Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[S:12][C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=2[C:9]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)=O.[C:26](OCC)(=[O:34])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30].Cl>C(O)(C)(C)C.O>[OH:34][C:26]1[N:7]=[C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][C:10]=3[C:9]2=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:27]=1[CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc(-c2c(CC(=O)O)c(O)nc3sc4c(c23)CCCC4)cc1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
To a solution of potassium tert-butoxide (0.269 g; 2.4 mmol) in dry tert-butanol (10 mL) under a nitrogen atmosphere at 50° C. were added (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone (0.542 g; 2 mmol) and diethyl succinate (0.464 mL; 2.8 mmol). The mixture was heated at reflux for 24 h and then cooled down to room temperature. Water (8 ml) was added and then the reaction mixture was acidified with a solution of hydrochloric acid 1N until pH 1. The aqueous layer was extracted with diisopropylether (3×10 ml) and ethyl acetate (3×10 mL). The organics were combined and the volatiles were removed under reduced pressure. The remaining crude was crystallized from acetic acid to furnish 0.101 g (14%) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]([F:39])([F:38])[F:37])[N:28]=[CH:29][C:22]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:19])[C@@H:13]([O:18][C:21]2[C:22]3[CH:29]=[N:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:38])([F:39])[F:37])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:14][O:15][CH2:16][CH3:17])=[N:9][CH:10]=1)#[N:4]
Reactant: CCOC[C@H](O)C(=O)Nc1ccc(C#N)cn1
Reactant: FC(F)(F)c1ccccc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1C(F)(F)F)C(=O)Nc1ccc(C#N)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
60% Sodium hydride (60.0 mg, 1.50 mmol) was added in one portion to (S)—N-(5-cyanopyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H4) (235 mg, 1.00 mmol) in anhydrous THF (5 mL) and the mixture was cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and 4-chloro-1-(2-(trifluoromethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate P1) (298.6 mg, 1.00 mmol) as suspension in dry THF (4 mL) was added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric acid (4 mL) was added and the mixture extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 20 to 100% ethyl acetate in isohexane to give the product (430 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.62-3.70 (2H, m), 4.08-4.14 (2H, m), 6.04 (1H, t), 7.53-7.55 (1H, m), 7.68-7.77 (2H, m), 7.91 (1H, dd), 7.97 (1H, dd), 8.39 (1H, dd), 8.41 (1H, s), 8.56 (1H, s), 8.57-8.59 (1H, m), 9.02 (1H, s); m/z (ESI−) (M−H)−=496; HPLC tR=2.55 min.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:29]=[C:30](I)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2].[N:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[C:1]([CH2:4][CH2:5][C:6]1[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[CH:29]=[C:30]([C:43]3[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=3)[CH:31]=2)=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([OH:3])=[O:2]
Reactant: OB(O)c1ccncc1
Reactant: O=C(O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3ccncc3)cc(-c3cccc(F)c3)c2)c1CCC(=O)O
Yield: 25.9 %

Procedure:
A similar procedure as described in Example 5, step 2 was used, starting from 4-{2-(2-carboxy-ethyl)-3-[6-(3′-fluoro-5-iodo-bi phenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (116 mg, 0.18 mmol) and pyridin-4-ylboronic acid (66 mg, 0.54 mmol) to obtain 4-{2-(2-carboxy-ethyl)-3-[6-(3′-fluoro-5-pyridin-4-yl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (28 mg, 26%) as an amorphous white solid: ES(+)-HRMS m/e calculated for C36H38FNO6 (M+H)+ 600.2756, found 600.2754.
Reaction SMILES: [CH2:1]([N:4]1[C:10](=O)[O:9][C:7](=[O:8])[C:6]2=[CH:12][N:13]=[CH:14][CH:15]=[C:5]12)[CH:2]=[CH2:3].[C-]#N.[K+].O>CN(C=O)C>[CH2:1]([N:4]1[C:5]2[C:6](=[CH:12][N:13]=[CH:14][CH:15]=2)[C:7](=[O:8])[C:10]1=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)oc(=O)c2cnccc21
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1C(=O)C(=O)c2cnccc21
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution of N-allyl-5-azaisatoic anhydride (20 mmol) in DMF is added dropwise to a suspension of pulverized potassium cyanide (21 mmol) in DMF at 100° C. The reaction mixture is stirred at 100° C. for an additional 5 min after which time the mixture is poured into cold water and extracted with ether. The organic layer is dried (Na2SO4), filtered and the solvent is removed. Stirring the resulting residue in 2N hydrochloric acid overnight and adjusting the pH to 7 gives, upon filtration, N-allyl-5-azaisatin.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C>ClCCl>[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:4][CH2:1][CH:2]=[CH2:3])=[CH:10][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: C=CCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNCc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of allylamine (17.8 g; 312 mmol) in 200 ml of dichloromethane was added 4-trifluoromethoxybenzyl bromide (16 g; 62.4 mmol) and DIEA 8.88 g; 68.4 mmol). After stirring at rt overnight the reaction mixture was extracted with one volume of water. The organic phase was dried over sodium sulfate and concentrated to afford N-[4-(trifluoromethoxy)benzyl]prop-2-en-1-amine (14 g; 97% crude yield), which was used in the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[CH:39][CH:40]=[CH:41][N:42]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ncccn2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ncccn2)ccc1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 8.3 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyrimidin-2-yl)benzamido)-4-phenylbenzoate (0.072 g) in ethyl acetate (4 mL) and methanol (4 mL), 10% palladium-carbon (36 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 45 minutes. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 75-60% hexane/ethyl acetate] to obtain 5 mg of tert-butyl 2-(2-hydroxy-5-(pyrimidin-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]N3N=NC(CC4C=CC(Cl)=C(Cl)C=4)=N3)[C:6](=[O:31])[N:5]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:4]=2[N:3]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[NH:48][N:47]=C(CCCO)C=2)=[CH:40][CH:39]=1>>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[C:44]([C:41]4[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=4)[NH:48][N:47]=3)[C:6](=[O:31])[N:5]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:4]=2[N:3]=1
Reactant: OCCCc1cc(-c2ccc(Cl)cc2)[nH]n1
Reactant: CCCCCn1c(=O)n(CCCCCn2nnc(Cc3ccc(Cl)c(Cl)c3)n2)c(=O)c2[nH]c(Cl)nc21
Product: CCCCCn1c(=O)n(CCCc2cc(-c3ccc(Cl)cc3)[nH]n2)c(=O)c2[nH]c(Cl)nc21
Yield: 30 %

Procedure:
Prepared as with 8-chloro-1-(5-{5-[(3,4-dichlorophenyl)methyl]-2H-tetrazol-2-yl}pentyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione (Comparative Example C) using 3-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]-1-propanol. The final product material was washed with ether to yield the title compound as a cream solid (30%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[N:24]([CH3:25])[N:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:14]=1.O>CC(N(C)C)=O>[CH3:25][N:24]1[C:20]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([N:5]3[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]3)[N:14]=2)=[CH:21][C:22]([C:26]([F:29])([F:27])[F:28])=[N:23]1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1Oc1cccc(-n2cc(C(F)(F)F)cn2)n1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
0.262 g of 4-trifluoromethylpyrazole is introduced under nitrogen in 7 ml of dimethylacetamide and at 0° C. 0.057 g of NaH is added. The mixture is allowed to come to RT over 30 min and then 0.5 g of 2-fluoro-6-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine is added and the mixture is heated at 140° C. for 7 h, cooled to RT and poured into water. The product is extracted twice with ethyl acetate/heptane (1:1), washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel gives 0.349 g of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(4-trifluoromethylpyrazol-1-yl)pyridine as white crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH:17]1([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2CC2)C1

Procedure:
(S)-tert-butyl pyrrolidin-3-ylcarbamate (415 mg), (1-ethoxycyclopropoxy)trimethylsilane (1.8 mL) and molecular sieves (500 mg) were combined in methanol (4.5 mL). Acetic acid (1.3 mL) was added, followed by sodium cyanoborohydride (420 mg). The resulting mixture was heated to reflux for 4 hours. Insoluble material was filtered off and reaction was made basic to pH 14 with addition of 6M aqueous NaOH solution. The solution was extracted three times with diethyl ether, and the combined extracts were dried over MgSO4, filtered and concentrated to obtain an oil, which was purified by flash chromatography, eluting first with 100% dichloromethane, followed by 5% methanol/dichloromethane and 10% methanol/dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4](=[O:7])[NH:5][N:6]=1.O=[C:17]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH2:18][C:19](OCC)=[O:20]>C(O)(=O)C>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:3]1[C:4]([OH:7])=[N:5][N:6]2[C:19](=[O:20])[CH:18]=[C:17]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[NH:1][C:2]=12
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC1=NNC(=O)C1Cc1ccccc1Cl
Solvent: CC(=O)O
Product: O=c1cc(-c2ccncc2)[nH]c2c(Cc3ccccc3Cl)c(O)nn12
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-amino-4-[(2-chlorophenyl)methyl]-2,4-dihydro-3H-pyrazol-3-one (500 mg, 2.23 mmol) in acetic acid (2 mL) was added ethyl 3-oxo-3-(4-pyridinyl)propanoate (432 mg, 2.23 mmol). The reaction mixture was irradiated (microwave) and stirred at 140° C. for 60 minutes. Reaction mixture was cooled down, diluted with acetic acid (2 mL) and stood still for 2 hours. Precipitate was collected by filtration. The solid was washed with acetic acid (1 mL), ethanol (1 mL×2) and dried. The titled product was obtained. (177 mg, 22%); LC/MS: MS (ES+) m/e 353 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 2H) 6.06 (d, J=1.52 Hz, 1H) 7.02 (s, 1H) 7.23 (dd, J=5.94, 3.41 Hz, 2H) 7.45 (dd, J=5.68, 3.66 Hz, 1H) 7.75 (d, J=6.06 Hz, 2H) 8.76 (d, J=6.06 Hz, 2H) 12.05 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](=S)=[S:10]>C(O)C>[SH:10][C:9]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccncc1N
Reactant: S=C=S
Solvent: CCO
Product: Sc1nc2cnccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 25 g (0.23 mol) of 3,4-diaminopyridine in 750 mL of ethanol containing 50 mL (63.2 g), 0.83 mol) of carbon disulfide was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and the beige precipitate which had formed was collected by filtration and allowed to air dry overnight. The product amounted to 33.5 g, m.p.>320° C.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:35]=[CH:34][C:10]([CH2:11][CH:12]([NH:24][S:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:13]3[N:18]=[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[N:3]1.[C:36](OC(=O)CN(C(OC(C)(C)C)=O)C1C=CC=C(C(S(C2C=CC=CN=2)(=O)=O)NCC2C=CC(C3SC=CN=3)=CC=2)N=1)(C)(C)[CH3:37]>>[CH2:36]([O:22][C:21](=[O:23])[CH2:20][NH:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH:6]=[CH:5][CH:4]=[N:3]3)=[CH:35][CH:34]=2)[NH:24][S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[N:18]=1)[CH3:37]
Reactant: O=C(O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Agent: Cl
Product: CCOC(=O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Yield: 95 %

Procedure:
Reaction was carried out in the same manner as in Example 27 except for using (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid hydrochloride (21.6 mg, 0.0367 mmol) obtained in Example 7-(b) in place of tert-butyl[tert-butoxycarbonyl(6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford the title compound (17.6 mg) as a colorless oil. (Yield: 95%)
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:9]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:10][CH:11]=[CH2:12])[O:5][P:6](Cl)Cl)#[N:2].C[Si](C)(C)[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C1(C)C=CC=CC=1>[C:1]([CH2:3][CH:4]([C:9]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:10][CH:11]=[CH2:12])[O:5][P:6]([C:20]1[NH:19][CH:23]=[CH:22][N:21]=1)[C:20]1[NH:21][CH:22]=[CH:23][N:19]=1)#[N:2]
Reactant: C[Si](C)(C)n1ccnc1
Reactant: C=CCC(CC)(CC)C(CC#N)OP(Cl)Cl
Solvent: Cc1ccccc1
Product: C=CCC(CC)(CC)C(CC#N)OP(c1ncc[nH]1)c1ncc[nH]1
Reaction time: 0.17 h

Procedure:
To toluene (3 ml) there were added 0.578 g (2.05 mmol) of 2-cyano-1-(1,1-diethyl-3-butenyl)ethoxydichlorophosphine and 0.632 g (4.50 mmol) of 1-(trimethylsilyl)imidazole under an argon atmosphere at room temperature, and reaction was conducted for 10 minutes. After by-product chlorotrimethylsilane and toluene were removed under reduced pressure for 25 minutes at room temperature, the residual toluene and excess 1-(trimethylsilyl)imidazole were removed under reduced pressure for 2 hours at 55° C. to obtain 2-cyano-1-(1,1-diethyl-3-butenyl)ethoxybisimidazolyl phosphine as a colorless transparent oil. This was dissolved in 4.1 ml of a mixed solution of chloroform-d and chloroform, and the solution (0.5 M) was added at −3.5° C. under an argon atmosphere to 1.414 g (2.15 mmol) of N6-benzoyl-5′-O-(4,4′-dimethoxytrityl)-2′- deoxyadenosine that had been subjected to azeotropic dehydration with 5 ml of 1,4-dioxane at room temperature for one hour. Upon reaching homogeneity, the mixture was allowed to stand overnight at 4° C. for reaction to obtain the target nucleotide derivative. The 31P NMR {external standard: (CH3O)3P=140 ppm, CDCl3} was δ; 129.5, 130.3, 131.1, 134.3 ppm (measuring the 31P NMR spectrum with a 161.7 MHz NMR measuring apparatus).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCCC)=[N:18][C:17]3=[O:25])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:36]([O:40][C:41]([N:43]1[CH2:50][CH2:49][NH:48][CH2:47][C:44]21[CH2:46][CH2:45]2)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[CH2:50][CH2:49][N:48]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:31])[F:32])=[CH:29][C:3]=3[C:2]([F:34])([F:35])[F:1])[N:7]=[CH:8]4)[C:17](=[O:25])[N:18]=2)[CH2:47][C:44]21[CH2:45][CH2:46]2)=[O:42])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNCC12CC2
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CC12CC2

Procedure:
7-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4,7-Diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester following general procedure B.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:12][C:13](=[O:27])[C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([NH:29][CH2:30][C@H:31]([OH:32])[C:33]3[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from (2S)-2-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-3-phenyl-propionic acid methyl ester (which was obtained in Example 164) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as an off-white solid; mp>98° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.80–1.90 (m, 2 H), 2.05–2.90 (m, 5 H), 2.91 (s, 3 H), 3.00–3.20 (m, 2 H), 3.70–3.80 (m, 2 H), 4.47 (dd, J=8.0, 4.3 Hz, 1 H), 4.50–4.65 (m, 1 H), 6.81 (d, J=8.2 Hz, 1 H), 6.92 (d, J=8.9 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.10–7.30 (m, 6 H), 7.67 (d, J=8.9 Hz, 2 H), 8.47 (d, J=7.8 Hz, 1 H); MS (ES) m/z: 611.2 (MH+); HRMS Calcd. for C31H39N4O7S (MH+): 611.2534. Found: 611.2525.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-])=O)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C)C.O1CCCC1.[C].[Pd]>[NH2:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][O:28][C:19]2[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)(=[O:13])=[O:12])[C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[N:33][CH:34]=1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
To a solution of 4-tert-butyl-N-{5-(4-methylphenyl)-6-{2-(5-nitropyridin-2-yloxy)ethoxy}pyrimidin-4-yl}benzenesulfonamide (975 mg) in isopropanol/tetrahydrofuran (1:1) (20 ml) is added 10% palladium-carbon (200 mg), and the mixture is stirred at room temperature for 1.5 hour under hydrogen atmosphere (1 atm). The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=2:1), and recrystallized from ethyl acetate/n-hexane to give N-{6-{2-(5-aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (829 mg) as crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1>[O:8]1[C:4]2[CH:3]=[C:2]([CH:19]=[O:20])[CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7]1
Reactant: Brc1ccc2c(c1)OCC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-bromo-2,3-dihydro-1-benzofuran (190 mg, 0.955 mmol) in THF (4 ml) at −78° C. was added n-BuLi (1.313 ml, 2.100 mmol). The reaction mixture was stirred at −78° C. for 45 min then a solution of DMF (1.109 ml, 1.6 M in hexanes, 14.32 mmol) in THF (2 ml) was added dropwise and the reaction was stirred at −78° C. for 10 min then warmed to rt and stirred for 1 h. LCMS showed no starting material remaining. The reaction was stirred at rt for a further 2.5 h. The reaction mixture was poured cautiously into 2 M HCl (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (50 ml), dried over MgSO4, filtered, evaporated and chromatographed (eluting 0-100% EtOAc/Hexane). The relevant fractions were combined and evaporated to deliver the product as a clear, colourless oil (44 mg, 0.297 mmol, 31%).