Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])[CH2:7][O:8]C(=O)C)(=[O:3])[NH2:2].C(OC[C@@H](C1C=CC=CC=1)COC(=O)C)(=O)N>>[C:1]([O:4][CH2:5][C@@H:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])[CH2:7][OH:8])(=[O:3])[NH2:2]
Reactant: COc1ccc([C@@H](COC(C)=O)COC(N)=O)c(OC)c1
Agent: CC(=O)OC[C@@H](COC(N)=O)c1ccccc1
Product: COc1ccc([C@@H](CO)COC(N)=O)c(OC)c1
Yield: 65.3 %

Procedure:
The title compound was synthesized in a similar manner to that of Example XXII, except that (S)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol carbamate, instead of (S)-3-acetoxy-2-phenylpropanol carbamate, was used as a starting material. Yield 65.3%. Purity 99.2%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[O:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH:53]([NH2:61])[CH2:52]1.C(N(CC)CC)C>ClCCCl>[O:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH:53]([NH:61][C:18]([C:17]2[CH:21]=[CH:22][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:15][CH:16]=2)=[O:20])[CH2:52]1
Reactant: NC1COc2ccccc2C1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4COc5ccccc5C4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.4 %

Procedure:
A mixture of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (0.0308 g, 0.0871 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.01838 g, 0.0958 mmol), 1-hydroxybenzotriazole monohydrate (0.0146 g, 0.095 mmol), and 1,2-dichloroethane (1 ml) was stirred at ambient temperature for 20 minutes. A mixture of chroman-3-amine hydrochloride (0.01780 g, 0.09589 mmol), triethylamine (0.06075 ml, 0.435 mmol), and 1,2-dichloroethane (1 ml) was added to the activated acid and the mixture was stirred for 17 hours at ambient temperature. The crude mixture was purified on silica gel (MeOH in dichloromethane gradient) to provide 27.6 mg of the title compound as a foamy film (65%)
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH2:18][CH2:19][NH:20][C:2]2[N:10]=[C:9]3[C:5]([NH:6][CH:7]=[N:8]3)=[C:4]([NH2:11])[N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCc1ccccc1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Product: Nc1nc(NCCc2ccccc2)nc2nc[nH]c12

Procedure:
The starting material 2-(2-phenylethylamino)-adenine is prepared by reacting 2-chloroadenine with excess 2-phenylethylamine at about 140°.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[O:16])=[CH:10][CH:9]=1)=[O:4].[CH2:18]([OH:21])[CH2:19][OH:20]>O>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:20][CH2:19][CH2:18][OH:21])=[O:16])=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)COC(=O)c1ccc(N=C=O)cc1
Reactant: OCCO
Solvent: O
Product: COC(=O)COC(=O)c1ccc(NC(=O)OCCO)cc1
Reaction time: 6 h

Procedure:
4-Isocyanato-benzoic acid methoxycarbonylmethyl ester 9 (5 grams, 21.09 mmol) is added to ethylene glycol (20 mL) at room temperature and stirred for 6 hours. Water (100 mL) is added, and crude 10 is filtered, dried, and purified by a suitable method.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[C:14]2=[O:19].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[C:25]([F:31])[CH:24]=1.O>CN(C)C=O.ClC1C=CC=CC=1.O1CCCC1>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]([F:7])([F:20])[F:21])[C:14](=[O:19])[C:15]2=[O:18])=[C:25]([F:31])[CH:24]=1
Reactant: O=C1Nc2c(cccc2C(F)(F)F)C1=O
Reactant: Fc1cc(Br)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccc(Br)cc2F)c2c1cccc2C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous potassium carbonate (10.7 g.) and 7-trifluoromethyl indoline-2,3-dione (14.4 g.) were stirred in N,N-dimethylformamide (DMF) (100 ml.) for 30 minutes. A portion (78.9 ml.) of a 25% w/v solution of 4-bromo-2-fluorobenzyl bromide in chlorobenzene was then added and the mixture was stirred at 75°-78° C. for 2 hours. The mixture was then cooled to ambient temperature and poured into water (400 ml.). Petrol 60-80 (200 ml.) was added to the aqueous mixture and the whole was stirred for 30 minutes. The solid which formed was separated by filtration to give 1-(4-bromo-2-fluorobenzyl)-7-trifluoromethyl indoline-2,3-dione (17.8 g.), m.p. 141°-143° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:12][C:13]([F:16])([F:15])[F:14])=[C:7]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)[N:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[F:21][C:18]([F:19])([F:20])[CH2:17][N:11]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(N(CC(F)(F)F)CC(F)(F)F)c(OCC2CC2)n1

Procedure:
A solution of 5-(bis(2,2,2-trifluoroethyl)amino)-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (60 mg, 0.16 mmol) and sodium hydroxide (9 mg, 0.23 mmol) in ethanol (20 mL) was reacted for 2 h at 90° C. The reaction mixture was concentrated under reduced pressure, dissolved in water and extracted with ethyl acetate (10 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid; the aqueous layer was extracted with ethyl acetate (3×10 mL), washed with brine (2×10 mL), dried over Na2SO4 and evaporated to dryness (0.03 g, crude). The crude product was used for next step without further purification; MS: m/e=373.1 [M+H]+.
Reaction SMILES: OCC(CO)(CO)CO.N1C=CC=CC=1.CN(C=O)C.[CH3:21][CH:22]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:51])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:23][CH2:24][CH2:25][C:26](OC[C@@H]([C@@H](CO)O)O)=[O:27].C(Cl)[Cl:53]>>[CH3:21][CH:22]([CH2:36][CH2:37][CH2:38][CH:39]([CH3:51])[CH2:40][CH2:41][CH2:42][CH:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:23][CH2:24][CH2:25][C:26]([Cl:53])=[O:27]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCC(=O)OC[C@H](O)[C@H](O)CO
Reactant: ClCCl
Agent: OCC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCC(=O)Cl
Temperature: 25 °C

Procedure:
Pentaerythritol (3.81 g), 2.21 g of pyridine, and 120 ml of dry DMF were mixed and dissolved with heating. The product was cooled to room temperature, the solution of 5 g of 5,9,13,17-tetramethyloctadecanoic acid chloride obtained in the step of synthesis of 1-O-(5,9,13,17-tetramethyloctadecanoyl)erythritol [formula (7)] in 5 ml of methylene chloride was added dropwise thereto, and the mixture was then agitated at room temperature for 1 hour. 100 ml of Methylene chloride was added to the resulting reaction solution, the mixture was washed 3 times with saturated saline, and dried over anhydrous sodium sulfate. Following filtration and concentration under reduced pressure, the concentrate was purified by silica gel column chromatography to obtain 2.50 g of mono-O-(5,9,13,17-tetramethyloctadecanoyl)pentaerythritol having the following properties. The purity determined by HPLC analysis was not lower than 99.5%. The results of NMR analysis are as shown below.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][C:11]([CH3:17])=[C:12]([CH3:16])[C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([N:8]([C:9]1[S:10][C:11]([CH3:17])=[C:12]([CH3:16])[C:13]=1[C:14]#[N:15])[C:27]([NH:26][C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[S:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1sc(NCc2ccccc2)c(C#N)c1C
Reactant: O=C(N=C=S)c1ccccc1
Product: Cc1sc(N(Cc2ccccc2)C(=S)NC(=O)c2ccccc2)c(C#N)c1C

Procedure:
Prepared as in Example 1a from 2-(benzylamino)-4,5-dimethylthiophene-3-carbonitrile (Example 20b) and benzoyl isothiocyanate. MS 406 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:20]=4[N:21]=[C:13]3[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:4]=1)#[N:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15]4[N:16]=[CH:17][N:18]=[CH:19][C:20]=4[N:21]=[C:13]3[N:12]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=3)[C:11]([CH3:22])=[C:10]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)Nc2nc3cncnc3n2C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc3cncnc3n2C1c1ccc(C#N)cc1
Reaction time: 12 h

Procedure:
(rac)-Ethyl 9-(4-cyanophenyl)-7-methyl-6,9-dihydropyrimido[1,2-e]purine-8-carboxylate (20 mg, 55 μmol), 3-(trifluoromethyl)phenylboronic acid (21 mg, 0.11 mmol, 2 eq.), anhydrous copper(II) acetate (20 mg, 0.11 mmol, 2 eq.) and molecular sieve (50 mg, 4 Å) were initially charged. Under an atmosphere of argon, abs. dichloromethane (2 ml), pyridine (18 μl, 0.22 mmol, 4 eq.) and triethylamine (15 μl, 0.11 mmol, 2 eq.) were added. After 12 h of stirring, the mixture was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (5.6 mg, 19% of theory).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH2:8][CH2:9][CH2:10][OH:11].O>N1C=CC=CC=1>[S:2]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[OH:6])([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(O)c1ccc2ccccc2c1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)OCCCC(O)c1ccc2ccccc2c1

Procedure:
Methanesulfonyl chloride (0.77 g was added slowly with stirring to a cooled (-40° C.) solution of rac-delta-hydroxy-2-naphthalenebutanol (1.45 g) in dry pyridine (6 mL). The mixture was stirred at -40° C. for 5 hours, then was poured into water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed in turn with water (2×10 mL), saturated magnesium sulfate solution (3×15 mL) and brine, then were dried (MgSO4) and evaporated. The resulting oil was purified by HPLC (ethyl acetate-hexane; 2:3) to provide 1.25 g of rac-alpha-(3-mesyloxypropyl)-2-naphthalenemethanol as an oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:18][C:19]=2[CH2:20][CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])[CH2:37][C:38](=O)[CH3:39])=[CH:32][CH:31]=1.C(N(CC)CC)C>CO.COC(OC)OC.C(Cl)Cl>[CH2:20]([C:19]1[O:18][C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:16][C:15]=1[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([NH:1]/[C:38](/[CH3:39])=[CH:37]\[C:36](=[O:41])[C:33]2[CH:34]=[CH:35][C:30]([C:29]([F:28])([F:42])[F:43])=[CH:31][CH:32]=2)[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1)[CH3:21]
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCc1oc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: CO
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CCc1oc(-c2ccccc2)nc1COc1ccc(C[C@H](N/C(C)=C\C(=O)c2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 98 mg (0.27 mmol) of Intermediate 61, 62 mg (0.27 mmol) of Intermediate 24, and 0.08 mL triethylamine in MeOH (2.0 mL) and trimethylorthoformate (0.5 mL) to yield 95 mg (61% yield) of Example 75 after silica gel chromatography (5%-15% MeOH in DCM): TLC (DCM/MeOH, 4/1): Rf=0.59; 1H NMR (DMSO-d6, 300 MHz) δ11.55 (d, 1H, J=9.0), 7.98-7.90 (m, 4H), 7.73 (d, 2H, J=8.4), 7.51-7.48 (m, 3H), 7.17 (d, 2H, J=8.4), 6.91 (d, 2H, J=8.4), 5.61 (s, 1H), 4.93 (s, 2H), 4.24-4.18 (m, 1H), 3.23-3.16 (m, 1H), 2.86-2.73 (m, 4H), 1.72 (s, 3H), 1.17 (t, 3H, J=7.5); low resolution MS (ES+)m/e 579.05 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]2)=[CH:26][C:25]=1Br.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][C:12]([C:25]2[CH:26]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:36](=[O:38])[CH3:37])[CH2:32][CH2:31]3)[CH:28]=[CH:29][C:24]=2[NH2:23])=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: CC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(c2ccc(N)c(C3=CCCN(C(=O)OC(C)(C)C)C3)c2)CC1
Temperature: 80 °C
Reaction time: 4.5 h
Yield: 93 %

Procedure:
A solution of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (as prepared in Example 46, step (b), 0.62 g, 2.02 mmol) and 1-[4-(4-amino-3-bromo-phenyl)-piperidin-1-yl]-ethanone (as prepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOH (2:1, 9 mL) was treated with 2.0 M aqueous Na2CO3 (2.7 mL, 5.38 mmol) and was degassed with sonication under Ar. The mixture was heated to 80° C., treated with Pd(PPh3)4 (54 mg, 0.05 mmol), and stirred at 80° C. for 4.5 h. The reaction was cooled to room temperature, diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.25 g, 93%) as an off-white solid. LC-MS (ESI, m/z): Calcd. for C23H33N3O3 422.2 (M+Na). found 422.0.
Reaction SMILES: [O:1]([NH2:3])[CH3:2].N1C=CC=CC=1.[CH:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[C:11]1=O)[CH2:17]2>Cl.CO>[CH3:2][O:1][N:3]=[C:11]1[CH:12]2[CH2:18][CH:16]3[CH2:15][CH:14]([CH2:19][CH:10]1[CH2:17]3)[CH2:13]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 66 h
Yield: 66 %

Procedure:
3.76 g (45 mmol) of methoxylamine, in hydrochloride form, and 4.36 g (55.1 mmol) of pyridine are added to 4.51 g (30 mmol) of 2-adamantanone in 30 ml of methanol. The reaction medium is stirred at ambient temperature for 66 h, the solvents are evaporated off under vacuum, and the residue is then diluted with 50 ml of dichloromethane and 50 ml of water. The organic phase is separated and the aqueous phase is then extracted again with 30 ml of dichloromethane. The organic phases are combined, washed with two times 30 ml of dilute hydrochloric acid (1 M) and 30 ml of brine, and then dried over magnesium sulphate. After filtration and evaporation in a rotary evaporator, the product 35 is obtained in the form of a white powder: 3.57 g (yield=66%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])=[CH:5][CH:4]=1.CSC1C=CC(N)=CC=1.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[C:12]([NH2:13])=[N:32][N:31]=1
Reactant: NN
Reactant: CSc1ccc(NN=C(C#N)C#N)cc1
Agent: CSc1ccc(N)cc1
Solvent: N#CCC#N
Solvent: O
Product: CSc1ccc(NN=C2C(N)=NN=C2N)cc1
Yield: 77 %

Procedure:
This compound was prepared using 108 mg (0.5 mmol) of 2-[(4-methylsulfanylphenyl)-hydrazono]malononitrile, which was derived from 4-methylthioaniline (117 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube immediately after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 95 mg (77%) of the title compound as an orange solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=[O:7].O.[Na].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O>[CH2:11]([O:18][C:19]([N:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=[O:7])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCN1
Agent: Cl
Agent: [Na]
Solvent: O
Product: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of pyrrolidine-2-carboxylic acid (1.15 g, 10 mmol) of water (20 ml) was added sodium hydrate (1.6 g, 40 mmol). Then benzyloxycarbonyl chloride (2.02 g, 12 mmol) was added drop wise at 0° C. The mixture was stirred at 0° C. for 2 h. The resulting mixture was treated with 5N hydrochloric acid to pH=6 and extracted with ethyl acetate, the solvent was removed under reduced pressure and dried in vacuum. 2.0 g of 1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>ClCCl.C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc(SCCN)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(SCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To the solution of compound 1 (10 g, 54.6 mmol) and triethylamine (15 mL, 106 mmol) in 200 mL of dichloromethane was added benzyl chloroformate (7.24 mL, 51.5 mmol, diluted in 100 mL of dichloromethane) dropwise at 0° C. After the addition, the solution was stirred at r.t. for one hour. The solid was removed by filtration. The solution was extracted with 100 mL of 0.1 M HCl and 100 mL of sat. sodium carbonate, and dried over anhydrous sodium sulfate. Removal of solvent provided a white solid that was stirred in 200 mL of THF/hexane (1:20) for three hours. The solid was collected by filtration to give 14.2 g of the target compound in 87% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:20]=[CH:21][C:22]([O:24][CH3:25])=[O:23])[N:8]2S(C2C=CC=CN=2)(=O)=O)=[CH:4][CH:3]=1>CO.CCOC(C)=O>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C=Cc1cc2ccc(C)cc2n1S(=O)(=O)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1cc2ccc(C)cc2[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A suspension of 45 (1.86 g, 5.22 mmol) and Mg (2.54 g, 104.4 mmol) in MeOH (40 mL) was stirred at 0° C. for 2 h. The mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed with a sat. NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 10% EtOAc-hexanes to provide 0.69 g (60%) of product 46 as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.43 (s, 3H), 2.74 (t, J=7 Hz, 2H), 3.06 (t, J=7 Hz, 2H), 3.71 (s, 3H), 6.17 (m, 1H), 6.90 (d, J=8 Hz, 1H), 7.10 (s, 1H), 7.40 (d, J=8 Hz, 1H), 8.36 (brs, 1H). LC-MS (CI): m/z 218.1 [(M+H)+ C13H15NO2 requires 217.11].
Reaction SMILES: [H-].[Na+].CI.[CH3:5]N(C=O)C.[CH2:10]([O:17][C@@H:18]([CH3:31])[C@@H:19]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([OH:22])=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([O:17][C@@H:18]([CH3:31])[C@@H:19]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:5])[C:20]([OH:22])=[O:21])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)C=O
Reactant: C[C@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H](OCc1ccccc1)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
In a round bottom flask, under argon atmosphere, commercially available (2R,3S)-3-benzyloxy-2-(tert-butoxycarbonyl-amino)-butanoic acid was dissolved in dry THF (15 mL). Subsequently at 0° C., NaH (60% dispersion in mineral oil, 0.21 g, 5.33 mmol) was added in one portion. The reaction mixture was left to stir at the same temperature for 10 min and then MeI (0.95 mL, 15.22 mmol) followed by DMF (0.75 mL) were sequentially added. The reaction was left for 2.0 h at 0° C. and for 15 h at rt, then quenched with H2O (15 mL), diluted with EtOAc (30 mL) and acidified to pH 2 by dropwise addition of 2.0 N HCl aqueous solution. The organic layer was separated and the aqueous phase was back-extracted with EtOAc (2×30 mL). The organic phase was dried over Na2SO4, filtered and concentrated to dryness. The crude mixture was purified by column chromatography using a Teledyne ISCO apparatus eluting with Cy:TBME (60:40) to give the title compound (1.1 g, 67%), as a mixture of two rotamers (2:1 ratio), as a colorless oil. 1H NMR (DMSO-d6) δ 1.13-1.20 (m, 6H), 1.36 (s, 9H, minor rotamer), 1.41 (s, 9H, major rotamer), 2.84 (s, 3H, minor rotamer), 2.87 (s, 3H, major rotamer), 4.13-4.24 (m, 2H), 4.34-4.40 (m, 2H), 4.49 (d, J=5.5 Hz, 1H, minor rotamer), 4.57-4.62 (m, 2H), 4.71 (d, J=5.2 Hz, 1H, major rotamer), 7.23-7.35 (m, 10H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1)#[CH:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C.[OH-].[OH-].[Pd+2]>[N:12]1([CH2:2][CH2:1][C:3]2[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5][CH:4]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C#Cc1cncc([N+](=O)[O-])c1
Reactant: C1CCNC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Nc1cncc(CCN2CCCC2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 117.6 %

Procedure:
To a solution of 3-ethynyl-5-nitropyridine (250 mg, 1.69 mmol) in ethanol (5 mL) was added pyrrolidine (0.56 mL, 6.76 mmol) and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was cooled and palladium hydroxide on carbon (20 mg) was added. The flask was charged with H2 (ballon) and stirred at rt for 16 h. The mixture was filtered over celite and the filtrate was concentrated to afford crude product (380 mg) as a dark red oil: ESI MS m/z 192 [C11H17N3+H]+.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.O>[CH3:18][S:19]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCOc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of 2-phenoxyethanol (10.0 mL, 80.0 mmol) and triethylamine (13.5 mL, 96.9 mmol) in anhydrous CH2Cl2 (250 mL) at 0° C. is added methanesulfonyl chloride (6.80 mL, 87.9 mmol). The resulting cloudy mixture is stirred at 0° C. for 2 h. The mixture is diluted with water (75 mL) and extracted. The organic layer is washed with 1N HCl (75 mL) then saturated NaHCO3/brine (1:1; 75 mL) dried (Na2SO4), filtered, and concentrated. The residue is dried to constant weight under reduced pressure to provide the title compound as a pale yellow oil (17.1 g, 99%). This material is used in the next step without further purification.