Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:48])[C:7]1[CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=[C:9]([O:17][C:18]2[CH:23]=[CH:22][C:21]([P:24]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([F:47])[CH:40]=3)([O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=3)=[O:25])=[CH:20][CH:19]=2)[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.CCOC(C)=O>[F:36][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[O:34][CH3:35])[CH2:27][O:26][P:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:9]2[CH:8]=[C:7]([CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=2)[C:6]([OH:48])=[O:5])=[CH:19][CH:20]=1)([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([F:47])[CH:40]=1)=[O:25]
Reactant: COc1ccc(COP(=O)(OCc2ccc(OC)c(F)c2)c2ccc(Oc3cc(OC(C)C)cc(C(=O)OCC[Si](C)(C)C)c3)cc2)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(COP(=O)(OCc2ccc(OC)c(F)c2)c2ccc(Oc3cc(OC(C)C)cc(C(=O)O)c3)cc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 3-{-4-[bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoic acid 2-trimethylsilanyl-ethyl ester (536 mg, 0.735 mmol) in DMF (10 mL) was added tetrabutylammonium fluoride (1.0 M solution in THF) (1.84 mL, 1.84 mmol). Stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and washed with H2O (2×) and brine (2×). Dried with MgSO4 and evaporated solvent to provide 462 mg (100%) of 3-{4-[bis-(3-fluoro-4-methoxy-benzyloxy)-phosphoryl]-phenoxy}-5-isopropoxy-benzoic acid. 1H NMR (300 MHz, DMSO-d6): δ 13.20 (bs, 1H), 7.74 (dd, J=13, 9 Hz, 2H), 7.27 (dd, J=2, 1 Hz, 1H), 7.13 (m, 9H), 6.94 (t, J=2 Hz, 1H), 4.97 (dd, J=9, 2 Hz, 4H), 4.67 (m, 1H), 3.82 (s, 6H), 1.27 (s, J=6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:24])([CH2:21][CH:22]=[CH2:23])[CH2:9][CH2:10][NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:21]([C@@:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:24][C:33](=[O:35])[N:11]([C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[CH2:10][CH2:9]1)[CH:22]=[CH2:23]
Reactant: C=CCC(O)(CCN[C@@H](C)c1cccc(F)c1)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2cccc(F)c2)C(=O)O1
Yield: 43 %

Procedure:
To a solution of 3-(4-fluorophenyl)-1-((S)-1-(3-fluorophenyl)ethylamino)hex-5-en-3-ol (350 mg, 1.1 mmol) and Et3N (333 mg, 3.3 mmol) in anhydrous CH2Cl2 (6 mL) was added triphosgene (155 mg, 0.52 mmol) in portions at 0° C. under N2. Then the solution was refluxed overnight. After the solvent was removed under reduced pressure, the residue was purified by preparative TLC to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(3-fluorophenyl)ethyl)-1,3-oxazinan-2-one (80 mg, 21%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=2)[CH2:19][CH2:18]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](Cl)=[O:38]>CC(C)=O.O>[CH3:7][N:8]([CH:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][Cl:32])[CH:25]=2)[CH2:19][CH2:18]1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCCCCl
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cccc(N)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cccc(NC(=O)CCCCCl)c2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.3 g of potassium carbonate was added to a solution of 2.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-(3-aminobenzoyl)piperidine in 30 ml of acetone and 20 ml of water. Thereto was dropwise added 0.9 ml of 5-chlorovaleryl chloride with ice-cooling. The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into ice water. The mixture was extracted with methylene chloride. The extract was washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, and concentrated under reduced pressure to obtain 2.2 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-(5-chlorovalerylamino)benzoyl]piperidine as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:6](=[O:23])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2.COC(=O)C.[C:30]([O:34][C:35](=[O:41])[NH:36][CH2:37][CH2:38][CH2:39]Br)([CH3:33])([CH3:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:6](=[O:23])[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH2:39][CH2:38][CH2:37][NH:36][C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:41])[CH:9]=2
Reactant: COC(=O)Cc1cc2ccc(O)cc2n(Cc2ccccc2)c1=O
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: COC(C)=O
Product: COC(=O)Cc1cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2n(Cc2ccccc2)c1=O

Procedure:
The title compound was prepared using the procedure of Example 75 and (1-benzyl-7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid methyl ester in place of 7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)acetic acid methyl ester and (3-bromopropyl)carbamic acid tert-butyl ester in place of (2-bromoethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[CH2:9]([N:11]([CH2:32][CH3:33])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2C=C(C3C=CSC=3)[NH:24][N:23]=2)=[CH:17][CH:16]=1)[CH3:10]>C(Cl)Cl.CO>[CH2:32]([N:11]([CH2:9][CH3:10])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[CH:2]=[C:1]([C:4]3[S:5][CH:6]=[CH:7][CH:8]=3)[NH:24][N:23]=2)=[CH:17][CH:16]=1)[CH3:33]
Reactant: CCN(CC)CCOc1ccc(Nc2cc(-c3ccsc3)[nH]n2)cc1
Reactant: CC(=O)c1cccs1
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(Nc2cc(-c3cccs3)[nH]n2)cc1

Procedure:
The title compound is prepared as described in Example 33 but using 2-acetylthiophene and diethyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-amine (Example 37). Title compound: ES-MS: 357.1 [M+H]+; single peak at tR=2.98 min (System 2); Rf=0.11 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[S:7][C:6]([CH3:8])=[C:5]([Cl:9])[C:4]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:30]([C:32]([CH3:44])=[CH:33][CH:34]=[CH:35][C:36]([CH3:43])=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=O>C1OCCC1>[CH2:41]([O:40][C:38](=[O:39])[CH:37]=[C:36]([CH3:43])/[CH:35]=[CH:34]/[CH:33]=[C:32]([CH3:44])[CH:30]=[CH:10][C:4]1[C:5]([Cl:9])=[C:6]([CH3:8])[S:7][C:3]=1[Cl:2])[CH3:42]
Reactant: Cc1sc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1Cl
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)/C=C/C=C(C)C=Cc1c(Cl)sc(C)c1Cl

Procedure:
A suspension of 10.83 g. (22.6 mmol) of (2,4-dichloro-5-methyl-3-thenyl)triphenyl phosphonium chloride and 5.15 g. (24.8 mmol) of ethyl 7-formyl-3-methyl-2,4,6-octatrienoate in 350 ml. of butylene oxide was heated to 70° C. for 4.5 hrs. The resulting clear solution was cooled, poured into 500 ml. of a methanol/water mixture (6:4) and extracted with hexane. The combined hexane extracts were washed with methanol/water (6:4), dried and evaporated. The resulting crude material was purified by chromatography (silica gel, hexane/ethyl acetate=4:1) to yield after recrystallization from hexane, all trans-3,7-dimethyl-9-(2,4-dichloro-5-methyl-3-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester, m.p. 99°-100° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:23]=[O:24].CCN(CC)CC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[NH:21][C:23]([NH:22][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(Cc2ccccc2)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a round bottom flask was added (1R,2R)—N1-(1-benzylpiperidin-3-yl)cyclohexane-1,2-diamine (3.23 g, 8.05 mmol), THF (30 mL), isocyanatobenzene (0.958 g, 8.05 mmol) and Et3N (5.61 mL, 40.2 mmol). The reaction was stirred at rt for 2 hrs. After this time, the reaction mixture was concentrated. The residue was diluted with EtOAc (100 ml). The resulting solution was washed with water (50 ml) and saturated aqueous NaCl (50 ml). The organic layer was dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with 5% MeOH/CH2Cl2 with NH3) to give the product, 1-((1R,2R)-2-(1-benzylpiperidin-3-ylamino)cyclohexyl)-3-phenylurea (1.4 g, 3.44 mmol, 42.8% yield), as a white solid. Anal. Calcd. for C25H32N4O m/z 407, found: 408.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.41-7.15 (m, 9H), 6.97 (q, J=7.15 Hz, 1H), 4.51-4.27 (m, 1H), 3.58-3.34 (m, 2H), 3.23-3.08 (m, 1H), 2.96-2.80 (m, 1H), 2.66 (br. s., 1H), 2.40 (br. s., 1H), 2.29-2.11 (m, 2H), 2.11-1.92 (m, 2H), 1.77-1.57 (m, 5H), 1.57-1.42 (m, 1H), 1.31 (d, J=3.85 Hz, 1H), 1.30-1.05 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Cl:17]>>[Cl:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: ClCCCCCBr
Product: CC(=O)c1cccc(OCCCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 1-(3-hydroxyphenyl)ethanone and 1-bromo-5-chloropentane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:20])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH3:19])[CH:7]=[CH:8][CH:9]=1.N1C=CN=C1.[C:26]([Si:30](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.O>[Si:30]([O:1][CH2:2][CH2:3][C:4]1[C:5](=[O:20])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH3:19])[CH:7]=[CH:8][CH:9]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Reaction time: 8 h

Procedure:
38 g (138 mmol) of the compound from Example 14A are dissolved in 200 ml of anhydrous N,N-dimethylformamide, and 12.2 g (198 mmol) of imidazole and, a little at a time, 46 g (135 mmol) of tert-butyl(chloro)diphenylsilane are added at 0° C. The mixture is stirred overnight and then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is applied to silica gel and chromatographed using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and evaporated to dryness under reduced pressure. This gives 62 g (88% of theory) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](N)[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13].N([O-])=O.[Na+].[ClH:21]>Cl[Cu]>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:21])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:16]
Reactant: COC(=O)Cc1ccc(N)cc1C(=O)OC
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)Cc1ccc(Cl)cc1C(=O)OC

Procedure:
5-amino-2-methoxycarbonylmethyl-benzoic acid methyl ester (5 g, 22.4 mmol) was dissolved in hydrochloric acid (50 mL). To the solution was added dropwise aq.NaNO2 (1.7 g, 24.6 mmol) at below 5° C. After addition completed, the color became maroon. Then CuCl (2.4 g, 24.6 mmol) solution was added to the reaction mixture. The reaction mixture was reacted at below 5° C. for 1 hour. The reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2.3 g of 5-chloro-2-methoxycarbonylmethyl-benzoic acid methyl ester (18E).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[CH2:14][N:15](CC3C=CC=CC=3)[CH2:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[CH2:14][NH:15][CH2:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2CN(Cc3ccccc3)CC2C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2CNCC2C1
Yield: 99.8 %

Procedure:
2-Benzyloctahydropyrrolo[3,4-c]pyridine-5-carboxylic acid tert-butyl ester (Example A26, 24.98 g, 78.8 mmol) in 400 mL of methanol is treated with 2.5 g of 20% Pd/C and shaken for 20.5 hours under 50 PSI of hydrogen. The solution is filtered and concentrated to afford 17.8 g of the title compound as a solid. MS APCI: m/z 228 (MH+).
Reaction SMILES: CC(=CC)C.[C:6]([O:10][C:11]([C@@:13]1([CH2:36][CH:37]=[O:38])[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:27])[N:15]([C@@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:29])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].Cl([O-])=[O:40].[Na+].O.O.P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[C:6]([O:10][C:11]([C@@:13]1([CH2:36][C:37]([OH:40])=[O:38])[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:27])[N:15]([C@@H:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:29])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: [O-][Cl+][O-]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CC=O)(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)C1=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@H](c1ccccc1)N1C[C@@](CC(=O)O)(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)C1=O
Yield: 83.2 %

Procedure:
2-Methyl-2-butene was added to a solution of (3S,4S)-4-benzyloxymethyl-5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.58 g, 10.1 mmol) in tert-butyl alcohol (25.2 mL) under ice-cooling, and the mixture was stirred. Sodium chlorite (2.29 g, 25.3 mmol) was added to a solution of sodium dihydrogenphosphate dihydrate (4.10 g, 26.3 mmol) in water (20.2 mL) to separately prepare a solution. This solution was added to the above solution under ice-cooling, and the mixture was stirred at room temperature for one hour. The precipitated solid was collected by filtration, washed with water and hexane, and then dried under reduced pressure at 40° C. to give 3.93 g of the title compound as white powder crystals.
Reaction SMILES: C(O[C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=O)C.[OH2:17]>>[C:7]1(=[O:16])[N:6]([CH2:4][CH2:4][NH:6][CH2:7][CH2:8][OH:17])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: O
Product: O=C1c2ccccc2C(=O)N1CCNCCO
Reaction time: 2 h

Procedure:
10.4 g (0.1 mol) of N,N-(2-hydroxyethyl),ethyl amine and 22 g (0.1 mol) of N-ethoxycarbonyl phthalimide were dissolved in 50 ml of H2O and stirred for 2 hours. The reaction mixture was lyophilized and the solid product washed with methanol (40 ml). The remaining white solid (Compound 14) was collected and dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:42]([O:44]C)=[O:43])[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[C:29]4[C:24](=[CH:25][N:26]=[C:27]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:28]=4)[N:23]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:22]=3)[N:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>CO.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([C:42]([OH:44])=[O:43])[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[C:29]4[C:24](=[CH:25][N:26]=[C:27]([C:30]5[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=5)[CH:28]=4)[N:23]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][O:37]4)[N:22]=3)[N:16]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)n2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A mixture of 240 mg (0.39 mmol) of methyl 4-(tert-butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxylate and 3 ml of 1 M aqueous solution of lithium hydroxide in 20 ml of methanol and 10 ml of tetrahydrofuran was stirred for 18 hours at room temperature and 2 hours at 60° C. The mixture was concentrated in vacuum, neutralized to pH 5 by careful addition of 1 N aqueous HCl and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated to afford 150 mg (43%) of 4-(tert-Butoxycarbonylamino)-1-(6-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidine-4-carboxylic acid over two steps. ESI MS m/z 600.2 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.N1C=CC=CC=1>>[CH:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=1)=[O:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
At 0° C., methanesulfonyl chloride (9.51 ml, 0.123 mol) was added to a solution of 4-hydroxybenzaldehyde (15 g, 0.123 mol) in pyridine (12.91 ml, 0.160 mol). The reaction mixture was stirred at 0° C. for 3 h and left at room temperature for 16 h. It was given onto conc. hydrochloric acid/ice (200 ml/200 ml). The mixture was extracted with ethyl acetate (4×300 ml). The combined organic layers were washed with a 5% aqueous solution of sodium hydrogen carbonate (3×200 ml) and brine (100 ml). They were dried over magnesium sulphate. The solvent was removed in vacuo to give 22.87 g of crude methanesulfonic acid 4-formylphenyl ester, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([NH:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1.Cl.[N:23]([O-])=[O:24].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([N:18]([CH3:19])[N:23]=[O:24])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1
Reactant: O=N[O-]
Reactant: CNc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N(C)N=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.9 g. of 2,4-diamino-5-[3,5-dimethoxy-4-(methylamino)-benzyl]-pyrimidine in 40 ml. of 1N hydrochloric acid was treated dropwise with a solution of 830 mg. of sodium nitrite in 10 ml. of water with stirring and ice-cooling. The mixture was stirred for 3 hours at room temperature and then sodium carbonate was added to obtain an alkaline reaction. The precipitate was removed by filtration with suction, washed with water and recrystallized from methanol, whereby there was obtained 2,4-diamino-5-[3,5-dimethoxy-4-(methyl-nitrosoamino)-benzyl]-pyrimidine having a melting point of 249°-250° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([OH:16])=O)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH:29]([OH:42])[CH2:30][O:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC(C)C)=O)C(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O>[NH2:1][C:2]1[C:3]([C:10]([NH:12][CH:13]([C:14](=[O:16])[NH:24][CH2:25][CH2:26][NH:27][CH2:28][CH:29]([OH:42])[CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: NCCNCC(O)COc1cccc2ccccc12
Reactant: Nc1nc(N)c(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)nc1Cl
Agent: CC(C)COC(=O)N1c2ccccc2C=CC1OCC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc(N)c(C(=O)NC(Cc2ccccc2)C(=O)NCCNCC(O)COc2cccc3ccccc23)nc1Cl
Temperature: 75 °C

Procedure:
A stirred mixture of (S)-2-(3,5-diamino-6-chloropyrazine-2-carboxamido)-3-phenylpropionic acid (1.8 g.), 1-β-aminoethylamino-3-α-naphthyloxypropan-2-ol (1.43 g.), 2-isobutoxy-1-isobutoxycarbonyl-1,2-dihydroquinoline (1.5 g.) and dimethylsulphoxide (30 ml.) was heated at 75° C. for 18 hours, cooled and poured into ice-water (600 ml.). Aqueous 6% w/v sodium bicarbonate solution (50 ml.) was added, the mixture was filtered and the solid product was washed with diethylether (100 ml.). There was thus obtained as solid product 3,5-diamino-6-chloro-N-{1-[N-β-(2-hydroxy-3-α-naphthyloxypropylamino)ethylcarbamoyl]-2-phenylethyl}pyrazine-2-carboxamide, m.p. 142°-146° C.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)[CH2:2][CH3:3].C[Si](Cl)(C)C.C1C=CC=CC=1.ClC1C=CC(C([C@@:30]2([OH:47])[C@@H:34]([CH:35](C(=O)C3C=CC(Cl)=CC=3)[OH:36])[O:33][CH:32](Cl)[CH2:31]2)=O)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH2:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[N:8]([CH:9]=1)[C@@H:32]1[O:33][C@H:34]([CH2:35][OH:36])[C@@H:30]([OH:47])[CH2:31]1)[CH2:2][CH3:3]
Reactant: CCCc1c[nH]c(=O)[nH]c1=O
Reactant: O=C(c1ccc(Cl)cc1)C(O)[C@H]1OC(Cl)C[C@@]1(O)C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [Hg+2]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 24 h
Yield: 166.5 %

Procedure:
To a solution of 15,4 g 5-propyluracil (0.1 mole) and 21,7 g trimethylsilyl chloride (0,2 mole) in 250 ml anhydrous benzene 20.2 g dry triethylamine (0,2 mole) are added dropwise under stirring and exclusion of humidity within a time span of 15 minutes. After further stirring for about 12 hours the unreacted 5-propyl-uracil and the precipitated dry ethylamine hydrochloride are separated and the filtrate is concentrated under vacuum. The residue is dissolved in 150 ml of absolute toluene and under stirring a solution of 43 g 3,5-di-(p-chlorobenzoyl)-2-desoxy-D-ribofuranosyl chloride (0,1 mole) in 500 ml toluene and thereafter 31,8 g mercury (II)-acetate are added and the stirring is continued another 24 hours. After filtration the filtrate is extracted with a 30% aqueous potassium iodide solution and thereafter washed with water. After drying over sodium sulfate the toluene solution is concentrated to approximately 100 ml. Upon standing the protected nucleoside crystallizes. 45 g of a product with melting point 140°-165° C. are obtained.