Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:16]([CH3:18])[CH3:17])[C@@H:9]([CH2:14][CH3:15])[C:10](OC)=[O:11])[C:5]([N+:19]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:19][C:10](=[O:11])[C@H:9]([CH2:14][CH3:15])[N:8]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: CC[C@@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C(C)C
Agent: [Fe]
Solvent: CC(=O)O
Product: CC[C@H]1C(=O)Nc2cnc(Cl)nc2N1C(C)C
Temperature: 65 °C
Reaction time: 4 h
Yield: 101.6 %

Procedure:
Methyl (2S)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]butanoate 43b (8.74 g, 27.7 mmol) was dissolved in 100 mL of acetic acid followed by the addition of iron powder (6.20 g, 0.11 mol). The reaction mixture was heated to 65° C., stirred for 4 hours and filtered. The filter cake was washed with dichloromethane (100 mL). The filtrate was concentrated under reduced pressure, then added with 100 mL of water and filtered. The filter cake was dried by heating to obtain the crude compound (7S)-2-chloro-8-isopropyl-7-ethyl-5,7-dihydropteridin-6-one 43c (7.17 g) as a gray solid, which was used in the next step without further furification.
Reaction SMILES: [I-].[CH3:2][C:3]1[N:10]2[C:6](=[N+:7]([CH3:15])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][CH:4]=1.[CH3:16][O-:17].[Na+]>CO>[CH3:15][N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10](/[C:3](/[CH3:2])=[CH:4]\[S:5][CH3:6])[C:16]1=[O:17]
Reactant: Cc1csc2n1c1ccccc1[n+]2C
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CS/C=C(/C)n1c(=O)n(C)c2ccccc21
Temperature: 25 °C
Yield: 80.5 %

Procedure:
350 mg of 3,9-dimethyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide (1.06 mmol) were solubilized in methanol (60 mL), then 230 mg of NaOMe (4 eq) were added and the solution stirred at room temperature. After 48 h the solvent was evaporated, water was added (25 mL) and the mixture extracted with CH2Cl2 (3×25 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure. The residue was then purified by flash chromatography on silica gel (eluent: CH2Cl2) to afford 1-methyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one as a white powder (200 mg, 80% yield). Under other experimental conditions: 100 mg of iodide (III-R3=R1=Me) (0.30 mmol) were solubilised in methanol (20 mL), then 65 mg of NaOMe (4 eq) were added and the solution refluxed for 2 h. Then, the solvent was evaporated, water was added (15 mL) and the mixture extracted with CH2Cl2 (3×15 mL). 1-methyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one was recovered (87%, 62 mg) as the sole (Z) isomer.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][NH:5][S:6]([CH3:9])(=[O:8])=[O:7].[H-].[Na+].Br[CH2:14][C:15]1[S:23][C:22]2[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:20][C:19]([Cl:30])=[N:18][C:17]=2[CH:16]=1>O1CCCC1>[Cl:30][C:19]1[N:20]=[C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:22]2[S:23][C:15]([CH2:14][N:5]([CH2:4][CH2:3][N:2]([CH3:10])[CH3:1])[S:6]([CH3:9])(=[O:8])=[O:7])=[CH:16][C:17]=2[N:18]=1
Reactant: CN(C)CCNS(C)(=O)=O
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-dimethylamino-ethyl)-methanesulfonamide (50 mg) in tetrahydrofuran under nitrogen was added sodium hydride, 60% dispersion in mineral oil, (13 mg). The reaction mixture was stirred at room temperature for 30 minutes, the 6-Bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine in tetrahydrofuran (5 ml) was added dropwise. The reaction mixture was stirred for 5 days. The solvents were removed in vacuo to give a crude product which was purified by flash chromatography to yield N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(2-dimethylamino-ethyl)-methanesulfonamide (35 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[S:20][CH2:19][CH2:18][CH2:17][CH2:16][S:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:15]1[CH2:16][CH2:17][CH2:18][CH2:19][S:20][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: ClCC1SCCCCS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1SCCCCS1

Procedure:
2,6-Diethylaniline (75 grams), 2-chloromethyl- 1,3-dithiepane (36.5 grams), potassium carbonate (34 grams) and dimethylformamide (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 18 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dithiepan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O.BrC[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:9]1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: BrCCc1ccccc1
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)N(c1ccccc1)[C@@H]1CCCN(CCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
3(R)-(Phenyl-propionyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (169) (100 mg) was dissolved in a mixture of TFA-CH2Cl2 (1 ml, 20%) and stirred for 1 hr. After removal of solvent, the residue was dried under vacuum for 30 min and dissolved in 5 ml of CH2Cl2, washed with sat. K2CO3, dried (Na2SO4), filtered. After evaporation of the solvent, the residue was dissolved in CH3CN (1 ml). Then K2CO3 (125 mg, 3 eq), water (1 ml) and (2-bromoethyl)benzene (0.05 ml, 1.2 eq) was added. The mixture was heated at 70° C. for 12 hr. After cooling to room temperature, the mixture was diluted with sat. NAHCO3 (5 ml), extracted with CH2Cl2 (2×10 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by silica gel chromatography (100% CH2Cl2, 2%-4% MeOH in CH2Cl2) to give 170 as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ7.40 (m, 3H), 7.10 (m, 2H), 4.80 (m, 1H), 0.20 (m, 1H), 4.00 (m, 1H), 2.40 (m, 2H), 1.95 (m, 3H), 1.61 (m, 1H), 1.51 (m, 1H), 1.50 (s, 9H), 1.30 (m, 1H), 1.00 (t, 3H) ppm; LRMS (calculated for C22H28N2O2)+336, found 336; IR (film) 2978, 2937, 2860, 1693, 1662, 1698, 1494, 1422, 1363, 1264, 1151, 1386, 1182 cm−1.
Reaction SMILES: Br[CH:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:8](=[O:17])[CH:7]=[CH:6][N:5]=1)[CH3:3].[CH3:18][NH2:19]>C(O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:8](=[O:17])[CH:7]=[CH:6][N:5]=[C:4]2[CH:2]([NH:19][CH3:18])[CH3:3])=[CH:11][CH:12]=1
Reactant: CC(Br)c1nccc(=O)n1-c1ccc(F)cc1
Reactant: CN
Solvent: CCO
Product: CNC(C)c1nccc(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76 %

Procedure:
The bromide (25) (190 mg, 0.64 mmol) was dissolved in a 33% solution of methylamine in ethanol (5 mL) and stirred at ambient temperature. After 3.5 h, the solvent and excess methylamine were evaporated under reduced pressure and residue was partitioned between water (10 mL) and dichloromethane (10 mL). The organic layer was washed again with water (10 mL), dried (MgSO4), and concentrated to give the title amine (26) (120 mg, 76%) as a yellow oil:
Reaction SMILES: [CH3:1][C:2]([CH:5]([CH2:11]C=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])C>>[CH2:33]([O:32][CH:28]([O:29][CH2:30][CH3:31])[CH2:11][CH:5]([C:2]([CH3:3])([CH3:1])[CH3:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:34]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(CC=O)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C(CC(OCC)OCC)C(C)(C)C

Procedure:
Ethyl (RS)-2-(1,1-dimethylethyl)-4-oxo-butanoate (0.57 g) was dissolved in excess triethylorthoformate and a catalytic amount of p-toluenesulphonic acid was added. After stirring for 1 hour at the ambient temperature, excess triethylorthoformate was evaporated under reduced pressure to give ethyl (RS)-4,4-diethoxy-2-(1,1-dimethylethyl)butanoate, the spectral data of which were identical to those obtained in Example 6 (ii).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[Br:11][C:12]1[C:20]2[S:19][C:18](C(O)=O)=[CH:17][C:16]=2[CH:15]=[C:14]([C:24]([F:27])([F:26])[F:25])[CH:13]=1>[Cu]>[Br:11][C:12]1[C:20]2[S:19][CH:18]=[CH:17][C:16]=2[CH:15]=[C:14]([C:24]([F:27])([F:25])[F:26])[CH:13]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cc(Br)c2s1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: FC(F)(F)c1cc(Br)c2sccc2c1
Temperature: 200 °C

Procedure:
To a mixture of quinoline (5 mL) and copper powder (0.39 g, 6.2 mmol) in a sealed tube was added 7-bromo-5-(trifluoromethyl)-1-benzothiophene-2-carboxylic acid (1.0 g, 3.1 mmol). The mixture was heated to 200° C. for 20 minutes, then allowed to cool to room temperature. The mixture was filtered, then the collected precipitate was washed with toluene. The filtrate was concentrated, then the resulting brown oil was diluted with EtOAc and poured into 6.0 M HCl (aq). The layers were separated, then the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 6.0 M HCl (aq), water, then saturated NaCl (aq), dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 0-1% EtOAc/hexanes to afford the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.10 (br s, 1H); 7.77 (br s, 1H); 7.69 (d, J=5.5 Hz, 1H); 7.57 (d, J=5.5 Hz, 1H). LC1: 4.02 min. Compound does not ionize.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]=[N:15]O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(C1N=[C:22]([C:32]2[C:33]([O:39][CH3:40])=[N:34][CH:35]=[CH:36][C:37]=2[I:38])[N:23]([OH:31])C=1C1C=CC=CC=1)C>>[I:38][C:37]1[CH:36]=[CH:35][N:34]=[C:33]([O:39][CH3:40])[C:32]=1[C:22]1[N:23]([OH:31])[C:13]([C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:12][CH:11]=2)=[CH:14][N:15]=1
Reactant: CCc1nc(-c2c(I)ccnc2OC)n(O)c1-c1ccccc1
Reactant: O=C(C=NO)c1ccc(N2CCOCC2)cc1
Product: COc1nccc(I)c1-c1ncc(-c2ccc(N3CCOCC3)cc2)n1O
Yield: 22 %

Procedure:
(4-Morpholin-4-yl-phenyl)-oxo-acetaldehyde oxime (0.111 g, 0.474 mmol) was reacted as described for the synthesis of 4-ethyl-2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol and afforded the title material (0.049 g, 22%).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([CH2:32][O:33][C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[C:22]3[CH3:31])=[C:15]([O:42][CH3:43])[CH:14]=1)=[O:11])=O)(C)(C)C.[ClH:44].O1CCOCC1>O1CCOCC1>[ClH:44].[NH2:8][CH2:9][C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([CH2:32][O:33][C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[CH3:41])=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24]([CH3:30])([CH3:29])[CH:23]=[C:22]3[CH3:31])=[C:15]([O:42][CH3:43])[CH:14]=1)=[O:11]
Reactant: COc1cc(OC(=O)CNC(=O)OC(C)(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(OC(=O)CN)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
6-(4-t-Butoxycarbonylaminoacetoxy-2-methoxyphenyl)-5-(5-fluoro-2-methylphenoxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 1-2, 20.1 mg, 0.034 mmol) was dissolved in 1,4-dioxane (0.5 mL), 4N HCl/1,4-dioxane solution (34 μL) was added thereto, and then the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the titled compound (17.5 mg) as a colorless solid. (Yield 98%)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.Cl>C(Cl)Cl>[C:1]([C:8]1[S:7][C:6]([Br:5])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: Brc1cccs1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(=O)c1ccc(Br)s1
Reaction time: 1 h

Procedure:
When 1.56 ml (1.1 equivalents) of acetyl chloride was added to a solution of 3.26 g (0.02 mmol) of 2-bromothiophene in 30 ml of CH2Cl2, the mixture foamed and turned black. After stirring for 1 hr. at room temperature, the mixture was mixed with ice and concentrated hydrochloric acid. While being decolored with active carbon, the mixture was extracted with CH2Cl2, whereby 3.53 g (Yield : 86.1%) of the objective product, 2-acetyl-5-bromothiophene (b-1) was obtained as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12](Cl)[O:13][CH3:14].O>CN(C=O)C>[CH3:12][O:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-hydroxybenzaldehyde (1.22 g, 10 mmol) was dissolved in 100 ml dried DMF and stirred at room temperature. NaH (0.8 g) was added in to the reaction. After 10 min, MOMCl (1.5 ml) was added into the reaction by drop. Then the result solution was stirred at room temperature, and monitored by TLC. When the reaction was completed, 500 ml H2O was added. The resulting solution was extracted by ethyl acetate, and the organic layers were combined, dried by Na2SO4, concentrated by reduce pressure. The resulting oil was directly used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ: 3.50 (s, 3H), 5.26 (s, 2H), 7.14 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 9.90 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[C:10]([CH2:21][C:22]2([CH3:25])[CH2:24][O:23]2)=[C:9]([O:26]CC2C=CC=CC=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>CO.[Pd]>[C:1]([O:5][C:6]([C:7]1[CH:12]=[C:11]([OH:13])[C:10]2[CH2:21][C:22]([CH2:24][OH:23])([CH3:25])[O:26][C:9]=2[CH:8]=1)=[O:34])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2(C)CO2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
A mixture of 3,5-bis-benzyloxy-4-(2-methyl-oxiranylmethyl)-benzoic acid tert-butyl ester (227b) (158 g, 0.343 mol), 10% Pd/C (15 g), Et3N (57.3 mL, 0.412 mol) and K2Co3 (56.94 g, 0.412 mol) in MeOH (1.5 L) was stirred under 760 mmHg of H2 at room temperature overnight. TLC (EtOAc/petroleum ether=1/3) showed that the reaction was complete. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc/petroleum ether=1/3) to give a brown oil. The brown oil was further purified by prep. HPLC to give the title compound (18 g, 18.7% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 6.98 (s, 1H), 6.82(s, 1H), 3.67 (d, 1 H), 3.56 (d, 1H), 2.80 (d, 1H), 1.48 (s, 9H), 1.35 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:35]4[CH2:36][CH2:37][N:32]([C:29](=[O:31])[CH3:30])[CH2:33][CH2:34]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(=O)N1CCNCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: CC(=O)N1CCN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.528 mmol) and 1-acetyl piperazine (75 mg, 0.581 mmol) gave 2-[5-(4-acetyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as an off white solid (96 mg, 37%) [following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/dichloromethane].
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].N1C=CN=C1.[OH:14][CH:15]([C:26]1[S:41][C:29]2[N:30]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:31](=[O:36])[N:32]([CH3:35])[C:33](=[O:34])[C:28]=2[CH:27]=1)[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH3:1][Si:2]([CH3:7])([C:3]([CH3:6])([CH3:5])[CH3:4])[O:14][CH:15]([C:26]1[S:41][C:29]2[N:30]([CH2:37][CH:38]([CH3:39])[CH3:40])[C:31](=[O:36])[N:32]([CH3:35])[C:33](=[O:34])[C:28]=2[CH:27]=1)[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O)c3cccc4ccccc34)sc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O[Si](C)(C)C(C)(C)C)c3cccc4ccccc34)sc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.9 %

Procedure:
Dimethyl-(1,1-dimethylethyl)silyl chloride (230 mg) and imidazole (130 mg) were added to a solution of (±)6-(1-hydroxy-1-[1-naphthalenyl]methyl)-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (500 mg) in dimethylformamide (10 ml). The solution was stirred at ambient temperature for 3 days. The reaction mixture was quenched with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was separated and washed twice with dilute hydrochloric acid and once with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on silica gel eluting with isohexane:ethyl acetate (4:1 to 2:1) gave the subtitle product (0.47 g).
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH3:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][N:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C1(C)CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 65 °C
Reaction time: 6 h
Yield: 83.1 %

Procedure:
To a round bottom flask was added ethyl 3-methylpiperidine-3-carboxylate (2.040 g, 11.91 mmol), 1-fluoro-4-nitrobenzene (1.765 g, 12.51 mmol), DMF (20 ml) and K2CO3 (2.140 g, 15.49 mmol). The reaction was stirred at 65° C. for 6 hrs. After this time, the reaction was diluted with EtOAc. The resulting solution was washed with water (2×) and saturated aqueous NaCl. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give the product, ethyl 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylate (2.922 g, 9.90 mmol, 83% yield) as a yellow oily residue. Anal. Calcd. for C15H20N2O4 m/z 292.3, found: 293.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (d, J=9.34 Hz, 2H), 6.87 (d, J=9.34 Hz, 2H), 4.18 (d, J=13.19 Hz, 1H), 4.11 (q, J=7.15 Hz, 2H), 3.80-3.58 (m, 1H), 3.00 (s, 1H), 2.90 (d, J=13.19 Hz, 1H), 2.40-2.23 (m, 1H), 1.75 (dd, J=8.52, 4.12 Hz, 2H), 1.42 (s, 1H), 1.26-1.14 (m, 6H).
Reaction SMILES: [NH2:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([OH:9])[CH2:3]2.N1C=CC=CC=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH3:16])[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]23[CH2:8][CH:5]([CH2:6][CH2:7]2)[CH:4]([OH:9])[CH2:3]3)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: NC12CCC(C1)C(O)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NC23CCC(C2)C(O)C3)cc1
Reaction time: 2 h

Procedure:
0.7 g of A1 are dissolved in 7 ml of dichloromethane and mixed with 0.9 ml of pyridine. 1.05 g of p-toluenesulfochloride are added whilst cooling with ice, and the reaction mixture is stirred for 2 hours. The mixture is diluted with 50 ml of dichloromethane, washed with water (1×), dried over MgSO4 and concentrated by evaporation on a rotary evaporator. From the residue, the title compound A5 is obtained as a white solid by flash chromatography (SiO2 60F/dichloromethane/methanol 20:1) and subsequent recrystallisation from toluene (0.53 g, 35% of theory). Melting point: 110-111° C. 1H-NMR (400 Hz, DMSOd6) δ: 0.92 (2H); 1.14 (2H); 1.90 (4H); 2.40 (3H); 3.70 (1H); 4.22 (1H); 5.72 (1H); 7.40 (2H); 7.50 (1H); 7.70 (2H).
Reaction SMILES: [S-2:1].[Na+:2].[Na+].S.[C:5](Cl)(=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O>[C:5]([O-:15])(=[S:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Na+:2]
Reactant: [S-2]
Reactant: CCCCCCCCCC(=O)Cl
Agent: S
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCC([O-])=S
Temperature: 25 °C

Procedure:
Into a 2-liter round-bottomed flask was added 82 grams of sodium sulfide and 164 grams of water and the mixture was stirred at room temperature until the solids were dissolved. An excess of hydrogen sulfide was added below the surface until bubbling was seen in the trap. The reaction mixture was then cooled with an ice water bath to 17° C. Decanoyl chloride was then added slowly. Foaming was observed after about half of the decanoyl chloride had been added. At this point, the addition of decanoyl chloride was slowed and occasionally stopped to control foaming. The reactor temperature was kept at about 17° C. The decanoyl chloride addition was complete after a total of 2.5 hours. The pH of the resulting solution containing sodium thiodecanoate was measured with pH paper, giving an alkaline reading. An additional 2.7 grams of decanoyl chloride was then titrated into the solution to neutralize it, giving a final neutral pH reading.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]#[N:10])[N:3]=1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:18][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]#[N:10])[N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(C#N)nc1Br
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)nc1OCc1ccccc1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of 2-bromo-6-cyano-3-methylpyridine (272 mg) and benzyl alcohol (156 mg) in tetrahydrofuran (20 mL) was added sodium hydride (40 mg), and the mixture was heated under reflux for one hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. After removal of the sodium sulfate by filtration, the organic solvent was evaporated off in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=19:1) to give the title compound (161 mg) as a colorless liquid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.[C:11]1([C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH2:19][CH2:20]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:11]1([C:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH2:19][CH2:20][N:1]2[CH2:5][CH2:4][CH:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCC=C(c1ccccc1)c1ccccc1
Reactant: COC(=O)CC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CC1CCN(CCC=C(c2ccccc2)c2ccccc2)C1

Procedure:
A mixture of 44.5 g. (0.138 mole) of methyl 3-pyrrolidineacetate hexamate, 40.3 g. (0.140 mole) of 4,4-diphenyl-3-butenyl bromide and 38.2 g. (0.276 mole) of potassium carbonate in 400 ml. of acetone was refluxed for 43 hours. The mixture was chilled, filtered, concentrated and chromatographed on silica gel to give methyl 1-(4,4-diphenyl-3-butenyl)-3-pyrrolidineacetate.