Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][C@H:9]([C:13]([NH:15][CH:16]([CH:24]([OH:51])[CH:25]([NH:33][C:34](=[O:50])[C@H:35]([CH:47]([CH3:49])[CH3:48])[NH:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O>C(Cl)(Cl)Cl>[C:37]([NH:36][C@H:35]([C:34]([NH:33][CH:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:24]([OH:51])[CH:16]([NH:15][C:13](=[O:14])[C@H:9]([CH:10]([CH3:12])[CH3:11])[NH2:8])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:50])[CH:47]([CH3:49])[CH3:48])([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](N)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 89 %

Procedure:
Using the procedure of Example 12 with the resultant compound of Example 239 provided a crude hydrochloride salt which was partitioned between chloroform and aqueous NaHCO3, dried over Na2SO4, and concentrated. Chromatography of the residue on silica gel using 3% methanol in chloroform provided in 89% yield the desired compound (Rf 0.5, 10% methanol in chloroform) as a white solid, m.p. 126°-127° C. Mass spectrum: (M+H)+ =603.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18](CC)(C)C)[CH:15]=[C:14]([C:23]([CH2:26]C)([CH3:25])[CH3:24])[C:13]=1[OH:28])([O-])=O.[N+](C1C(N=NC2C=CC=C(C(C)(C)C)C=2O)=CC([Cl:39])(C)CC=1)([O-])=O>>[Cl:39][C:7]1[CH:8]=[CH:9][C:4]2=[N:1][N:11]([C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:23]([CH3:26])([CH3:24])[CH3:25])[C:13]=3[OH:28])[N:10]=[C:5]2[CH:6]=1
Reactant: CC1(Cl)C=C(N=Nc2cccc(C(C)(C)C)c2O)C([N+](=O)[O-])=CC1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Product: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
When in Example 1, the 2-nitro-2'-hydroxy-3',5'-di-tert-amylazobenzene is replaced by an equivalent amount of 2-nitro-5-chloro-2'-hydroxy-3'-tert-butyl-5-methylazobenzene, the above noted product is obtained.
Reaction SMILES: [CH3:1][Li].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH3:31])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15](OP(OCC)(OCC)=O)[CH2:14][CH:13]([CH3:30])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].[Cl-].[NH4+]>C(OCC)C.[Cu]I>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([CH3:31])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:1])[CH2:14][CH:13]([CH3:30])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: [Li]C
Reactant: CCOP(=O)(OCC)OC1=C(C(=O)OC)C(C)(c2ccc(Cl)c(Cl)c2)CC(C)C1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C1=C(C)CC(C)CC1(C)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred suspension of copper (I) iodide (213 mg) in diethyl ether (10 mL) at 0° C. was treated with methyllithium (1.6 M, 1 equivalent), forming a cloudy yellow mixture. Additional methyllithium (1.6 M, 1 equivalent) was added, forming a cloudy grey mixture. This cloudy grey mixture was stirred at 0° C. for 15 min, and then treated with a solution of methyl (4RS,6SR)-6-(3,4-dichlorophenyl)-2-(diethoxyphosphoryloxy)-4,6-dimethylcyclohexen-1-carboxylate (130 mg) in diethyl ether (5 mL). A deep red color formed over 30 min. Stirring was continued while warming to rt for 2 h more. At the conclusion of this period, the resulting mixture was treated with 3:1 saturated aqueous ammonium chloride/concentrated ammonium hydroxide, and stirred for 10 min. The mixture was then extracted three times with diethyl ether, and the combined organic layers were washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel, eluting with 15% ethyl acetate/hexanes, to provide methyl (4RS,6RS)-6-(3,4-dichlorophenyl)-2,4,6-trimethylcyclohex-1-enecarboxylate (57 mg). Mass spectrum m/z 349.17 (M+Na+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28]O>S(=O)(=O)(O)O>[CH3:28][O:18][C:17](=[O:19])[CH2:16][C:14]1[N:15]=[C:11]([NH:10][C:8](=[O:9])[CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[S:12][CH:13]=1
Reactant: CO
Reactant: O=C(O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid (prepared in Example 18, 95.4 mg, 0.223 mmol) in methanol (1.1 mL) was treated with 1 drop of concentrated sulfuric acid. The reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with ethyl acetate (100 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (77.2 mg, 78%) as a yellow viscous oil: FAB-HRMS m/e calcd for C20H22Cl2N2O3S (M+H)+ 441.0807, found 441.0804.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[CH2:21][CH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH:26]3[CH2:27][CH2:28][N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CCCN1CCC(=O)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CCCN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 30 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with 1-propyl-piperidin-4-one using standard reductive amination conditions. The resulting crude solid was triturated was with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-propyl-piperidin-4-yl)amine as a solid (30% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethylether and methanol to give 344 as a solid (77% yield). NMR (CDCl3, 400 MHz), 0.92 (3H, t, J=7.3), 1.49-1.56 (2H, m), 1.64-1.72 (2H, m), 1.82-1.86 (2H, m), 1.93 (2H, t, J=11.3), 2.29 (2H, dd, J=7.7 and 7.9), 2.37 (3H, s), 2.50-2.56 (1H, m), 3.03 (2H, d, J=11.6), 3.88-3.91 (4H, m), 3.93 (2H, s), 4.03-4.06 (4H, m), 5.22 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=483
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3]C1C=C2C(C=CN2)=CC=1.[C:15]([C:18]1[C:26]2[C:21](=[CH:22][C:23](F)=[C:24](F)[CH:25]=2)[N:20]([CH2:29][C:30]([OH:32])=[O:31])[CH:19]=1)(=[O:17])[NH2:16]>>[C:15]([C:18]1[C:26]2[C:21](=[CH:22][C:23]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:24][CH:25]=2)[N:20]([CH2:29][C:30]([OH:32])=[O:31])[CH:19]=1)(=[O:17])[NH2:16]
Reactant: FC(F)(F)Oc1ccc2cc[nH]c2c1
Reactant: NC(=O)c1cn(CC(=O)O)c2cc(F)c(F)cc12
Product: NC(=O)c1cn(CC(=O)O)c2cc(OC(F)(F)F)ccc12

Procedure:
was prepared from 6-trifluoromethoxy-1H-indole [467451-91-8] in a similar manner as described for the preparation of (3-carbamoyl-5,6-difluoro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 303.0 [M+H]+, 605.0 [2M+H]+; tR (HPLC conditions k): 2.75 min.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:34]=[C:33]([S:35][C:36]2[N:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([O:49]CC)=[O:48])[CH:42]=3)[N:39]=[N:38][N:37]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[OH:52])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[K+].Cl>CO.O>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[CH:34]=[C:33]([S:35][C:36]2[N:40]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([OH:49])=[O:48])[CH:42]=3)[N:39]=[N:38][N:37]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[OH:52])=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2cccc(C(=O)OCC)c2)c2ccccc2c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2cccc(C(=O)O)c2)c2ccccc2c1O
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
2-(2-Tetradecyloxyphenyl)carbamoyl-4-[1-(3-ethoxycarbonylphenyl)-5-tetrazolylthio]-1-naphthol (19.5 g) was added to a solution of 5.3 g of potassium hydroxide in 50 ml of methanol and stirred for 30 minutes at 40°-50° C. Then 10 ml of concentrated hydrochloric acid was diluted with 500 ml of water and poured into the reaction solution. Crystals precipitated were collected by filtration and recrystallized from methanol to obtain 16.1 g of 2-(2-tetradecyloxyphenyl)carbamoyl-4-[1-(3-carboxyphenyl)-5-tetrazolylthio]-1-naphthol, m.p., 136°-138° C. Yield was 86%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[CH2:9]([Li])CCC.IC.O>O1CCCC1>[CH3:9][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccsc1
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: Cc1sccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Thiophenecarboxylic acid (3.84 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 41.3 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Iodomethane (3.7 ml) in tetrahydrofuran (10 ml) was added dropwise. The resulting mixture was heated to room temperature and stirred for 15 hours. The mixture was poured into water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3-thiophenecarboxylic acid (3.98 g) as crystals.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](I)[CH:12]([CH3:14])[CH3:13]>>[CH2:11]([S:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH:12]([CH3:14])[CH3:13]
Reactant: O=C(O)c1cccnc1S
Reactant: CC(C)CI
Product: CC(C)CSc1ncccc1C(=O)O
Yield: 92 %

Procedure:
2-Mercapto-nicotinic acid (2 g, 12.8 mmol) and isobutyliodide were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (2.175 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH2:39][CH2:38][CH:37](O)[CH2:36]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(=O)(O)[O-].[Na+].C(Cl)Cl.CO.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH:37]3[CH2:38][CH2:39][N:35]([CH3:34])[CH2:36]3)=[CH:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Reactant: CN1CCC(O)C1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(Oc2ccc(CC3c4ccc(OCc5ccccc5)cc4CCN3c3ccc(F)cc3)cc2)C1
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-(4-hydroxybenzyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.450 g, 1.02 mmol) in THF (5 ml) was added 1-methyl-3-pyrrolidinol (0.22 ml, 2.04 mmol), tri-n-butyl-phosphine (0.5 ml, 2.04 mmol) and 1,1′ azodicarbonyl dipiperidine (0.5 g, 2.04 mmol) respectively. Dichloromethane (4 ml) was added and the reaction was allowed to stir overnight. The reaction was diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated. The product was purified by radial chromatography (100% CH2Cl2, then CH2Cl2/MeOH, 95:5) to yield the title compound (0.30 g, 56% yield): ES-MS (m/z) 523 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[CH:10]=[C:11]1[CH2:16][CH2:15][O:14][N:13]([CH3:17])[C:12]1=[O:18])([CH3:6])([CH3:5])[CH3:4].[CH3:27]S(C)=O.CI>O>[C:3]([C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[O:22][CH3:27])[CH:10]=[C:11]1[CH2:16][CH2:15][O:14][N:13]([CH3:17])[C:12]1=[O:18])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN1OCCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1c(C(C)(C)C)cc(C=C2CCON(C)C2=O)cc1C(C)(C)C
Reaction time: 50 h
Yield: 71 %

Procedure:
Sodium hydride (0.33 g, 8.3 mmol), 60% in mineral oil dispersion, kept under nitrogen purge, was washed twice with 20 ml portions of hexane. Dimethyl sulfoxide (10 ml) was added, followed by the addition of 2.5 g (7.6 mmol) of dihydro-4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-methyl-2H-1,2-oxazin-3(4H)-one. Gas evolution was observed and the mixture became yellow following which an additional 5 ml of dimethyl sulfoxide was added. One hour later, 1.1 g (7.7 mmol) of methyl iodide was added and the mixture was stirred for 50 hours. The reaction mixture was diluted with 75 ml of water and precipitation occurred in the form of crystals which were collected and air dried to yield 3.3 g of crude product. Recrystallization from acetone-hexane afforded 1.85 g (5.4 mmol, 71%) of dihydro-4-(3,5-di-tert-butyl-4-methoxybenzylidene)-2-methyl-2H-1,2-oxazin-3(4H)-one having a melting point of 119°-121° C.
Reaction SMILES: Cl.Cl.C(S[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]=1)C.Cl.[F:49][C:50]([F:54])([F:53])[CH2:51][NH2:52].C([O-])(=O)C.[Na+].C(O)(=O)C>C(Cl)(Cl)Cl>[CH2:15]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH:52][CH2:51][C:50]([F:54])([F:53])[F:49])=[NH:47])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: NCC(F)(F)F
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)SCC)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)NCC(F)(F)F)c1
Reaction time: 12 h
Yield: 86 %

Procedure:
Ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-thiobenzimidate dihydrochloride (1.074 g., 1.5 mmoles) was added to a slurry of 2,2,2-trifluoroethylamine hydrochloride (406 mg., 3.0 mmoles) and anhydrous sodium acetate (246 mg., 3.0 mmoles) in chloroform (10 ml.) and glacial acetic acid (0.3 ml., 5.3 mmoles). The mixture was held for 12 hours at room temperature. It was then diluted to 300 ml. with chloroform, washed with saturated aqueous sodium bicarbonate solution (2 × 50 ml.), washed with saturated aqueous sodium chloride solution (2 × 50 ml.), dried (Na2 SO4) and filtered. The filtrate was acidified with a 10% solution of anhydrous hydrogen chloride in dioxane (5ml.) and then evaporated in vacuo to a foam. The foam was crystallized from 1,2-dimethoxyethane [974 mg., 86% yield, Rf .39 (4:1, benzene: ethanol on silicic acid), m.p.-forms a gel at 125°-127° C.].
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][N:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH3:27])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[CH:8]=2)=[O:4].[OH-].[Na+]>C1COCC1>[CH:28]1([N:26]([CH3:27])[CH2:25][CH2:24][NH:23][C:22]([CH2:21][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)[CH:8]=3)[CH:13]=[C:5]2[C:3]([OH:4])=[O:2])=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2n1CC(=O)NCCN(C)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3cc(C(=O)O)n(CC(=O)NCCN(C)C4CCCCC4)c3c2)cc1
Temperature: 25 °C

Procedure:
The methyl ester (15a) obtained above (2.7 mg, 0.006 mmol) was dissolved in THF (600 μL) and to the resultant solution was added 300 μL of a 3M NaOH(aq) and the reaction solution was stirred at rt. The crude product 16a was purified by HPLC (MeCN/H2O/0.1% TFA) to give 1.5 mg (16a): LC-MS (Method B, retention time=2.172 min. MS calc'd for C27H34N3O3 (MH+): 448.3. Found 448.5.
Reaction SMILES: [CH:1]([Si:4]([O:11][CH2:12][C@@H:13]([OH:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:31]Br>C1COCC1>[CH:8]([Si:4]([O:11][CH2:12][C@@H:13]([O:23][CH2:31][C:30]1[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH3:26])[CH:29]=1)[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])([CH3:9])[CH3:10]
Reactant: COc1ccc(CBr)cc1OC
Reactant: CC(C)[Si](OC[C@@H](O)CNC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CO[C@@H](CNC(=O)OC(C)(C)C)CO[Si](C(C)C)(C(C)C)C(C)C)cc1OC
Reaction time: 1 h
Yield: 12.8 %

Procedure:
To a 0° C. mixture of (2S)-3-(t-butoxycarbonylamino)-2-hydroxypropyl triisopropylsilyl ether (6 g, 17.2 mmol) and THF (35 mL) was added NaH (60% dispersion in oil, hexane washed). The reaction was stirred for 1 h, 3,4-dimethoxy-benzyl bromide (4.3 g, 18.9 mmol) in THF (20 mL) was added, and then stirred at ambient temperature for 18 h. The mixture was concentrated and chromatographed on SiO2 (gradient CH2Cl2 to EtOAc) to give the title compound (1.1 g, 12.8%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[C:28]([O:32][C:33]([N:35]([CH3:40])[CH2:36][C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:37](=[O:38])[CH2:36][N:35]([CH3:40])[C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:31])[CH3:29])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 2-[(tert-butoxycarbonyl)(methyl)amino]acetic acid (0.0033 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-oxoethyl)-N-methylcarbamate. The solid was dissolved in dichloromethane (2 mL) and a 25% solution of trifluoroacetic acid in dichloromethane (4 mL) was slowly added to the reaction at 0° C. The reaction mixture was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure. A 5 N aqueous solution of sodium hydroxide was added to pH 11 at 0° C. The water phase was extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (1×60 mL) and brine (1×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-(dimethylamino)-1-ethanone acetate (0.022 g, 0.00004 mol).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]1=[O:17])(=O)C.C(N(CC)CC)C>CO>[F:23][C:21]1[C:19](=[O:20])[NH:18][C:16](=[O:17])[N:15]([CH:22]=1)[C@@H:6]1[O:7][C@H:8]([CH3:14])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(=O)[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Yield: 98 %

Procedure:
2.5 g of 1-(5-deoxy-2,3-di-O-acetyl-β-D-ribofuranosyl)-5-fluorouracil were heated under reflux in 60 ml of methanol in the presence of 0.3 ml of triethylamine until starting material could no longer be detected by thin-layer chromatography. The colourless, clear solution was concentrated under reduced pressure and the white, crystalline material obtained was recrystallised from water. There was obtained pure 5'-deoxy-5-fluorouridine, m.p. 192°-193° C., in 98% yield.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[N+:17]([O-])([O-:19])=[O:18].[K+]>C(O)(=O)C.S(=O)(=O)(O)O>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18])[C:2]([CH3:4])=[O:3]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
4-Acetaminobiphenyl (17 g, 80.57 mmol)in glacial acetic acid (600 ml) was added a solution of potassium nitrate (18 g, 178 mmol) in conc. sulphuric acid (75 ml) at such a rate that the temperature was kept below 30° C. Following the addition the mixture was stirred at ambient temperature for 72 hours. The reaction mixture was poured into ice-water (1200 ml). The product was filtered off, washed thoroughly with water and dried. Recrystallization from EtOH (99%, 150 ml) afforded 4-acetamino-3-nitrobiphenyl (8.7 g).