solution of n-BuLi (2.0 M in hexanes, 11.1 mL, 22.2 mmol) in anhydrous THF (17 mL) at −78° C. was added drop wise 2,2,6,6-tetramethylpiperidine (3.26 g, 22.1 mmol). After being stirred for 15 minutes, a solution of the product from step A (5.86 g, 22.1 mmol) in THF (20 mL) was added. The reaction mixture was stirred at −78° C. for 2 hours, then dry ice (100 g) was added. The mixture was allowed to stand at room temperature overnight, then it was diluted with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered, then concentrated to afford the title compound. The material was used directly in the next step without further purification. 1H NMR (500 MHz, CDCl3): δ 7.70 (d, J=4.4 Hz, 1H); 0.44 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]2[N:22]=[C:23]([NH2:25])[S:24][CH:2]=2)=[C:6]([CH3:21])[CH:7]=1
Reactant: NC(N)=S
Reactant: COc1cccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)c1
Solvent: CCO
Product: COc1cccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)c1
Yield: 65.9 %

Procedure:
A mixture of 2-bromo-1-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (6.98 g, 20.0 mmol) and thiourea (1.52 g, 20.0 mmol) in 95% EtOH (28.5 mL) was heated at reflux for 5.0 h. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL), and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 4-(4-(3-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (4.30 g) as deep-brown oil, which was used directly for the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([OH:35])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:39][NH2:40]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33]([NH:40][CH3:39])=[O:35])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: CN
Product: CNC(=O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution of methylamine (1.0 ml in DMF) were combined to give 11 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 544 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:10]2[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][C:12]=3[C:13]3[O:18][C@@H:17]([CH3:19])[C@H:16]([CH3:20])[C@H:15]([OH:21])[C:14]=3[C:9]=2[O:8][C:6](=[O:7])[CH:5]=1.[CH3:28][CH2:29][CH2:30]C1C2C3OC(C)(C)C=CC=3C3OC(C)C(C)C(O)C=3C=2OC(=O)C=1>CO.O=[Pt]=O>[CH3:20][C@@H:16]1[C@H:15]([OH:21])[C:14]2[C:9]3[O:8][C:6]([CH:5]=[C:4]([C:3]4[CH:28]=[CH:29][CH:30]=[CH:1][CH:2]=4)[C:10]=3[C:11]3[O:25][C:24]([CH3:27])([CH3:26])[CH:23]=[CH:22][C:12]=3[C:13]=2[O:18][C@H:17]1[CH3:19])=[O:7]
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)CC4)O[C@@H](C)[C@H](C)[C@@H]3O
Reactant: CCCc1cc(=O)oc2c3c(c4c(c12)OC(C)(C)C=C4)OC(C)C(C)C3O
Agent: O=[Pt]=O
Solvent: CO
Product: C[C@H]1[C@H](C)Oc2c3c(c4c(-c5ccccc5)cc(=O)oc4c2[C@H]1O)OC(C)(C)C=C3

Procedure:
This example illustrates the preparation of antiviral 7,8-dihydro compounds (FIG. 6) of series 2, specifically 7,8-dihydrocalanolide A, 7,8-dihydrocalanolide B, 7,8-dihydro-costatolide, and 7,8-dihydrosoulattrolide from the corresponding 7,8-unsaturated compounds of series 1. Of these six compounds, only one structure (7,8-dihydrocostatolide; Stout, G. H., et al., J. Org. Chem., 29, 3604-3609 (1964)) had been previously reported, however none of the six were known heretofore to have antiviral activity. The 7,8-dihydro compounds were made by catalytic hydrogenation of the selected appropriate 7,8-unsaturated precursors. In a typical procedure, 10 mg of calanolide A was stirred with 2.5 mg PtO2 (Aldrich) in 4 ml MeOH under an atmosphere of H2 (a balloon filled with H2 was attached to the reaction vessel to provide a slightly positive pressure of H2) for 30 min. The mixture was filtered, and the solvent removed in vacuo to provide a light yellow oil which was purified by SiO2HPLC (21.1×300 mm, Dynamax column) eluted with 25 ml/min hexane/EtOAc (7:3) to give 9.0 mg of 7,8-dihydrocalanolide A (EIMS m/z 372, appropriate for C22H28O5 ; 1H NMR, see Table 5). In an exactly analogous fashion, 6 mg of calanolide B with 3 mg PtO2 in 4 ml MeOH was converted to 3.6 mg of 7,8-dihydrocalanolide B (EIMS m/z 372, appropriate for C22H28O5 ; 1H NMR, see Table 5); 100 mg of costatolide with 15 mg PtO2 in 20 ml MeOH was converted to 89.9 mg 7,8-dihydrocostatolide (EIMS m/z 372, appropriate for C22H28O5 ; 1H NMR, see Table 5); and 12 mg of soulattrolide with 3 mg PtO2 in 4 ml MeOH was converted to 8.9 mg 7,8-dihydrosoulattrolide (EIMS m/z 406, appropriate for C25H26O5 ; 1H NMR, see Table 5).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)=[O:4].[C:16]([C:19]1[C:20](=[O:28])[N:21]([CH3:27])[C:22]([CH3:26])=[CH:23][C:24]=1[OH:25])(=[O:18])[CH3:17]>>[OH:25][C:24]1[CH:23]=[C:22]([CH3:26])[N:21]([CH3:27])[C:20](=[O:28])[C:19]=1[C:16](=[O:18])[CH:17]=[CH:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][C:3]([N:2]([CH3:15])[CH3:1])=[O:4])[CH:8]=1
Reactant: CC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: CN(C)C(=O)COc1cccc(C=O)c1
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(OCC(=O)N(C)C)c2)c(=O)n1C
Yield: 15.7 %

Procedure:
According to the same manner as that of Example a-1 except that 4.29 g of 3-[(dimethylaminocarbonyl)methoxy]benzaldehyde was used in place of 3-[(methoxycarbonyl)methoxy]benzaldehyde, and 3.40 g of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, 1.09 g of 4-hydroxy-3-[3-[3-[(dimethylaminocarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (38a)] was obtained as a yellow crystal.
Reaction SMILES: [CH3:1][N+:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([SH:8])[CH2:4][CH2:3]1.[OH:10][C@@H:11]([C@H:13]1[C:33](=[O:34])[N:15]2[CH:16]([C:20]([O:22]CC3C=CC([N+]([O-])=O)=CC=3)=[O:21])[C:17](=O)[CH2:18][C@H:14]12)[CH3:12]>>[CH3:1][N+:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([S:8][C:17]2[CH2:18][C@@H:14]3[C@@H:13]([C@H:11]([OH:10])[CH3:12])[C:33](=[O:34])[N:15]3[C:16]=2[C:20]([O-:22])=[O:21])[CH2:4][CH2:3]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: C[N+]1(C)CCC(S)CC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SC3CC[N+](C)(C)CC3)C[C@H]12
Yield: 6.8 %

Procedure:
Following a procedure similar to that described in Example 6, but using 368 mg of the crude 1,1-dimethyl-4-mercaptopiperidinium salt prepared as described in Example 7-(1) and, 363 mg of 4-nitrobenzyl (5R, 6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate, 24 mg of the title compound were obtained.
Reaction SMILES: [P:1]([O-:19])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:26]1[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]3[CH:43]=[CH:44][C:45]([NH:47][C:39]=3[CH:38]=2)=O)[CH2:30][CH2:29][N:28]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:27]1.CC(C)([O-])C.[K+]>ClCCl.CN(C)C=O>[P:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:19][C:45]1[CH:44]=[CH:43][C:40]2[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[CH2:30][CH2:29][N:28]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=4[Cl:55])[CH2:27][CH2:26]3)=[CH:42][CH:41]=2)[N:47]=1)=[O:2]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dibenzyl phosphate (2.48 g, 8.91 mmol) in dichloromethane (25 ml) was added dimethyl formamide (1 drop) followed by oxalyl chloride (0.75 mL, 8.91 mmol). After 2 hours the reaction mixture was concentrated in vacuo. The residue was dissolved in 2-methyltetrahydrfuran (5 mL) and added to a suspension of dehydro-aripiprazole (1.66 g, 3.71 mmol) and potassium t-butoxide (0.92 g, 8.17 mmol) in 2-methyltetrahydrfuran (35 mL) at 0° C. under Ar (g) then allowed to gradually warm to room temperature. After stirring overnight the reaction was quenched with water (25 mL) and 28% aq NH3 (15 mL) and stirred for 10 minutes. The reaction mixture was then extracted with ethyl acetate (2×40 mL). The combined organics were washed with water (50 mL) and brine (50 mL) then dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with 5% methanol (1:1 ethyl acetate/dichloromethane) to give the product. The 1H-NMR showed minor impurities still present (impurities not observed by LCMS). Various further purifications were attempted but failed to remove these impurities.
Reaction SMILES: [N:1](OCCC(C)C)=O.[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([NH2:28])=[C:23]([CH3:29])[C:22]=1[CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].C([O-])(=O)C.[K+]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[C:22]([CH2:30][O:31][C:32](=[O:34])[CH3:33])=[C:23]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:28][N:1]=[CH:29]2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Isoamyl nitrite (700 μL, 5.2 mmol), was added dropwise to an ice cold solution of 2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic acid diethyl ester (1.91 g, 4.8 mmol) in 5% acetic acid in toluene (81.2 mL). Mixture stirred at 0° C. for 45 minutes. Potassium acetate (1.50 g, 15.3 mmol) was added to the mixture. Reaction was stirred at room temperature for 14 hours. Mixture was quenched with water. Mixture was extracted with ethyl acetate (30 mL). Mixture was washed 2× saturated aqueous sodium bicarbonate. Organic was dried (magnesium sulfate) filtered and concentrated. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 80% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=8.23 (s, 1H), 7.26 (s, 1H), 5.45 (s, 2H), 4.09 (q, J=7.0, 4H), 3.20 (dd, J1=7.32, J2=13.2, 1H), 3.10 (m, 1H), 2.97 (dd, J1=7.0, J2=13.3, 1H), 2.73 (dd, J1=8.4, J2=16.8, 1H), 2.44 (dd, J1=5.5, J2=16.8, 1H), 2.08 (s, 3H), 1.18 (m, 6H). MS m/e (M+H)+=411.0.