Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)CCCCC1.C(N)CN.O.[CH:13]1([NH:19][CH2:20][CH2:21][NH:22]C2CCCCC2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>[Pt]>[CH:13]1([NH:19][CH2:20][CH2:21][NH2:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCC(NCCNC2CCCCC2)CC1
Agent: [Pt]
Solvent: NCCN
Solvent: O=C1CCCCC1
Solvent: O
Product: NCCNC1CCCCC1
Reaction time: 7 h
Yield: 95 %

Procedure:
To a 850 cc glass liner for a rotating autoclave was charged 12.25 g (0.125 mole) cyclohexanone, 3.7 g of a catalyst consisting of 0.3 weight percent platinum (sulfided) on alpha alumina, and an 80 weight percent solution of ethylenediamine in de-ionized water (37.5 g (0.63 mole) ethylenediamine and 9.37 g (0.52 mole) water). An exotherm was generated immediately associated with the formation of Schiff bases from the reaction of cyclohexanone and ethylenediamine. The liner was placed into a rotating autoclave, purged with nitrogen, charged to 1,000 psig with hydrogen or 500 psig each of hydrogen and nitrogen, and then the autoclave was rotated at approximately 30 rpm for 6-8 hours at 160°-180° C. The cooled liner was vented, flushed with nitrogen to avoid catalyst ignition, and the cooled product mixture was removed to afford a clear to pale yellow viscous liquid containing some solids which were principally N,N'-dicylohexyl ethylenediamine (DICEDA). The product mixture was filtered through diatomaceous earth to remove catalyst and DICEDA, and the resulting filtrate contained, in addition to unreacted ethylenediamine, CEDA with only traces of DICEDA. The liner and filter cake were rinsed with methanol and subsequent removal of volatile material at 80° C. afforded product which was principally DICEDA. Removal of volatiles at 80° C. at 30 inches vacuum afforded 15 grams CEDA. Conversion of cyclohexanone amounted to 99+% with a 95% yield of CEDA and 5% DICEDA.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][C:8](O)=[O:9])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:5][CH:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:7][CH2:8][OH:9]
Reactant: CNC(=O)CC(CC(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCCC(CCO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A suspension of 4-(N-methylcarbamoyl)-3-phenylbutyric acid (250 mg, 1.13 mmol) in 5.0 mL of THF was stirred in an ice bath as a 1.0 M solution of LAH (4.5 mL, 4.5 mmol) in THF was added dropwise over 10 min. The mixture was stirred 1 h at room temperature followed by 3 h at reflux. The reaction was then cooled in the ice bath and quenched with 0.70 mL of saturated aqueous Rochelle salt. The resulting precipitate was filtered and washed with 100 mL of ethyl acetate, and the combined filtrates were concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 10-15% methanol in dichloromethane containing 1% ammonium hydroxide, to give 151 mg of the title compound as a viscous oil. 1NMR (400 MHz, CD3OD): δ 7.32-7.26 (m, 2H), 7.22-7.16 (m, 3H), 3.45-3.32 (m, 2H). 2.80-2.70 (m, 1H), 2.44 (ddd, 1H, J=12, 10, 6 Hz), 2.32 (ddd, 1H, J=12, 10, 6 Hz), 2.28 (s, 3H), 1.94-1.74 (m, 4H). Mass spectrum (NH3 /CI): m/z=194 (M+1).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12].[Cl:14][CH2:15][C:16](Cl)=[O:17]>CC#N.CO>[Cl:14][CH2:15][C:16]([NH:8][CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: NC[C@@H](O)CO
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CO
Product: O=C(CCl)NC[C@@H](O)CO
Reaction time: 16 h
Yield: 77.6 %

Procedure:
Triethylamine (1.83 mL, 13.2 mmol) was added to a solution of (R)-3-amino-1,2-propanediol (1.00 g, 11.0 mmol) in a mixture CH3CN/MeOH (36 mL/16 mL) at −10° C. under nitrogen. Chloroacetyl chloride (0.98 ml, 12.0 mmol) was added dropwise at −10° C. over 30 min. The reaction mixture was allowed to reach room temperature and stirred for 16 h. The mixture was concentrated and purified by flash column chromatography on silica gel, eluting with methanol/ethyl acetate (8/92), to give the title compound as a white solid (1.43 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:10]2=[O:27])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:42])[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.C(OCC)(=O)C>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([N:11]2[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:34](=[O:42])[O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:7]=3)[C:10]2=[O:27])=[CH:22][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)n3)C(C)(C)C2=O)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)Oc4ccccc4)n3)C(C)(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of 100 mg of 1-[(2-aminopyrimidin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione obtained in stage f) of Example 1, in 3 mL of tetrahydrofuran, are added, at 0° C., 0.034 mL of pyridine and 0.045 mL of phenyl chlorocarbonate. The reaction mixture is stirred for 4.5 hours at room temperature and then diluted with ethyl acetate and washed with twice 30 mL of aqueous 1N hydrochloric acid solution, then with twice 30 mL of water, with twice 30 mL of saturated aqueous sodium hydrogen carbonate solution and finally with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with an ethyl acetate/cyclohexane mixture (62/38 by volume) to give 70 mg of phenyl (4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyrimidin-2-yl)carbamate in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C([O-])(=[S:15])C.C(O)(=S)C>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][SH:15]
Reactant: CC([O-])=S
Reactant: C=CCCCCCCCCCBr
Agent: CC(O)=S
Solvent: Cc1ccccc1
Product: SCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 6 h

Procedure:
11-Bromo-1-undecanethiol was synthesized in two steps (see FIG. 11). First, 11-bromo-1-undecene (5.0 g) was converted to a thioacetate by reacting with AiBN (1.5 g) and thioacetic acid (10 mL) in toluene (50 mL). The reaction was run under Ar and refluxed for 2 h. The solution was washed with excess water and the toluene removed by rotary evaporation. The thioacetate was converted into a thiol by exposing the 11-bromo-1-undecanethioacetate to dry HCI. Acetyl chloride (6 mL) was added dropwise to dry methanol in an ice bath under Ar. The solution was allowed to warm to room temperature and the reaction progressed for approximately 6 h. Methylene chloride and water were added and the methylene chloride layer was washed several times with water. The solvent was removed by rotary evaporation.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].ClCCl.[CH3:41][N:42]([CH:44]=O)C>C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:31])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:21]3[CH:20]=[C:44]4[C:14]([C:12]([CH3:13])=[N:8][N:42]4[CH3:41])=[CH:23][CH:22]=3)[C:3]=12
Reactant: CN(C)C=O
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1nn(C)c2cc(-c3nn(C(C)c4oc5ccccc5c(=O)c4-c4cccc(F)c4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 17 %

Procedure:
To a solution of Example 57c (0.400 g, 0.758 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), intermediate 115 (0.309 g, 1.137 mmoles) and sodium carbonate (0.241 g, 2.27 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.043 g, 0.037 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.071 g, 17% yield). MP: 270-272° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.08 (s, 1H), 8.04 (d, J=6.8 Hz, 1H), 7.84 (m, 2H), 7.69 (s, 1H), 7.69 (d, J=10.8 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.03-6.95 (m, 3H), 6.06 (q, J=7.1 Hz, 1H), 3.99 (s, 3H), 2.48 (s, 3H), 1.92 (d, J=7.0 Hz, 3H). Mass: 546.24 (M++1).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[Cl:14]N(C(C)C)C(C)C>>[Cl:14][CH:5]([CH3:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: CC(C)N(Cl)C(C)C
Reactant: CCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: CC(Cl)CCCC(=O)O

Procedure:
144 parts by mass of the obtained caproic acid were added to 1,000 parts by mass of 84% sulfuric acid and an equivalent amount of N-chlorodiisopropylamine and were reacted for 5 hours at 25° C. to obtain 173 parts by mass of 5-chlorocaproic acid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[F:5][C:6]1([F:24])[O:11][C:10]2[CH:12]=[C:13]([F:19])[C:14]([N:16]=[C:17]=[S:18])=[CH:15][C:9]=2[N:8]([CH2:20][C:21]#[CH:22])[C:7]1=[O:23]>ClCCl>[CH2:1]([NH:4][C:17]([NH:16][C:14]1[C:13]([F:19])=[CH:12][C:10]2[O:11][C:6]([F:24])([F:5])[C:7](=[O:23])[N:8]([CH2:20][C:21]#[CH:22])[C:9]=2[CH:15]=1)=[S:18])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(N=C=S)cc21
Solvent: ClCCl
Product: C#CCN1C(=O)C(F)(F)Oc2cc(F)c(NC(=S)NCCC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Propan-1-amine (0.937 ml, 11.74 mmol) was added to a stirred solution of 2,2,7-trifluoro-6-isothiocyanato-4-(prop-2-ynyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (the product of Step 4.1 above, 1.0 g, 3.35 mmol) in dichloromethane (10 ml) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 1 hour, by which time TLC analysis indicated that the reaction was complete. The reaction mixture was evaporated in vacuo to yield 1.3 g of the desired product (purity>95%), which was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([CH3:28])[CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C>C(O)C>[CH3:28][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])[C:24]=1[N+:25]([O-:27])=[O:26]
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccnc(Nc2ccc3[nH]cc(CC4CCCN4C)c3c2)c1[N+](=O)[O-]
Yield: 34 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 2-chloro-4-methyl-3-nitropyridine were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 24 hours. Column chromatography afforded the title compound (34%) as a red amorphous solid: 1H NMR (CDCl3) δ9.26 (brs, NH),8.79 (brs, NH),8.10 (d,J=4.8 Hz, 1H), 7.64(d,J=1.7 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.17 (dd, J=8.5 and 1.9 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.56 (d, J=4.8 Hz, 1H), 3.25-3.16 (m, 2H), 2.67 (dd, J=13.2 and 9.4 Hz, 1H), 2.64-2.56 (m, 1H), 2.56 (s, 3H), 2.46 (s, 3H), 2.30 (dd, J=17.7 and 9.4 Hz, 1H), 1.90-1.60 (m, 4H); 13C NMR (CDCl3) δ152.2, 151.5, 146.6, 134.3, 131.0, 130.0, 127.9, 123.4, 119.4, 117.1, 114.0, 113.3, 111.6, 67.0, 57.4, 40.7, 31.4, 29.5, 21.8, 21.7; FAB HRMS calculated for [C20H23N5O2.H]366.1932, found 366.1957.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C[C:23]([N:25](C)C)=O.Cl[C:29]1[N:37]=[C:36]2[C:32]([N:33]=[CH:34][N:35]2[CH3:38])=[C:31]([C:39]2[CH:44]=[CH:43][C:42]([O:45]CC3C=CC(OC)=CC=3)=[C:41]([C:55]([F:58])([F:57])[F:56])[CH:40]=2)[N:30]=1>[Zn].[C-]#N.[Zn+2].[C-]#N.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.O>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([C:31]2[N:30]=[C:29]([C:23]#[N:25])[N:37]=[C:36]3[C:32]=2[N:33]=[CH:34][N:35]3[CH3:38])=[CH:40][C:41]=1[C:55]([F:56])([F:57])[F:58]
Reactant: CC(=O)N(C)C
Reactant: COc1ccc(COc2ccc(-c3nc(Cl)nc4c3ncn4C)cc2C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: Cn1cnc2c(-c3ccc(O)c(C(F)(F)F)c3)nc(C#N)nc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Zinc (64 mg), 2-(di-tert-butylphosphino)biphenyl (163 mg), zinc cyanide (230 mg), and palladium (II) trifluoroacetate (81 mg) were added to a DMAc (16.5 mL) solution of 2-chloro-6-{4-[(4-methoxybenzyl)oxy]-3-(trifluoromethyl)phenyl}-9-methyl-9H-purine (1.1 g) at room temperature in an argon atmosphere, and the mixture was stirred at 100° C. for 3 hours. After the reaction mixture was cooled to room temperature, water was added thereto, then extraction thereof was performed using EtOAc, and the extract was washed with water. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=1:1 to 1:4), whereby a mixture of 6-{4-[(4-methoxybenzyl)oxy]-3-(trifluoromethyl)phenyl}-9-methyl-9H-purine-2-carbonitrile and 6-[4-hydroxy-3-(trifluoromethyl)phenyl]-9-methyl-9H-purine-2-carbonitrile (502 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH:27]=3)=[N:20][CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>ClCCl>[CH3:31][S:28]([N:25]1[CH2:24][CH:23]=[C:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:21][N:20]=2)[CH2:27][CH2:26]1)(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)nc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)N1CC=C(c2ccc(OCC3CCNCC3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 3-necked flask with a mechanical stirrer is added 4-(1′-methanesulfonyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-5-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (407 g, 0.90 mol) and 6N aq hydrogen chloride (2000 mL, 12.0 mol) is added dropwise at 25° C. The mixture is stirred mechanically at 25° C. for 0.5 h. 1000 mL of dichloromethane are added at 25° C. and the mixture is stirred for 20˜30 min. Layers are separated and aqueous NaOH (1500 mL, 11.6 mol) is added dropwise to the aqueous solution to pH=9˜10 at 25° C. 3200 mL of dichloromethane are added and the mixture is stirred at 25˜30° C. for 40 min. Aqueous solution of NaOH (300 mL, 2.3 mol) is added dropwise to pH >14, until complete dissolution of the solid, the solution is stirred for 20 to 30 min and layers are separated. The aqueous layer is extracted with 1700 mL of dichloromethane. The combined organic layers are washed with 900 mL of water and concentrated. The residue is used for the next step without further purification.
Reaction SMILES: [N+]([O-])(O[C@@H]1C2[C@](C)(CCCC2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C24OCCOC2(OCCO4)C3)C1)=O.[N+:32]([O-:56])([O:34][C@@H:35]1[CH:52]2[C@:47]([CH3:54])([CH2:48][CH2:49][C:50](=[O:53])[CH2:51]2)[C@@H:46]2[C@H:37]([C@H:38]3[C@@:42]([CH2:44][CH2:45]2)([CH3:43])[C:41](=[O:55])[CH2:40][CH2:39]3)[CH2:36]1)=[O:33]>>[N+:32]([O-:56])([O:34][C@H:35]1[CH:52]2[C@:47]([CH3:54])([CH2:48][CH2:49][C:50](=[O:53])[CH2:51]2)[C@@H:46]2[C@H:37]([C@H:38]3[C@@:42]([CH2:44][CH2:45]2)([CH3:43])[C:41](=[O:55])[CH2:40][CH2:39]3)[CH2:36]1)=[O:33]
Reactant: C[C@]12CCC(=O)CC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12CCCCC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
Prepared in 75% yield from 3,3:17,17-bis(ethylendioxy)androstane-6α-yl nitrate following the procedure described above for the preparation of 3,17-dioxoandrostane-6α-yl nitrate (II-aa, Prepn 1). The crude product was purified by flash chromatography (SiO2, cyclo-hexane/acetone/CH2Cl2 70/15/15) to give II-ab. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.24 (ddd, 1H), 2.72 (dd, 1H), 2.57-0.96 (m, 19H), 1.25 (s, 3H), 0.90 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[H-].[Na+].[CH3:12]I>C1COCC1>[Cl:9][C:3]1[C:2]([NH:1][CH3:12])=[C:7]([Cl:8])[N:6]=[CH:5][N:4]=1
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1c(Cl)ncnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
Add 5-amino-4,6-dichloropyrimidine (2 g; 0.012 mol) to THF (60 mL). Cool to 0° C. and add portion-wise NaH (0.53 g; 0.013 mol). Stir at 0° C. for 30 min. Add drop-wise methyl iodide (0.7 mL, 0.012 mol). Stir at 0° C. for 1 h and then RT for 30 min. Quench with saturated ammonium chloride aqueous and extract with EA. Evaporate the organic layer and purify the residue through a silica gel column using acetone and hexane as eluent to give the title compound (0.6 g; 27.64%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[N:2]1.[NH2:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16].N1C=CC=CC=1>CC#N.CN(C1C=CN=CC=1)C>[C:15]([C:14]1[CH:13]=[CH:12][S:11][C:10]=1[NH:9][C:6]([C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:7])(=[O:16])[NH2:17]
Reactant: NC(=O)c1ccsc1N
Reactant: O=C(Cl)c1cc[nH]n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC#N
Product: NC(=O)c1ccsc1NC(=O)c1cc[nH]n1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A solution of 1H-Pyrazole-3-carbonyl chloride (5 mmol) in MeCN (5 mL) is added drop wise to a solution of 2-amino-thiophene-3-carboxylic acid amide (570 mg, 4 mmol), pyridine (0.5 mL, 6 mmol) and DMAP (25 mg, 0.20 mmol) in MeCN (5 mL). The resulting solution is than stirred at 60° C. over 2 days. Next, the mixture is quenched with aqueous NaHCO3. Evaporation of the MeCN gives a suspension that is filtered, the cake is dried, and used as such.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1I.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]([F:9])([F:20])[F:19])=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccccc1I
Reactant: Sc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccccc1Sc1ccc(Br)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 2-(trifluoromethoxy)iodobenzene (0.73 g, 2.53 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-bromo-4-(2-(trifluoromethoxy)phenylsulfanyl)benzene (0.72 g) as a solid.
Reaction SMILES: C1C=CC=CC=1.[OH:7][CH:8]1[CH:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[CH:10]=[CH:9]1.[Al]>CC(C)=O>[O:7]=[C:8]1[CH:12]([CH2:13][CH:14]=[CH2:15])[C:11](=[O:16])[CH:10]=[CH:9]1
Reactant: C=CCC1C(=O)C=CC1O
Agent: [Al]
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: C=CCC1C(=O)C=CC1=O
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Into a mixture of 150 ml of dried benzene and 100 ml of acetone, was dissolved 1.5 g of 4-hydroxy-5-allyl-2-cyclopentenone. After adding 3 g of freshly distilled aluminum isoproproxide, the mixture was heated under reflux for 12 hours. The reaction mixture was cooled to room temperature, washed twice with 30% sulfuric acid, then with water until the washings had become neutral. After drying over anhydrous sodium sulfate, the mixture was stripped of the solvent by distillation and the residue was distilled in vacuo to obtain 1.2 g (81% yield) of 4-keto-5-allyl-2-cyclopentenone boiling at 53° C./4 mmHg.
Reaction SMILES: [CH3:1][C:2]1([CH:7]([CH3:19])[C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])OCC[O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:19][CH:7]([C:2](=[O:3])[CH3:1])[C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9]
Reactant: CC(C(=O)NCCc1ccccc1)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)C(C)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
2-(2-Methyl-[1,3]dioxolan-2-yl)-N-phenethyl-propionamide of Example 1c (0.40 g, 1.5 mmol) was added to p-toluenesulfonic acid monohydrate (0.48 g, 2.5 mmol) in water (20 mmol) under a nitrogen atmosphere at room temperature. Acetone (20 mL) was added, and the reaction mixture was stirred overnight at room temperature and then heated at 95° C. for 3 h. After cooling to room temperature, the solution was made basic with sodium carbonate (0.5 g). The acetone was removed at room temperature under vacuum and the remaining aqueous material was extracted with dichloromethane (50 mL). The organic layer was washed with water (50 mL), brine (50 mL) and then dried with sodium sulfate. After concentration, the product was purified by crystallization from hexanes-ethyl acetate (1:1) to give 2-methyl-3-oxo-N-phenethyl-butyramide (0.17 g, 52%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O.O.NN>CO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CO)c1
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCOc1cccc(CO)c1
Yield: 52.1 %

Procedure:
N-[3-(3-hydroxymethylphenoxy)propyl]phthalimide (16 g) was dissolved in 300 ml of methanol, and 5 g of hydrazine hydrate was added. The mixture was refluxed for 5 hours, and after cooling, the insoluble matter was removed by filtration. The filtrate was concentrated to give 4.85 g (yield 52.1%) of 3-(3-hydroxymethylphenoxy)propylamine.