Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([C:18]3([O:26][CH3:27])[CH2:22][CH2:21][N:20]([CH2:23][C:24]#[CH:25])[CH2:19]3)[CH:14]=[C:15]([F:17])[CH:16]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:29][OH:30]>>[F:17][C:15]1[CH:16]=[C:11]([S:10][C:7]2[CH:6]=[CH:5][C:4]([C:1](=[N:29][OH:30])[CH3:2])=[CH:9][CH:8]=2)[CH:12]=[C:13]([C:18]2([O:26][CH3:27])[CH2:22][CH2:21][N:20]([CH2:23][C:24]#[CH:25])[CH2:19]2)[CH:14]=1
Reactant: NO
Reactant: C#CCN1CCC(OC)(c2cc(F)cc(Sc3ccc(C(C)=O)cc3)c2)C1
Agent: Cl
Product: C#CCN1CCC(OC)(c2cc(F)cc(Sc3ccc(C(C)=NO)cc3)c2)C1
Yield: 96 %

Procedure:
Using an analogous procedure to that described in Example 27, 3-[3-(4-acetylphenylthio)-5-fluorophenyl]-3-methoxy-1-(prop-2-ynyl)pyrrolidine was reacted with hydroxylamine hydrochloride to give 3-{5-fluoro-3-[4-(1-hydroxyiminoethyl)phenylthio]phenyl}-3-methoxy-1-(prop-2-ynyl)pyrrolidine in 96% yield, m.p. 97°-99° C. (recrystallised from a mixture of hexane and diethyl ether).
Reaction SMILES: [OH:1][C:2]1[C:19]([OH:20])=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([OH:22])=[C:14]([OH:21])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([OH:24])=[C:8]([OH:23])[CH:9]=3)[C:4]=2[CH:3]=1.[C:25](Cl)(=[O:35])[O:26][C@H:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28].Cl>N1C=CC=CC=1>[CH3:28][C@H:27]([O:26][C:25]([O:1][C:2]1[C:19]([O:20][C:25]([O:26][C@H:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])=[O:35])=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([O:22][C:25]([O:26][C@H:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])=[O:35])=[C:14]([O:21][C:25]([O:26][C@H:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])=[O:35])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([O:24][C:25]([O:26][C@H:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])=[O:35])=[C:8]([O:23][C:25]([O:26][C@H:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])=[O:35])[CH:9]=3)[C:4]=2[CH:3]=1)=[O:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Oc1cc2c3cc(O)c(O)cc3c3cc(O)c(O)cc3c2cc1O
Reactant: CCCCCC[C@H](C)OC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCC[C@H](C)OC(=O)Oc1cc2c3cc(OC(=O)O[C@@H](C)CCCCCC)c(OC(=O)O[C@@H](C)CCCCCC)cc3c3cc(OC(=O)O[C@@H](C)CCCCCC)c(OC(=O)O[C@@H](C)CCCCCC)cc3c2cc1OC(=O)O[C@@H](C)CCCCCC
Temperature: 25 °C
Yield: 69 %

Procedure:
A TFT solution of 4.86 g (15 mmol) of 2,3,6,7,10,11-hexahydroxytriphenylene and 135 mmol of (s)-2-octyl chlorocarbonate was stirred while chilled with ice. After 40 ml of pyridine was slowly and dropwise added, the liquid was heated for 50 minutes to the room temperature. The solution was poured into diluted hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic phase was collected, washed with diluted hydrochloric acid, water and saturated aqueous solution of sodium chloride, and then dried with anhydrous magnesium sulfate. After the solvent was distilled off, the obtained brown oily product (26.2 g) was purified through silica-gel chromatography (hexane:ethyl acetate =10:1) to prepare 13.75 g of the titled optically active triphenylene compound (5) [colorless oily product at room temperature, yield: 69%].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][C:26]([C:27]([C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=1)=[O:28])=[C:7]2[CH2:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Reactant: Cc1ccnc(C(=O)CBr)c1
Agent: Br
Product: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 8 (Method A) from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (step 3) and 2-bromoacetyl-4-methylpyridine hydrobromide (F. H. Case et al., J. Am. Chem. Soc., 1956, 78, 5842).
Reaction SMILES: C(OC(=O)N[C@@H](C)CO)(C)(C)C.C(OC(C1NN=C(COC2C=CC=CC=2)C=1)=O)C.C(OC([C:36]1[N:37]([CH2:49][CH:50]([NH:52][C:53]([O:55]C(C)(C)C)=O)[CH3:51])[N:38]=[C:39]([CH2:41][O:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=1)=O)C.O(CC1C=C2C(=O)NCCN2N=1)C1C=CC=CC=1>>[CH3:51][C@@H:50]1[CH2:49][N:37]2[N:38]=[C:39]([CH2:41][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:40]=[C:36]2[C:53](=[O:55])[NH:52]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Agent: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=C1NCCn2nc(COc3ccccc3)cc21
Product: C[C@@H]1Cn2nc(COc3ccccc3)cc2C(=O)N1

Procedure:
The compound was prepared from (S)-(2-hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester and 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester using the methods described in the preceding examples 7 ((rac)-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester) and 6 (2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH:4]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:12]=[C:11]([N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH-].[Na+].C1COCC1>[CH2:36]([N:25]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=1)[C:11]1[CH:10]=[C:9]([CH:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:40])=[O:2])[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[N:12]=1)[CH:37]([CH3:38])[CH3:39]
Reactant: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A solution of 2-[2-[isobutyl-(4-trifluoromethyl-phenyl)-amino]-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-4-methyl-pentanoic acid methyl ester (40 mg, 0.07 mmol) in NaOH (1N, 0.5 mL) and THF (3 mL) was stirred at 40° C. overnight. The mixture was cooled to room temperature, acidified with 10% citric acid, and extracted with CH2Cl2 (3×). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (5-20% ethyl acetate in CH2Cl2) to give the product as a white solid (28 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 8.11 (d, J=8.29 Hz, 2H), 7.70 (d, J=8.29 Hz, 2H), 7.57-7.67 (m, 2H), 7.38 (d, J=8.29 Hz, 2H), 7.18 (s, 1H), 6.57 (s, 1H), 3.96 (d, J=7.54 Hz, 2H), 3.55 (t, J=7.54 Hz, 1H), 2.07-2.23 (m, 1H), 1.83-1.95 (m, 1H), 1.65 (dt, J=7.06, 13.75 Hz, 1H), 1.52 (dd, J=6.59, 13.37 Hz, 1H), 0.97 (d, J=6.78 Hz, 6H), 0.90 (dd, J=4.52, 6.40 Hz, 6H). MS m/e 553.3 (M+H).
Reaction SMILES: [OH2:1].[OH2:2].C[N+]([O-])(C)C.[NH:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]2([CH2:20][CH:19]=[CH:18][CH2:17]2)[C:9]1=[O:21]>ClCCl.[Os](=O)(=O)(=O)=O>[OH:1][CH:18]1[CH:19]([OH:2])[CH2:20][C:10]2([C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8][C:9]2=[O:21])[CH2:17]1
Reactant: O=C1Nc2ncccc2C12CC=CC2
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Solvent: ClCCl
Product: O=C1Nc2ncccc2C12CC(O)C(O)C2
Yield: 85.7 %

Procedure:
To a mixture of trimethylamine-N-oxide dihydrate (408 mg, 3.67 mmol) and spiro[cyclopent-3-ene-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (622 mg, 3.34 mmol) in dichloromethane (115 mL) was added osmium tetroxide (25 uL of 2.5% solution in 2-methyl-2-propanol). After 24 h the reaction mixture was concentrated. The crude product was loaded onto a silica gel chromatography column with a minimal amount of methanol and eluted with a gradient of 5 to 20% methanol: dichloromethane to give the title compound (0.63 g). MS: m/z=221.0 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([S:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15])[CH2:8][CH2:9][CH3:10].O>C1COCC1>[CH2:7]([S:11][C:12]1[C:13]([CH2:14][OH:15])=[CH:17][CH:18]=[CH:19][N:20]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCSc1ncccc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCSc1ncccc1CO
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Anhydrous THF (30 mL) in dried flask was cooled to 0° C., LAH (1.14 g, 30 mmol) was added slowly thereto, and the mixture was stirred for 30 minutes. 2-Butylsulfanyl-nicotinic acid (1.27 g, 5.58 mmol) obtained in Step A which is dissolved in anhydrous THF (10 mL) was added slowly thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, water (10 mL) was added slowly thereto at 0° C., and the mixture was stirred for 30 minutes. The reactant was extracted with EtOAc, and the organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.85 g, 77%).
Reaction SMILES: C([O:4][CH2:5][C@@H:6]([N:8]1[C:13](=O)[CH:12]2[CH:10]([CH2:11]2)[C:9]1=O)[CH3:7])(=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH:10]12[CH2:11][CH:12]1[CH2:13][N:8]([C@@H:6]([CH3:7])[CH2:5][OH:4])[CH2:9]2
Reactant: CC(=O)OC[C@H](C)N1C(=O)C2CC2C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C[C@@H](CO)N1CC2CC2C1
Reaction time: 9 h
Yield: 67.7 %

Procedure:
A solution of (2S)-2-(2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)propyl acetate (485 mg, 2.3 mmol) and anhydrous diethyl ether (3 mL) was added over 5 min to a suspension of LiAlH4 (262 mg, 6.9 mmol) and anhydrous diethyl ether (20 mL) at rt under N2 (water bath used to control exotherm). After ˜9 h, anhydrous diethyl ether (10 mL) was added. After 24 h, Na2SO4*10H2O was added one crystal at a time until the bubbling ceased. The mixture was diluted with diethyl ether (50 mL) and filtered through Celite with additional diethyl ether (100 mL). The filtrate was concentrated and purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give 220 mg of (2S)-2-(3-azabicyclo[3.1.0]hexan-3-yl)propan-1-ol. 1H NMR (DMSO-d6): δ 4.26 (t, 1H), 3.42 (m, 1H), 3.13 (ddd, 1H), 2.91 (d, 1H), 2.85 (d, 1H), 2.39-2.28 (m, 3H), 1.31 (m, 2H), 0.93 (d, 3H), 0.54 (m, 1H), 0.25 (m, 1H); MS: 142.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([O:35]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:12]1)[C:8](=[O:47])[NH:7]2)=[O:5])[CH3:2].CO.O.[Li+].[OH-]>C1COCC1.CC(O)=O>[CH2:1]([O:3][C:4]([C:6]12[CH2:24][CH:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:14](=[O:34])[N:13]1[CH:9]([CH2:10][CH:11]([OH:35])[CH2:12]1)[C:8](=[O:47])[NH:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(OC(=O)c3ccc([N+](=O)[O-])cc3)CC1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(O)CC1C(=O)N2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
Crude compound 21e (445 mg) was dissolved in THF (20 ml), MeOH (10 ml) and water (10 ml). After cooling to 0° C. 1M LiOH (2 ml) was added. After 1.5 h the hydrolysis was completed and HOAc (1 ml) was added and the solution was evaporated to appr 10 ml. Water was added and the mixture was extracted with DCM (2×30 ml). The pooled organic phase was washed with NaHCO3 (aq), water, brine and dried over MgSO4. The crude product was purified by column chromatography on silica (DCM/MeOH: 100/0-80/20) to give the title compound (201 mg, 67%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]([O:25][C:26]1[CH:31]=[C:30]([O:32][C:33](=O)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:27]=1[CH2:41][C:42](O)=[O:43])(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O.O>[CH2:17]([O:25][C:26]1[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:27]=1[CH2:41][C:42]([N:12]1[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)=[O:43])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(O)Cc1ccc(OC(=O)c2ccccc2)cc1OC(=O)c1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(C(=O)Cc2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To solution (20 ml) of 4-(4-fluorobenzoyl) piperidine. hydrochloride (670 mg) and 2,4-dibenzoyloxyphenylacetic acid (1.0 g) in N,N-dimethylformamide are added triethylamine (1.2 ml) and diethyl cyanophosphate (561 mg) and the mixture is stirred at room temperature for 10 minutes. To the reaction solution is added water and the mixture stirred for 20 minutes. The product is extracted with dichloromethane. The dichloromethane layer is washed with water and dried over anhydrous sodium sulfate, and then the solvent is distilled off. The residue is purified by silica gel column chromatography. The crude product is obtained from a fraction eluted with dichloromethane-ethyl acetate mixture (2:1). Recrystallization of the product from dichloromethane-diethyl ether mixture yields 1-(2,4-dibenzyloxyphenylacetyl)-4-(4-fluorobenzoyl)piperidine (1.25 g) in the colorless columnar crystal form. Melting point 158°-159° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH:30]([CH3:32])[CH3:31])=[C:13]([C:15]2[NH:28][C:18]3=[N:19][CH:20]=[C:21]([C:23](OCC)=[O:24])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH:30]([CH3:32])[CH3:31])=[C:13]([C:15]2[NH:28][C:18]3=[N:19][CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2[nH]c(-c3cc(OCc4ccccc4)ccc3OC(C)C)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2cc(CO)cnc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a mixture of ethyl 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine-6-carboxylate (0.36 g) in tetrahydrofuran (5 ml) was added lithium aluminum hydride (48 mg) under ice-cooling, and the reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The obtained crude crystals were washed with diethyl ether to give the title compound (0.12 g, yield 37%) as colorless crystals. melting point 167-168(C. purity 98%. M+H: 390.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C@@H:18]([CH3:19])[C@H:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1COCC1>[CH2:7]([N:14]1[CH2:15][CH2:16][C@@H:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:18]1[CH3:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@H]1[C@H](OCc2ccccc2)CC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1[C@H](OCc2ccccc2)CCN1Cc1ccccc1
Temperature: 0 °C
Yield: 48.5 %

Procedure:
To a cooled (0° C.) suspension of lithium aluminium hydride (2.81 g, 74 mmol) in dry THF (30 ml) was added a solution of (4R,5S)-1-benzyl-4-benzyloxy-5-methyl-pyrrolidin-2-one (3.13 g, 11 mmol) (Tetrahedron 1998, 54, 12547) in THF (20 mL). The mixture was allowed to come to room temperature and stirred for 16 h after which lime it was cooled to 0° C. and water was cautiously added. The resulting suspension was the filtered over Hyflo, washing the salts with EtOAc. The filtrate was washed with brine, dried (Na2SO4) and concentrated. Purification by flash column chromatography (CH2Cl2:MeOH 98:2-5:95) afforded the title compound (1.5 g, 50%) as a yellow oil. MS: 282.2 (MH+).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][CH:16]([CH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[C:17]([OH:19])=O.O>ClCCCl>[CH3:26][C:23]1[S:22][C:21]2[CH2:20][CH:16]([CH3:15])[C:17](=[O:19])[C:25]=2[CH:24]=1
Reactant: Cc1ccc(CC(C)C(=O)O)s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCCl
Solvent: O
Product: Cc1cc2c(s1)CC(C)C2=O
Temperature: 140 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
Under nitrogen atmosphere, a reactor was loaded with polyphosphoric acid (72.1 g) and phosphorus pentoxide (72.1 g, 0.51 mol) was added thereto and stirred at 140° C. for 1 hour. Then, a solution of 2-methyl-3-[5-methylthiophen-2-yl]propanoic acid (43.0 g, 0.23 mol) in 1,2-dichloroethane (75 mL) was added dropwise and stirred at 100° C. for 2 hours. The reaction mixture was added to iced water (1,000 mL) with stirring and after 30 minutes, extracted with chloroform to obtain an organic layer. The organic layer was washed with an aqueous saturated sodium carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a black oil. The oil was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to obtain 2,5-dimethyl-5,6-dihydrocyclopenta[1,2-b]thiophen-4-one (32.6 g, 84.1%) as a reddish brown oil.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)S(C(F)(F)F)(=O)=O.[CH2:19]([N:22]([CH3:24])[CH3:23])[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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.[Fe+2].O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[C:20](=[CH2:21])[CH2:19][N:22]([CH3:24])[CH3:23]
Reactant: C=CCN(C)C
Reactant: O=S(=O)(Oc1ccc2ccccc2c1)C(F)(F)F
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C=C(CN(C)C)c1ccc2ccccc2c1
Yield: 64 %

Procedure:
Table 1, Entry 9. In the reaction tube were mixed 2-naphthyl triflate (0.276 g, 1.0 mmol), N-allyidimethylamine (0.426 g, 5.0 mmol), palladium acetate (0.00673 g, 0.030 mmol), DPPF (0.0366 g, 0.066 mmol), potassium carbonate (0.207 g, 1.5 mmol) and 1.0 ml acetonitrile.under nitrogen. The contents of the flask were irradiated for 5.00 min with an effect of 50 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml diethyl ether. The combined extracts were washed two times with 25 ml saline and concentrated to an oil. The crude product was purified by repeated Kugelrohr distillation. The yield was 64% (clear oil).
Reaction SMILES: CC(OC(=O)[NH:7][C@@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]([OH:15])[C:10]([NH:12][CH2:13][CH3:14])=[O:11])(C)C.[ClH:24].O1CCOCC1>>[ClH:24].[NH2:7][C@@H:8]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]([OH:15])[C:10]([NH:12][CH2:13][CH3:14])=[O:11]
Reactant: CCNC(=O)C(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)C(O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
((1S)-1-benzyl-3-ethylamino-2-hydroxy-3-oxopropyl)carbamic acid 1,1-dimethylethyl ester (5.5 g, 17 mmol) was dissolved in 4N hydrochloric acid/dioxane solution (65 mL), and the solution was stirred at room temperature for 3 hours. This solution was concentrated in vacuo to quantitatively yield the title compound (4.4 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)=O)[CH3:2].Cl.[Cl:22][C:23]1[CH:24]=[C:25]([NH:29][NH2:30])[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=3)=[CH:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:20])=[N:30]2)[CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccc(OC)c(OC)c2)n(-c2cccc(Cl)c2)n1
Yield: 74 %

Procedure:
Starting from 1 g (3.57 mmol) of 4-(3,4-dimethoxyphenyl)-2,4-dioxobutanoic acid ethyl ester from example 12A and 868.8 mg (4.85 mmol) of 3-chlorophenylhydrazine hydrochloride, 1.03 g (2.7 mmol, 74% yield of theory) of product are obtained according to the method described in example 4A and after purification by preparative HPLC.
Reaction SMILES: C1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13](=[CH2:23])[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=O)C=CC=CC=1.C(O)CC.O.[NH2:29][NH2:30]>CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=3)[CH2:23][NH:30][N:29]=2)=[CH:17][CH:18]=1
Reactant: NN
Reactant: C=C(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1
Solvent: CCCO
Solvent: O
Solvent: CO
Product: Clc1ccc(C2=NNCC2c2ccccc2)cc1

Procedure:
In a 500 ml round bottomed flask equipped with a reflux condensor was mixed 98 g of 2-phenyl 4'-chlorophenyl acrylophenone (0.40 mole), 200 ml n-propanol, and 50 ml hydrazine monohydrate (1.0 mole). The mixture was refluxed for 1 hour, cooled slightly and 100 ml of methanol added. The resulting solution was cooled in an ice bath and the resulting solid filtered and washed twice with cold ethyl ether yielding 55 g of a white solid. mp 156°-162° C. NMR data was consistent with the structure.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[CH:4]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:4]=1)=[O:22]
Reactant: COc1ccccc1CC(=O)c1c[nH]c2ccccc12
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCn1cc(C(=O)Cc2ccccc2OC)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
60% Sodium hydride in mineral oil (1.8 g, 45.23 mmol) was suspended in dimethylformamide (100 ml) and 1-(1H-indol-3-yl)-2-(2-methoxyphenyl)ethanone 3 (10 g, 37.70 mmol) was added portionwise at room temperature, allowing to stir further 45 min at room temperature after the addition was finished. 1-Bromopentane (7.02 ml, 56.55 mmol) was added dropwise at room temperature and the reaction mixture was stirred at room temperature overnight. Water (200 ml) was added and the mixture was extracted three times with ethyl acetate (3×200 ml). The organic fractions were combined, washed with water (200 ml) and brine (200 ml) and dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (Biotage Isolera 4, SNAP-100 g, 5%-20% ethyl acetate hexane containing 5% dichloromethane) to give 6.2 g (41%) of 2-(2-methoxyphenyl)-1-(1-pentyl-1H-indol-3-yl)ethanone (JWH-250) 4 as an orange/tan solid.