Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=C(F)C=3)[C:19]=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]([N:38]1[C:43](=[O:44])[C:42]([CH2:45]OS(C)(=O)=O)=[CH:41][C:40]([C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=2)=[N:39]1)[CH:35]([CH3:37])[CH3:36].C(N1CCNCC1)C1C=CC=CC=1>>[CH2:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:45][C:42]2[C:43](=[O:44])[N:38]([CH2:34][CH:35]([CH3:37])[CH3:36])[N:39]=[C:40]([C:51]3[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=3)[CH:41]=2)[CH2:13][CH2:12]1)[C:19]1[CH:18]=[CH:21][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC(C)C)n2)cc1
Yield: 97.7 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a pale yellow oil (yield: 97.7%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)C.[NH3:25]>CO.ClCCl>[CH2:17]([C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([NH2:25])=[O:3])=[CH:6][CH:7]=2)[N:16]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: N
Reactant: CCCCCCCc1ccnc(-c2ccc(C(=O)OCC)cc2)n1
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCc1ccnc(-c2ccc(C(N)=O)cc2)n1

Procedure:
4.4 g. of 4-(4-n-heptylpyrimid-2-yl)-benzoic acid ethyl ester dissolved in 50 ml. of a methanol-dichloromethane (1:1) mixture are treated with 30 ml. of liquid ammonia in a laboratory autoclave and then heated to 90° for 5 hours (pressure: 16 atmospheres). The reaction mixture is evaporated to dryness and the poorly soluble amide separated from the unreacted educt, whereby there is obtained 4-(4-n-heptylpyrimid-2yl)-benzoic acid amide.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30](O)=[O:31])[CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.[O:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:28]=[C:27]([CH3:29])[C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)[C:30](=[O:31])[N:46]3[CH2:45][CH2:44][N:43]([CH:40]4[CH2:41][CH2:42][O:37][CH2:38][CH2:39]4)[CH2:48][CH2:47]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc[nH]c12
Reactant: C1CN(C2CCOCC2)CCN1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc2nc[nH]c12

Procedure:
Prepared analogously to Example 1h from 120 mg (0.22 mmol) (R)-1-carboxy-2-(7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 50 mg (0.29 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])C1C=CC=CC=1OC.[Li+].[OH-:31].Cl>O.C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([C:10](=[O:11])[NH:12][CH:13]3[CH2:14][CH2:15]3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([OH:29])=[O:31]
Reactant: COc1ccccc1C(=O)c1cnn(-c2cc(C(=O)NC3CC3)ccc2C)c1N
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)O)c1N
Yield: 88 %

Procedure:
A solution of 5-amino-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g, see Example 44), LiOH (1.2 g) in water/ethanol (15 ml/20 ml) was heated at 50° C. overnight. The solution was neutralized with dilute HCl (2M), and extracted with ethyl acetate (200 ml×2), dried over Na2SO4. The solvent was evaporated under reduced pressure and ethyl acetate and diethyl ether was added. The resulting solid was filtered to give the desired 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid. (0.8 g; yield: 88%.).
Reaction SMILES: N#N.CC([O-])(C)C.[K+].[CH2:9]([OH:12])[CH2:10][OH:11].Cl[C:14]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]=[O:29])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2>O>[OH:11][CH2:10][CH2:9][O:12][C:14]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]=[O:29])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [K+]
Solvent: O
Product: O=Cc1c2ccccc2c(OCCO)c2ccccc12
Reaction time: 0.5 h

Procedure:
A 3 L 2-neck flask fitted with thermometer, condenser, stirring bar, N2 line and bubbler was charged with KOtBu (MCB, 25 g, 0.22 mol), 1,2-ethylene glycol (Fisher, 1.5 L) and 10-chloro-9-anthraldehyde (Aldrich, 50 g, 0.207 mol). The mixture was stirred at 100° for 1.5 h. An additional 5 g (45 mmol) of KOtBu was added and the stirring continued for an additional 0.5 h. The reaction mixture was cooled poured into cold H2O (1.5 L), then stirred for 10 min before the precipitate was collected by filtration. The yellow solid was dissolved in CH2Cl2 (1 L) and passed through a plug of SiO2 (100 g) using CH2Cl2 (9 L) as the eluting solvent. The CH2Cl2 contained impurities only and was discarded. The desired material was then eluted with EtOAc (12 L). The appropriate fractions were combined and the solvent removed to give (after drying at 50°) 28.82 g (53%), 10-(2-hydroxyethyloxy)-9-anthracenecarbaldehyde mp 142°-144°, (CH2Cl2 /hexane), (C, H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:25])[CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34]([C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:24])[C:9]([C:15]3[CH:16]=[CH:17][C:18](=[O:23])[N:19]([CH2:21][CH3:22])[CH:20]=3)([OH:14])[C:10]([F:11])([F:13])[F:12])=[C:4]([Cl:25])[CH:3]=2)=[CH:29][C:28]=1[O:27][CH3:26])=[O:35]
Reactant: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Product: CCn1cc(C(O)(C(C)c2ccc(-c3ccc(C(=O)OC)c(OC)c3)cc2Cl)C(F)(F)F)ccc1=O

Procedure:
In analogy to Example 150, step 2, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-ethyl-1H-pyridin-2-one (Example 183, step 2) was reacted with 3-methoxy-4-methoxycarbonylphenylboronic acid to give the title compound as an off-white solid. MS (m/e)=524.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[S:21][C:5]2[CH2:6][N:7]([C:10]([C:12]3[CH:20]=[CH:19][C:15]4[NH:16][N:17]=[N:18][C:14]=4[CH:13]=3)=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:22]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>N1C=CC=CC=1.CS(C)=O>[NH:16]1[C:15]2[CH:19]=[CH:20][C:12]([C:10]([N:7]3[CH2:8][CH2:9][C:4]4[C:3]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[C:2]([NH:1][C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=5)=[O:38])[S:21][C:5]=4[CH2:6]3)=[O:11])=[CH:13][C:14]=2[N:18]=[N:17]1
Reactant: Nc1sc2c(c1C(=O)N1CCCC1)CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cc1)Nc1sc2c(c1C(=O)N1CCCC1)CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 25 °C
Yield: 4 %

Procedure:
Starting material 13 (1.2 g, 20% content, 0.6 mmol) was dissolved in 5 ml pyridine and one half of 112 mg (0.7 mmol) p-chlorphenyl isocyanate was added. The reaction mixture was stirred over night at ambient temperature. Then the other half of the p-chlorphenyl isocyanate was added and the reaction was again stirred over night at ambient temperature. The reaction was now concentrated in vacuo and the thereby isolated crude product was dissolved in 7 ml DMSO and purified by prep. HPLC (Method 3). The pure fractions were combined, the solvent reduced and the product finally lyophilized. The desired product 14 could thereby be isolated as yellow solid (16.2 mg, 4%; and additional 17 mg, 84% content 14, 4% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N@:13]1[CH2:15][CH:14]1[C@H:16]1[O:20][C:19](=[O:21])[C@H:18]([CH2:22][CH2:23][CH3:24])[CH2:17]1)(=[O:12])=[O:11])([O-:3])=[O:2].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][CH2:34][C:33]1=[O:40]>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:33](=[O:40])[CH2:34][N:35]([CH2:15][C@H:14]([NH:13][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C@@H:16]2[CH2:17][C@@H:18]([CH2:22][CH2:23][CH3:24])[C:19](=[O:21])[O:20]2)[C:36]([CH3:39])([CH3:38])[CH2:37]1
Reactant: CC1(C)CN(c2ccccc2Cl)C(=O)CN1
Reactant: CCC[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: CCC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 75.6 %

Procedure:
A solution of 700 mg of (3R,5S)-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]-3-propyldihydrofuran-2-one obtained in Example (116g) (1.98 mmol) and 611 mg of 1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (1k) (2.57 mmol) in toluene (20 ml) was stirred at 110° C. for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone 5/1) to obtain 888 mg of the title compound (yield: 76%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:19])[CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:20][C:21]([CH3:26])([CH2:24]O)[CH2:22][OH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:23][CH2:22][C:21]([CH3:26])([CH3:24])[CH2:20][O:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)CSCC(=O)c1ccc2c(c1)OCO2
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CSCC1(c2ccc3c(c2)OCO3)OCC(C)(C)CO1

Procedure:
Ethyl {[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]thio}acetate (Method 11) (15.8 g, 0.056 mol) was dissolved in benzene (500 mL) and 2,2-dimethyl-1,3-propanediol (46.6 g, 0.45 mol) and p-toluene sulfonic acid (cat., 500 mg) were added. The mixture was stirred at reflux in a Dean-Stark apparatus for two hours, given room temperature and concentrated under reduced pressure. The resulting white solid was dissolved in CH2Cl2 (500 mL) and washed twice with water (300 mL) and brine (300 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude oil was purified by flash-chromatography (heptane:EtOAc 4:1) to afford the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:38]=[CH:37][C:17]([O:18][CH:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[C:26]([O:34][CH2:35][CH3:36])[CH:25]=2)[C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:38]=[CH:37][C:17]([O:18][CH:19]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:32])[CH3:33])=[C:26]([O:34][CH2:35][CH3:36])[CH:25]=2)[C:20]([OH:22])=[O:21])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(Oc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)OC)ccc1OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(Oc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To 9D (570 mg, 1.09 mmol) in THF (6.0 mL) and MeOH (0.5 mL) was added LiOH (1.0 M, 1.92 mL, 1.92 mmol). The mixture was stirred at rt for 1.0 h before it was acidified with 1.0 N HCl (5.0 mL). The mixture was extracted with ethyl acetate, washed with brine and dried over Na2SO4. After removal of solvent, 9E (500 mg, 90% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.16 Hz, 6H) 1.30 (t, J=7.03 Hz, 3H) 4.00 (q, J=7.03 Hz, 2H) 4.49 (m, 1H) 5.09 (s, 2H) 5.85 (s, 1H) 6.90-7.38 (m, 11H) 7.95 (d, J=9.20 Hz, 2H).
Reaction SMILES: [CH:1]1([C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[CH2:9]([N:12]=[C:13]=[O:14])[CH:10]=[CH2:11]>>[CH2:9]([NH:12][C:13]([CH:5]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:8])[C:6]#[N:7])=[O:14])[CH:10]=[CH2:11]
Reactant: N#CCC(=O)C1CC1
Reactant: C=CCN=C=O
Product: C=CCNC(=O)C(C#N)C(=O)C1CC1
Yield: 79.6 %

Procedure:
When β-cyclopropyl-β-oxopropionitrile (2,.00 g, 18.3 mmoles) [prepared in Example 1, Step A]was reacted with allylisocyanate (1.60 g, 19.2 mmoles) according to the general procedure of Example 1, Sep B, the title compound (2.8 g) was obtained as a white solid after recrystallization from 30% aqueous ethanol, m.p. 72°-73.5° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].[F-].[Cs+].C(O[Si](OCC)(OCC)OCC)C.[C:49]([O:53][CH2:54][CH3:55])(=[O:52])[CH:50]=[CH2:51]>C1COCC1>[CH2:54]([O:53][C:49](=[O:52])[CH2:50][CH2:51][N:13]1[C:12](=[O:22])[C:11]2([CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=3)[CH2:24][CH2:23]2)[N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14]1)[CH3:55]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: C=CC(=O)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a mixture of 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (1.0 g, 2.1 mmol), cesium fluoride (32 mg, 0.21 mmol) and tetraethoxysilane (475 μL, 2.1 mmol) in THF (10 mL) was added ethyl acrylate (254 μL, 2.3 mmol). The mixture was stirred for 1 d at room temperature. Evaporation of the solvent yielded a residue which was purified by chromatography on silica gel (ethyl acetate/n-hexane 1:2) to yield the desired product (0.9 g, 75%), MS: m/e=572.1 (M+H+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=[O:11])=[O:8].[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[CH:2]1[C:1]([N+:13]([O-:15])=[O:14])=[CH:6][C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]=2[CH:3]=1)=[O:11])=[O:8]
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
6-Nitrobenzoyleneurea was prepared using an adaptation of the method of Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962). To a solution of benzoyleneurea (0.201 g, 1.24 mmol) in 3.0 mL concentrated H2SO4 at 0° C. was added KNO3 (0.139 g, 1.37 mmol) in one portion. The reaction mixture was allowed to warm to room temperature then stirred overnight. The resulting yellow solution was poured onto 10 mL of ice giving a pale yellow precipitate. The precipitate was isolated on a Hirsch funnel and washed with 35 mL of deionized water. The solid was suspended in 25 mL deionized water, refiltered via Hirsch funnel and allowed to dry on the filter under vacuum for 30 minutes affording 0.155 g (60%) title compound as a pale yellow powder. An analytical sample was obtained by recrystallization from 50% glacial acetic acid as a pale brown microcrystalline solid: mp 327°-328° C. (lit., Varma and Singh; Ind. J. Chem. 296:578-81 (1990): 315°-316° C. dec.). FT-IR (cm-1) 3020, 2850, 1713, 1684, 1631, 1602, 1538, 1491, 1444, 1385, 1332, 1303, 1239, 1157. 1H NMR (DMSO-d6 at δ2.49): δ7.30 (d, J8,7 =9 Hz, 1 H, H8); 8.44 (dd, J7,8 =9 Hz, J7,5 =2.4 Hz, 1H, H7); 8.57 (d, J5,7 =2.7 Hz, 1H, H5); 11.71 (s, 1H, NH); 11.76 (s, 1H, NH). EIMS m/z 207 (M+, bp), 164 (43%), 134 (18%), 106 (22%), 90 (29%), 63 (27%). EIHRMS calc. for C8H5N3O4 207.02799, found 207.02910.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][O:15][C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[O:10][C@H:9]1[N:39]1[C:48]2[N:47]=[CH:46][N:45]=[C:43]([NH2:44])[C:42]=2[N:41]=[CH:40]1.[C:49]([CH2:51][CH2:52][O:53][C:54](ON1C(=O)CCC1=O)=[O:55])#[N:50]>CC#N.CCOC(C)=O>[C:49]([CH2:51][CH2:52][O:53][C:54]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C@@H:8]1[C@H:12]([OH:13])[C@@H:11]([CH2:14][O:15][C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[O:10][C@H:9]1[N:39]1[C:48]2[N:47]=[CH:46][N:45]=[C:43]([NH2:44])[C:42]=2[N:41]=[CH:40]1)=[O:55])#[N:50]
Reactant: N#CCCOC(=O)ON1C(=O)CCC1=O
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCN)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@H](OCCCCCNC(=O)OCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 96.3 %

Procedure:
To a solution of 2′-O-(5-aminopentyl)-5′-O-(4,4′-dimethoxytrityl)-adenosine (1.0 g, 1.52 mmol) in anhydrous CH3CN (8.0 mL) was added with stirring, under argon, N-(2-Cyanoethoxycarbonyl)oxy succinimide (0.43 g, 2.02 mmol) After stirring for 5 h at room temperature the reaction mixture was diluted with EtOAc (50 mL) and washed with aq saturated bicarbonate (3×20 mL) and water (20 mL), dried (Na2SO4) and evaporated to give 53 as a light yellow foam (1.1 g, 98% yield). This compound was used without further purification for the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH:14]=[CH2:15])[CH:4]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][C:28](O)=[O:29])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C.C(OP(C#N)(=O)OCC)C>CN(C=O)C>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH:27][C:28]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:5]([CH:14]=[CH2:15])[CH:4]=2)=[O:29])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: C=Cc1cc(CN)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Reaction time: 12 h
Yield: 51 %

Procedure:
A dried 25 ml two-neck round bottom flask was filled with argon gas and the solution of N-(4-aminomethyl-2-vinyl-phenyl)-methanesulfonamide (51 mg, 0.23 mmol) and 3-(4-t-butyl-phenyl)-acrylic acid (1.2 eq, 0.27 mmol, 55.26 mg) in DMF was put into the flask. To the solution were added triethylamine (2 eq, 0.46 mmol, 64.12 mg) and diethylcyanophosphonate (1.2 eq, 0.27 mmol, 41.88 μl) and stirred for 12 hours. After confirming the completion of the reaction with TLC, the reaction solution was extracted with methylenechloride, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (n-hexane/ethyl acetate=1/1) to yield a white solid (48.4 mg, 43.37%).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:36][O:37][C:38](=[O:41])[CH2:39]Cl.O>CN(C=O)C>[CH3:36][O:37][C:38](=[O:41])[CH2:39][N:26]([CH3:27])[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:22][CH2:23]2)(=[O:28])=[O:29]
Reactant: COC(=O)CCl
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN(C)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 4) (0.047 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (0.071 mmol) and chloro-acetic acid methyl ester (0.071 mmol). Stirred at 40° C. for 2 h and then added H2O (1.5 mL). Extracted with EtOAc (3×1 mL) and the combined organic phases were washed with brine (1 mL) and concentrated in vacuo. The residual oil was treated with TFA (1 mL) at rt for 1 h. The crude reaction mixture was concentrated in vacuo and redissolved in DMSO (0.5 mL). The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5][CH2:4]1)#[N:2].[CH:18]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([C:3]1([CH3:18])[CH2:4][CH2:5][CH:6]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)NCC1CCC(C#N)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C#N)CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a cooled (−78° C.) solution of tert-butyl (4-cyanocyclohexyl)methylcarbamate (500 mg) in tetrahydrofuran (10 mL) was added lithium diisopropylamide (2.0 mL, 2M in heptane). The mixture was stirred at −78° C. for 30 minutes before the addition of CH3I (1 mL). The mixture was then stirred and the temperature was allowed to warm to room temperature. The reaction was quenched with aqueous NH4Cl and the mixture was extracted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent and silica gel chromatography (40% ethyl acetate in hexane) of the crude material gave the title compound.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([CH:18]([C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)[CH2:19][CH3:20])[CH3:17].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:16]([CH:18]([C:21]1[N:22]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH:23]=[CH:24][N:25]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCC(CC)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccc(-n2ccnc2C(CC)CC)c([N+](=O)[O-])c1

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate 9.16 g, 2-(1-ethylpropyl)-1H-imidazole 5.94 g, N,N-diisopropylethylamine 11.2 mL and acetonitrile 86 mL were mixed and heated under reflux for 15 hours in nitrogen atmosphere. From the reaction liquid the solvent was distilled off, and the residue was dissolved in ethyl acetate and rendered weakly alkaline with saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated, washed with water and dried over magnesium sulfate. Distilling the solvent off, 13.16 g of the title compound was obtained.