Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48](O)=[O:49].C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:63]([CH3:66])([O-:65])=[O:64].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48](=[O:49])[CH2:66][N+:63]([O-:65])=[O:64]
Reactant: C[N+](=O)[O-]
Reactant: O=C(O)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a anhydrous THF (22 mL) solution of the carboxylic acid 55 (2.97 g, 4.28 mmol) was added 1,1′-carbonyl diimidazole (800 mg, 4.93 mmol) at room temperature. In separate flask, nitromethane (0.92 mL, 17.12 mmol) was added to a THF (9 mL) solution of NaH (200 mg, 4.93 mmol). The resulting white suspension was stirred at room temperature for 3 h. Then the prepared acyl imidazole solution was added to the suspension through a cannula at room temperature. After the transfer, the mixture was heated to 50° C. for 1.5 h. It was cooled to room temperature and quenched with 1.0 M HCl. The organic layer was extracted with ethyl acetate, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography to provide the titled compound (3.13 g, 99%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].Cl[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]>>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[N+:21]([O-:23])=[O:22]
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Product: O=Cc1ccc(Oc2ccc(Cl)cc2Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To powdered potassium hydroxide (9.0 g, 0.12 mol) at 110° C. was added 2,4-dichlorophenol (19.0 g, 0.12 mol) in one portion. The mixture was stirred for 15 min. and a homogenous solution resulted. 4-Chloro-3-nitrobenzaldehyde (20.0 g, 0.11 mol) was added and the thick mixture was stirred at 110° C. for 1 h. After cooling to room temperature, the mixture was partitioned between 2M aqueous sodium hydroxide and ethyl acetate. The organic layer was separated, washed with brine and dried over magnesium sulfate. Evaporation of solvent and recrystallization from ethanol afforded 27.0 g (80%) of the title compound as a pale yellow solid. 1H NMR (CDCl3) δ9.80 (s, 1H), 8.48 (s, 1H), 7.90 (d, 1H), 7.53 (s, 1H), 7.35 (d, 1H), 7.16 (d, 1H), 6.88 (d, 1H). 3-Amino-4-(2,4-dichlorophenoxy)benzaldehyde
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.Cl.[CH3:17][C@@H:18]1[CH2:23][O:22][CH2:21][CH2:20][NH:19]1.C(N(CC)CC)C>O1CCCC1>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=[C:2]1[N:19]1[CH2:20][CH2:21][O:22][CH2:23][C@H:18]1[CH3:17]
Reactant: C[C@@H]1COCCN1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1COCCN1c1nc(-c2ccncn2)cc(=O)n1C
Yield: 75 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.32 g, 1.44 mmol), (3R)-3-methylmorpholine hydrochloride (0.4 g, 2.9 mmol) and triethylamine (0.9 g, 8.9 mmol) in tetrahydrofuran (20 ml) was stirred for 10 hours at 100° C. The solution was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 3-methyl-2-((3R)-3-methylmorpholin-4-yl)-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.31 g, 1.08 mmol, 75%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:40][CH2:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]2[N:50]([CH2:53][CH3:54])[N:51]=[CH:52][C:44]=2[C:43]=1[NH:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>ClCCl>[CH2:53]([N:50]1[C:45]2=[N:46][C:47]([CH2:48][CH3:49])=[C:42]([CH2:41][NH:40][C:5]([C:4]3[CH:8]=[C:9]([CH:10]=[C:2]([CH3:1])[CH:3]=3)[C:11]([O:13][CH3:14])=[O:12])=[O:7])[C:43]([NH:55][CH:56]3[CH2:57][CH2:58][O:59][CH2:60][CH2:61]3)=[C:44]2[CH:52]=[N:51]1)[CH3:54]
Reactant: COC(=O)c1cc(C)cc(C(=O)O)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
3-Methyl-5-[(methyloxy)carbonyl]benzoic acid (2.91 g, 15.00 mmol) was partially dissolved in dichloromethane (DCM) (500 mL) with stirring under argon at room temperature. HBTU (5.69 g, 15.00 mmol) was added followed by 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (5.10 g, 15 mmol), and then TEA (4.18 mL, 30.0 mmol). The mixture was stirred under argon overnight. The solvent was concentrated and the residue partitioned between EtOAc (300 mL) and water (100 mL). The organic phase was washed with water (3×100 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. This was purified by CombiFlash on a 120 g silica column eluted with 35-100% EtOAc in hexane. The purified product was taken up in 300 mL of EtOAc, and washed with 50 mL of 1N NaOH, and then with water (3×100 mL), and 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a white solid. LC-MS m/z 480.0 (M+H)+, 0.81 min (ret time); mp 89-93° C.; analytical HPLC shows 95.4% purity, (ret time 12.251 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:30][CH2:29][C:24]2[N:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:15])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Reactant: NCc1ncccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ncccn2)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
In DMF (60 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio) pyrimidine-5-carboxylic acid (1.0 g, 2.95 mmol), pyrimidine 2-ylmethylamine (570 mg, 5.22 mmol) and HATU (2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 2.64 g, 6.96 mmol), then DIEA (152 mg, 1.2 mmol) was added dropwisely. The reaction mixture was stirred at 60° C. overnight, extracted with DCM after water was added and washed with brine. The organic phase was dried over sodium sulfate. The solvent was removed by rotary evaporation, then the solid obtained was purified by silica gel column chromatography (DCM/methanol=50/1) to give 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (350 mg, 13% yield).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8].Cl[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][N:21]=1)[C:17]#[N:18].Cl>CN(C)C=O>[C:17]([C:16]1[CH:19]=[CH:20][N:21]=[C:14]([S:3][C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])[CH:15]=1)#[N:18]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: O=C(O)c1cccc(S)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccnc(Sc2cccc(C(=O)O)c2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
Add sodium hydride (60% dispersion in mineral oil, 635 mg, 15.88 mmol) to a solution of 3-mercapto-benzoic acid (1.11 g, 7.22 mmol) in dimethylformamide (50 mL) chilled to 0° C. and stir. After 10 minutes add 2-chloro-isonicotinonitrile (1.00 g, 7.22 mmol). Warm gradually to ambient temperature. After 18 hours, add 1N aqueous hydrochloric acid (200 mL). Filter the resulting precipitate, washing with water and hexanes to yield the title compound as a tan solid (920 mg, 50%): 1H NMR (DMSO-d6) δ 7.62-7.66 (m, 3H), 7.84 (d, 1H), 8.03-8.08 (m, 2H), 8.62 (d, 1H), 13.26 (bs, 1H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[C:11]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH:13]=[CH:14][N:10]([CH2:9][CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:11]2=[O:24])=[CH:20][CH:19]=1
Reactant: O=c1n(CCCC2CCCCC2)ccn1-c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(-n2ccn(CCCC3CCCCC3)c2=O)cc1
Temperature: 70 °C

Procedure:
1-(3-Cyclohexyl-propyl)-3-(4-nitro-phenyl)-1,3-dihydro-imidazol-2-one (15.4 g, 46.8 mmol) and tin chloride dihydrate (53.0 g, 234.5 mmol, 5.0 equiv) were combined in ethanol and heated at 70° C. for two hours. The mixture was cooled to 25° C. and poured onto ice (500 mL). The aqueous mixture was adjusted to pH=8 with 1 N aqueous sodium hydroxide solution. The aqueous phase was extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated in vacuo to an orange solid (13.4 g, 95%). Mp 83-85° C.; 1H NMR (CDCl3, 300 MHz) δ 7.26 (d, 8.5 Hz, 2H), 6.64 (d, 8.5 Hz, 2H), 6.40 (d, 2.9 Hz, 1H), 6.24 (d, 2.9 Hz, 1H), 3.70 (br s, 2H), 3.57 (t, 7.4 Hz, 2H), 1.64 (m, 7 H), 1.19 (m, 6H), 0.85 (m, 2H); MS (CI) m/z 300 (MH+); Rf=0.24 (50:50 hexane/ethyl acetate).
Reaction SMILES: B.CSC.[Cl:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12]>O1CCCC1>[Cl:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[OH:12]
Reactant: CCOC(=O)C1(Cl)CCCCC1=O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)C1(Cl)CCCCC1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
First, ethyl 1-chloro-2-oxocyclohexanecarboxylate was prepared from ethyl 2-oxocyclohexanecarboxylate referring to the process described in Organic Synthesis volume 4, page 162. 17 g (0.1 mol) of ethyl 2-oxocyclohexanecarboxylate was dissolved in 50 ml of carbon tetrachloride, and to the solution was added dropwise 14.8 g (0.11 mol) of sulfuryl chloride dissolved in 15 ml of carbon tetrachloride at 0° C. After stirring at room temperature for 2 hours, the reaction solution was poured into 100 ml of ice water, the mixture was extracted three times with 50 ml each of carbon tetrachloride, and the extract was washed twice with 75 ml each of saturated aqueous sodium bicarbonate and once with 75 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled away to obtain 18 g (yield: 88%) of ethyl 1-chloro-2-oxocyclohexanecarboxylate. 1.22 ml (2 mmol) of dimethyl sulfide borane was dissolved in 40 ml of tetrahydrofuran, and 2.5 g (12 mmol) of ethyl 1-chloro-2-oxocyclohexanecarboxylate was added dropwise at -5° C. to 0° C. After stirring at 0° C. for 1 hour, the solvent was distilled away under reduced pressure and the reaction solution was poured into 50 ml of ice water. The mixture was extracted three times with 50 ml each of ethyl acetate, and the resulting organic layer was washed once with 75 ml of saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled away to obtain 2.2 g of a stereoisomer mixture of ethyl 1-chloro-2-hydroxy-1-cyclohexanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([SH:23])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:30][C:29]=1[F:39].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:27][C:28]3[C:33]([F:34])=[CH:32][C:31]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:30][C:29]=3[F:39])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: NS(=O)(=O)c1cc(F)c(CBr)c(F)c1
Reactant: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(N)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
A mixture of 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (170 mg, 0.45 mmol, 1.0 eq), 4-(bromomethyl)-3,5-difluorobenzenesulfonamide (155 mg, 0.54 mmol, 1.2 eq) and K2CO3(94 mg, 0.68 mmol, 1.5 eq) in acetone (2.3 mL) was stirred for 30 min. The reaction mixture was filtered, and the filtrate was concentrated and purified (silica, 0-75% EtOAc/Hex) to afford the title compound (252 mg, 96%) as a white solid. MS (EI) m/z 584 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:19]([O:21]C)=O)([CH3:18])[N:3]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].CO.C[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:18][C:2]1([CH3:1])[N:3]([C:4]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:5])[CH2:12][CH:13]([C:14]([O:16][CH3:17])=[O:15])[C:19]1=[O:21]
Reactant: COC(=O)CCN(C(=O)c1ccccc1)C(C)(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CN(C(=O)c2ccccc2)C(C)(C)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of methyl 2-methyl-N-[3-(methyloxy)-3-oxopropyl]-N-(phenylcarbonyl)alaninate (3.5589 g, 11.58 mmol) in toluene (115 mL) was added MeOH (0.94 mL, 23.21 mmol), and NaOMe (1.25 g, 23.14 mmol). The mixture was heated at 60° C. and stirred for 2 h. An additional portion of MeOH (10 mL) was added, and the mixture was stirred for an additional 2 h at 60° C. The mixture was then concentrated in vacuo, and the residue was partitioned between DCM (200 mL) and 1 N aq. HCl (100 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide crude methyl 5,5-dimethyl-4-oxo-1-(phenylcarbonyl)-3-pyrrolidinecarboxylate (2.746 g, 86% yield) as a colorless oil. LCMS: (M+H)+: 276.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].C(=O)([O-])[O-].[K+].[K+]>>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:12][CH2:11][NH2:14])[CH:7]=1)[CH3:10]
Reactant: CCOc1ccnc(Br)c1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccnc(NCCN)c1
Temperature: 140 °C
Yield: 64 %

Procedure:
A mixture of 2-bromo-4-ethoxypyridine (500 mg, 2.475 mmol), ethane-1,2-diamine (9.9 ml, 150 mmol) and potassium carbonate (685 mg, 4.95 mmol) was stirred under microwave heating at 140° C. for 2 hours. The reaction mixture was filtered, the remaining solids were rinsed with ethanol and the combined filtrates were concentrated under reduced pressure and purified by flash column chromatography (silica, gradient of 2%-100% 7N NH3 in MEOH in DCM) to yield 287 mg of a solid (1.584 mmol, 64%). MS(ESI) m/z=182.0 [M+1]+.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([I:14])=[CH:12][N:11]([C:15]([CH3:21])([CH3:20])[C:16]([O:18]C)=[O:17])[C:9]=2[N:10]=1>C1COCC1.O>[Cl:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([I:14])=[CH:12][N:11]([C:15]([CH3:21])([CH3:20])[C:16]([OH:18])=[O:17])[C:9]=2[N:10]=1
Reactant: COC(=O)C(C)(C)n1cc(I)c2cnc(Cl)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)n1cc(I)c2cnc(Cl)nc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Lithium hydroxide monohydrate (4.08 g, 97.5 mmol) was added to methyl 2-(2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropanoate (18.5 g, 48.7 mmol) (see Preparation 41) in THF (185 mL) and water (45 mL). The mixture was stirred at 60° C. for 3 hours then the reaction mixture volume was reduced to one third by evaporation in vacuo. The aqueous residue was acidified using aqueous HCl (2.0 M) then extracted with EtOAc (4×200 mL). The organic phase was evaporated in vacuo and the crude material was triturated with hexane (100 mL) to afford the title compound as a white solid in 90% yield, 16.0 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10]C)=[O:8].[OH-].[Na+].C(Cl)(Cl)=[O:16].C1(C)C=CC=CC=1>CO>[CH3:12][C:5]1[C:6]2[C:7](=[O:8])[O:9][C:10](=[O:16])[NH:1][C:2]=2[S:3][CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)c1c(C)csc1N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1csc2[nH]c(=O)oc(=O)c12
Yield: 59 %

Procedure:
A mixture of ethyl 2-amino-4-methylthiophene-3-carboxylate (5 g, 0.03 mol) in methanol (25 ml) and aq. 2M sodium hydroxide (20.24 ml, 0.04 mol) was heated under reflux for 4 h. After cooling the solvents were evaporated, the residue dissolved in water (30 ml) and a 20% solution of phosgene in toluene (24 ml, 0.05 mol) added dropwise with ice cooling. After a further 30 min the solid which had precipitated was filtered, washed with water then ether, and dried to give the title compound 2.93 g (59%). 1H NMR (d6-DMSO) δ 2.31 (3H, s), 6.78 (1H, s), 12.50 (1H, br. s).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25](=O)[CH3:26])=[O:4].Cl.[O:30]1[CH2:35][CH2:34][CH:33]([NH:36][NH2:37])[CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:36]([CH:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[N:37]=[C:25]([CH3:26])[CH:24]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: NNC1CCOCC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCOCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with (tetrahydropyran-4-yl)hydrazine hydrochloride (CAS Reg. No. 194543-22-1) to give the title compound as orange oil. MS (ESI): m/z=502.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH:5]=[N:4][C:3]=1[C:16]#[N:17].[C:18](#[N:20])[CH3:19]>CO.N>[CH3:19][C:18]1[N:20]=[C:16]([NH2:17])[C:3]2[N:4]=[CH:5][N:6]([C:2]=2[N:1]=1)[C@@H:7]1[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]1[OH:9]
Reactant: N#Cc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: CC#N
Agent: N
Solvent: CO
Product: Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 180 °C
Yield: 35.9 %

Procedure:
10 g of 5-amino-1-β-D-ribofuranosyl-4-imidazolecarbonitrile was dissolved in 20% ammonia methanol solution. 10 ml of acetonitrile was added thereto and the solution was heated for 5 hours at 180° C. The solvent was distilled off, purified by silica gel column chromatography and recrystallized from methanol to give 4.2 g of 2-methyladenosine (yield: 35.9%). 2-methyladenosine was methylated in the same manner as the above-mentioned [METHOD 1] to give Compound 5 and Compound 6.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[N:20][N:19]=[CH:18]2)=[CH:13][CH:12]=1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)(=O)C>[N:19]1[N:20]=[CH:21][N:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][OH:8])=[CH:16][CH:15]=2)[CH:18]=1
Reactant: [H][H]
Reactant: c1ccc(COCCc2ccc(-n3cnnc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: OCCc1ccc(-n2cnnc2)cc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
To a stirred solution of 4-[4-(2-benzyloxyethyl)phenyl]-4H-[1,2,4]triazole (0.237 g in 20 mL methanol) was added 183 mg of 10% palladium hydroxide on carbon catalyst followed by 0.20 mL acetic acid. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 11 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 90:7:1) gave the title compound (0.147 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: CCCCCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(CCC(=O)OCC)cc1-c1cc(CCC(=O)OCC)ccc1O
Yield: 82.2 %

Procedure:
To 5 ml of a DMF solution containing 100 mg (0.2591 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 331.3 μl (2.591 mmol) of pentyl bromide, there were added 42.9 mg (0.3109 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 7 g of WAKO-gel C-200, eluent: hexane and toluene/ethyl acetate of 50/1) to obtain 97.2 mg (0.2131 mmol, 82%) of 2-pentyloxy-2'-hydroxy-5,5'-bis (2ethoxycarbonylethyl) biphenyl as an oily product.