Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH2:32]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:33]#[CH:34]>O1CCCC1.C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)\[C:5]2[CH:6]=[CH:7][C:2]([C:34]#[C:33][CH2:32][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:3][CH:4]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#CCN3CCOCC3)cc2)cc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of the above ester (480 mg, 0.908 mmol) in a mixture of tetrahydrofuran (5 mL) and triethylamine (5 mL) was degassed and N-propargylmorpholine (237 mg, 1.89 mmol) was added under argon atmosphere. The solution was cooled, tetrakis(triphenylphosphine)palladium (84 mg, 0.073 mmol) and copper(I) iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture was stirred at ambient temperature for 6 h and then left to stand overnight. The mixture was evaporated in vacuo; the residue was dissolved in dichloromethane (20 mL) and the formed solution was washed with water (2×10 mL). The organic solution was dried with anhydrous magnesium sulfate and subsequently evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 1:1) yielding methyl (Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]phenoxy]acetate.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:23]=[N:22][C:21]([Cl:24])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>>[ClH:24].[ClH:24].[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:23]=[N:22][C:21]([NH:27][NH2:28])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2ccc(Cl)nn2)c(OCC(O)CNC(C)(C)C)c1
Reactant: NN
Solvent: O
Product: COc1ccc(-c2ccc(NN)nn2)c(OCC(O)CNC(C)(C)C)c1
Product: Cl

Procedure:
A stirred mixture of hydrazine hydrate (30 ml) and 6-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3-chloropyridazine (2.9 g) was heated under reflux for 5 hours, and was cooled to 0°. The oil which separated out was dissolved in chloroform and this solution was washed with water, and with dilute hydrochloric acid, and evaporated to give 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-6-hydrazinopyridazine dihydrochloride, m.p. 240°-245° (methanol)
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][OH:22])[CH3:17])=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:24]1[CH:56]=[CH:55][C:27]([CH2:28][CH:29]2[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]2=[O:54])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[N:18][O:19][CH2:20][CH2:21][O:22][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][CH:29]4[S:33][C:32](=[O:34])[N:31]([C:35]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]4=[O:54])=[CH:26][CH:25]=3)[CH3:17])=[CH:12][N:11]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=NOCCO)c1ccc(S(=O)(=O)c2ccccc2)nc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(S(=O)(=O)c2ccccc2)nc1
Yield: 33.4 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 640 mg of 2-[1-(2-phenylsulfonyl-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 33), 907 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 550 mg of triphenylphosphine and 365 mg of diethyl azodicarboxylate, 500 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:10](=O)[O:9][CH2:8]2.COC1C=C(C=CC=1)C=O.C1(P(=[CH:42][C:43]([O:45][CH3:46])=[O:44])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[OH:9][CH2:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=1/[CH:10]=[CH:42]/[C:43]([O:45][CH3:46])=[O:44]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1C(=O)OC2
Agent: COc1cccc(C=O)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1c(CO)cccc1OC
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
1-Hydroxy-7-methoxy-1,3-dihgydrobenzo[c]furan (1.08 g), which was prepared with using 7-methoxyphthalide which was synthesized with using 3-methoxybenzaldehyde by the method described in Journal of Organic Chemistry, 1980, 45, 1835-1838, was dissolved in chloroform (20 ml). Methyl (triphenylphosphoranylidene)acetate (2.68 g) was added to the solution. The mixture was stirred for 40 min. at 50° C. A temperature of the reaction mixture was down to room temperature. The reaction solution was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (1.25 g) having the following physical data.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][NH:10][CH2:9]1.C(N(CC)CC)C.O>ClCCl>[C:5]([N:10]1[CH2:9][CH2:8][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCNCC2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ccccc2CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A solution of acetic anhydride (6.37 g, 0.062 mol) in dichloromethane (50 ml) was added dropwise to a stirred solution of 2,3,4,5-tetrahydro-1H-3-benzazepine (8.35 g, 0.057 mol) and triethylamine (8.7 ml) in dichloromethane (50 ml) at 0° C. under argon. After stirring at room temperature for 18 h, water (80 ml) was added and the organic layer separated. The organic layer was washed with 0.5 M hydrochloric acid (50 ml), saturated sodium bicarbonate solution (50 ml), water (50 ml) and then dried (Na2SO4). Evaporation of the solvent in vacuo gave the title compound (10.24 g, 95%) as a yellow oil which solidified on standing.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](CCCC#N)[CH:2]=1.[N:12]1C=[CH:16][C:15](CCCBr)=[CH:14][CH:13]=1>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:16][CH2:15][CH2:14][C:13]#[N:12])=[CH:5][CH:6]=1
Reactant: BrCCCc1ccncc1
Reactant: N#CCCCc1cccnc1
Product: N#CCCCc1ccncc1
Yield: 51 %

Procedure:
4-Pyridinebutanenitrile was prepared according to the procedure employed in the synthesis of 3-pyridinebutanenitrile. From 73.1 g of the hydrobromide salt of 3-(4-pyridyl)propyl bromide there was obtained 19.35 g (51%) of 4-pyridinebutanenitrile, bp 140°-141° C./2.0 mm.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][OH:7])[CH2:2][CH3:3].[C:17](OC(=O)CC)(=O)[CH2:18][CH3:19]>>[CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]([CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:6][OH:7])[CH2:2][CH3:3]
Reactant: CCCNC(CO)CCOc1ccccc1
Reactant: CCC(=O)OC(=O)CC
Product: CCCN(CCC)C(CO)CCOc1ccccc1

Procedure:
2-(propylamino)-4-phenoxy-1-butanol, described in Example 6, with propionic anhydride, followed by reduction, gives 2-(dipropylamino)-4-phenoxy-1-butanol,
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[O:8](C(OC(C)(C)C)=O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=O.C(N(CC)CC)C>CO>[C:9]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8]
Reactant: NCCCC(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
NH2—(CH2)3—COOH (5.00 g, 48.5 mmol), (BOC)2O (11.6 g, 53.4 mmol) and triethylamine (5.39 g, 53.4 mmol) were dissolved in 200 mL of methanol, and the mixture was stirred at 60° C. for 12 hours. After the reaction completed, methanol was removed under reduced pressure, and the obtained material was redissolved in 100 mL of ethyl acetate. Then, the resultant solution was subjected to separation using 0.2 mol/l HCl (twice) and water (twice), and dehydrating was carried out with anhydrous sodium sulfate. After that, recrystallization with hexane at 4° C. and collection using a glass filter (G6) were performed, thereby obtaining Boc-NH—(CH2)3—COOH (6.98 g, 34.4 mmol, yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][C:8]=2[CH3:16])[CH:6]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[N:12]=[CH:11][C:10]([CH:13]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:14])=[CH:9][C:8]=2[CH3:16])[CH:6]=1
Reactant: CC(=O)c1cnc(-n2cc(Cl)cn2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1-n1cc(Cl)cn1
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (1.08 g, colorless amorphous) from 1-(6-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)ethanone (1.30 g, 5.52 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.00 g, 8.27 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH:18][C:19]1C2N=NNC=2C=CC=1.CNC(N=C=NCC)CCNC.C(NC(C)C)(C)C>ClCCl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:19]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NC(CCNC)NC
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3 g of para-nitrobenzoic acid in 50 mL of dichloromethane are successively added under argon, at 0° C., 1.15 mL of pyrrolidine, 0.189 g of hydroxybenzotriazole, 2.3 g of 1,3-dimethylaminopropyl-3-ethylcarbodiimide and 4.98 mL of diisopropylamine. The reaction mixture is then stirred at room temperature for 15 hours and then washed with water. The organic phase is then washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (55/45 by volume) to give 2.98 g of 1-[(4-nitrophenyl)acetyl]pyrrolidine, the characteristics of which are as follows:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[CH2:16][CH2:17][F:18].[H-].[Na+]>CN(C=O)C.CCOC(C)=O.O>[F:18][CH2:17][CH2:16][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(CCF)CC1
Temperature: 50 °C
Yield: 85.3 %

Procedure:
To a stirred mixture of tert-butyl piperidin-4-ylcarbamate (1.00 g, 5.0 mmol) and 1-bromo-2-fluoroethane (0.952 g, 7.50 mmol) in DMF (10 mL) was added NaH (0.180 g, 7.50 mmol) at ambient temperature. The mixture was heated to 50° C. for 18 hours under N2. After cooling to ambient temperature, the mixture was diluted with EtOAc and water. The phases were separated, and the organic phase was washed with water, brine, dried (Na2SO4), filtered, and concentrated. The product was obtained as a waxy solid (1.05 g, 84%).
Reaction SMILES: [C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][O:9][CH:10]=[C:6]2[CH2:5]1)([OH:3])=[O:2].[CH3:12]OC(OC)(C)C.S(=O)(=O)(O)O>CO>[C:1]([CH:4]1[CH2:11][C:7]2=[CH:8][O:9][CH:10]=[C:6]2[CH2:5]1)([O:3][CH3:12])=[O:2]
Reactant: O=C(O)C1Cc2cocc2C1
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)C1Cc2cocc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dissolve 5-(carboxy)-2,4,5,6-tetrahydro-cyclopenta[c]furan (3.6 g, 23.5 mmol) in methanol (60 mL) and treat with dimethoxypropane (5.8 mL, 47 mmol) and sulfuric acid (0.8 mL). Stir at room temperature for 1 day. Evaporate the solvent in vacuo, dilute with methylene chloride (75 mL) and wash with saturated sodium hydrogen carbonate (35 mL). Extract the aqueous phase with methylene chloride (30 mL), wash combined organics with brine (30 mL) and dry (Na2SO4). Evaporate the solvent in vacuo and pass through a plug of silica gel to give 5-(carbomethoxy)-2,4,5,6-tetrahydrocyclopenta[c]furan.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(C(C)(C)C)cc2)CC1
Yield: 34 %

Procedure:
To 1-bromo-4-tert-butyl-benzene (639 mg; 3.0 mmol), [1,4]diazepane-1-carboxylic acid tert-butyl ester (500 mg; 2.5 mmol), tris-(dibenzylidenacetone)-dipalladium (0) (45 mg; 0.049 mmol), sodium tert-butoxide (360 mg; 3.75 mmol) and (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (92 mg; 0.147 mmol) is added toluene (5 mL) and the resulting mixture is irradiated in a mono-mode microwave oven for 2 hours at 100° C. Further tris-(dibenzylidenacetone)-dipalladium (0) (45 mg; 0.049 mmol) and (±)-2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (92 mg; 0.147 mmol) are added and microwave irradiation at 120° C. is continued for another hour. The reaction mixture is then diluted with ethyl acetate and filtered. The filtrate is concentrated under high vacuum and the obtained residue is purified by column chromatography on silica gel (hexanes/dichloromethane 50:50 v/v to 100) to afford the desired compound (284 mg; 0.85 mmol).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[CH:23]=[C:22]([C:24]5[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=5)[NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1.C(N(CC)C(C)C)(C)C.[C:39]([N:43]=[C:44]=[O:45])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([NH:43][C:44]([N:27]1[CH2:26][CH:25]=[C:24]([C:22]2[NH:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([NH:14][C:10]4[CH:9]=[C:8]5[C:13](=[CH:12][CH:11]=4)[N:5]([CH3:4])[N:6]=[CH:7]5)[C:16]=3[CH:23]=2)[CH2:29][CH2:28]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCNCC5)cc34)ccc21
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc2cc(Nc3ncnc4[nH]c(C5=CCN(C(=O)NC(C)(C)C)CC5)cc34)ccc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suspension of (1-methyl-1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (166.8 mg, 0.3631 mmol, 1 eq) in anhydrous DMF (17 mL), N,N-diisopropylethylamine (DiPEA) (260 μL, 4.1 eq) was added at rt. The solution was then cooled to −20° C., after which tert-butyl isocyanate (36.5 mg, 0.368 mmol, 1 eq in anhydrous DMF (2 mL) was added. The solution was stirred at rt for 1 h. The reaction was cooled to 0° C., after which additional tert-butyl isocyanate (11.4 mg, 0.115 mmol, 0.3 eq) in anhydrous DMF (1 mL) was added. The reaction was stirred again at rt for 4 h. The reaction was quenched with MeOH, concentrated in vacuo, and dried under vacuum pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with MeOH:DCM 1%→5%]. Fractions containing product were combined and concentrated in vacuo. The material was further purified by trituration in MeOH, yielding the title compound as an off-white solid. 1H NMR (400 MHz, DMSOd6): δ=1.28 (s, 9H), 2.44 (s, br, 2H), 3.52 (t, J=5.6 Hz, 2H), 3.99 (d, J=2.0 Hz, 2H), 4.03 (s, 3H), 5.77 (s, —NH), 6.40 (s, br, 1H), 6.75 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.69 (dd, J=8.8, 2.0 Hz, 1H), 8.01 (s, 1H), 8.26 (s, 1H), 8.39 (s, 1H), 9.32 (s, —NH), 11.89 (s, —NH). MS (ES+): m/z 445.07 (100) [MH+]. HPLC: tR=2.29 min (ZQ2000, polar—5 min).
Reaction SMILES: Br[CH:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[N-:23]=[N+]=[N-].[Na+]>CN(C)C=O.O>[NH2:23][C:18]1[C:17](=[O:20])[CH2:16][CH2:15][C@@:14]2([CH3:21])[C:19]=1[CH:2]=[CH:3][C@@H:4]1[C@@H:13]2[CH2:12][CH2:11][C@@:9]2([CH3:10])[C@H:5]1[CH2:6][CH2:7][C:8]2=[O:22]
Reactant: C[C@]12CCC(=O)C=C1C(Br)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 100 °C
Yield: 36 %

Procedure:
To a stirred solution of 1.1 g of 6-bromoandrost-4-en-3,17-dione in 57.4 ml of dimethylformamide are added 0.250 g of sodium azide dissolved in 2 ml of water. The resulting mixture is heated at 100° C. for 90 minutes, cooled and worked up as described in the example 1. There are obtained 0.325 g of the title compound, m.p. 148°-150° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C:10]([C:18]#[N:19])=[C:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([CH3:24])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:8][C:9]([C:10]1([C:18]#[N:19])[CH2:24][C:11]1([CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH3:17])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: CCCC(CCC)=C(C#N)C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC1(CCC)CC1(C#N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a solution of 2-cyano-3-propyl-hex-2-enoic acid benzyl ester (0.91 g, 3.35 mmol) in 50 mL acetonitrile was added nitromethane (0.91 mL, 16.77 mmol), followed by DBU (0.50 mL, 3.35 mmol) resulting in an orange solution. The reaction was stirred at room temperature for 16 hours, then partitioned between Et2O and 1N HCl (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (5→10% EtOAc/hexanes) afforded 0.71 g (81%) of 1-cyano-2,2-dipropyl-cyclopropanecarboxylic acid benzyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.21 (dd, J=18.3, 12.4 Hz, 2H), 1.79 (d, J=5.1 Hz, 1H), 1.74 (m, 1H), 1.52 (m, 3H), 1.43 (d, J=5.1 Hz, 1H), 1.36 (m, 3H), 1.04 (m, 1H), 0.95 (t, J=7.1 Hz, 3H), 0.73 (t, J=7.1 Hz, 3H). 13C NMR δ 166.40, 135.22, 128.81, 128.69, 128.48, 118.60, 68.23, 41.26, 36.45, 30.27, 29.76, 24.91, 19.74, 19.65, 14.22, 14.10. IR (neat) 2240, 1734 cm−1. Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C, 75.38; H, 8.02; N, 4.97.
Reaction SMILES: [C:1]1([CH:7]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([NH:19][C@@H:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3O)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:26]2[O:32][C@H:31]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[C@@H:29]([OH:30])[C@H:27]2[OH:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1N=C2C(NC=N2)=CN=1>>[CH:20]1([NH:19][C:17]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[C@@H:26]3[O:32][C@H:31]([C:33]([NH:35][CH2:36][CH3:37])=[O:34])[C@@H:29]([OH:30])[C@H:27]3[OH:28])=[C:10]([NH:9][CH2:8][CH:7]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:18]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N[C@@H]4CCC[C@H]4O)nc32)[C@H](O)[C@@H]1O
Agent: Clc1ncc2[nH]cnc2n1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NC4CCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
(1R-trans)-1-deoxy-1-[6-[(2,2-diphenylethyl)amino]-2-[(2-hydroxycyclopentyl)amino]-9H-purin-9-yl]-N-ethyl-β-D-ribofuranuronamide, from the 2-chloropurine (0.35 g) and (R)-(trans)-2-aminocyclopentanol1 (1.0 g) at 130° C. for 10h. The product was purified on silica eluting with ethyl acetate:methanol 19:1 and then on silica eluting with dichloromethane:methanol:0.880 ammonia (100:8:1). The product had m.p. 122 to 130° C. Analysis found C,62.6, H,6.2, N,16.2%; C31H37N7O5.0.4H2O requires C,62.6, H,6.4, N,16.5%.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:26])[CH2:17][CH2:18]2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.CC(=O)CC.O>[C:1]([O:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)O[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
—Aluminium isopropoxide (18.1 g) was added to a solution of (3β,20S)-pregn-5-ene-3,20-diol 20-acetate (21.9 g) in dry toluene (252 ml) and dry 2-butanone (156 ml). The mixture was heated under reflux for 2 hours, then cooled, whereupon a solution of potassium sodium tartrate tetrahydrate (91.4 g) in water (90 ml) was added. The mixture was stirred for 30 min. and filtered. The filtrate was poured into brine and the product extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded (20S)-20-(acetyloxy)pregn-4-en-3-one (compound 6a; 17.9 g).