Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:17][OH:18])[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16].[C:19](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:21])[CH3:20]>CN(C)C=O>[C:19]([NH:1][CH2:2][C@:3]1([CH2:17][OH:18])[O:7][C@@H:6]([N:8]2[CH:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:16])(=[O:21])[CH3:20]
Reactant: NC[C@]1(CO)O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Reactant: CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Product: CC(=O)NC[C@]1(CO)O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-C-Aminomethyl-2′-deoxyuridine (13) (0.034 g, 0.13 mmol) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL) at ambient temperature. Excess pentafluorophenyl acetate (0.88 g, 0.39 mmol) was then added directly to the reaction mixture as a solid. The resulting solution was stirred for 18 hours at ambient temperature. The solvent was then removed under vacuum and the residue re-dissolved in water and then washed with toluene. The aqueous layer was then separated and the solvent removed under vacuum. The title compound was obtained as an amorphous solid (0.032 g, 82%). δH(300 MHz, D2O) 7.68(1H, d, H-6), 6.11(1H, dd, H-1′), 5.71(1H, d, H-5), 4.44(1H, dd, H-3′), 4.49(2H, 2d, H-5′), 3.33(2H, 2d, 4′-C—CH2), 2.33(2H, m, H-2′), 1.89(3H, s, CH3CONH); δC(75.45 MHz, D2O) 175.60, 167.08, 152.43, 142.86, 102.93, 88.93, 85.57, 71.91, 63.16, 40.37, 39.15, 22.72; ES +ve m/z 300(M+H)+, 242(M−CH3CONH)+.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu].[Cu](I)I>[C:25]1([N:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[NH:5][CH2:4][CH:3]([NH:13][C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[C:2]2=[O:1])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(NC1CNc2ccccc2NC1=O)OCc1ccccc1
Reactant: Ic1ccccc1
Agent: I[Cu]I
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(NC1CNc2ccccc2N(c2ccccc2)C1=O)OCc1ccccc1
Temperature: 150 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
2-Oxo-3-benzyloxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.38 g) was dissolved in N,N-dimethylformamide (20 ml), iodobenzene (1.36 g), copper powder (286 mg), copper iodide (446 mg) and potassium carbonate (622 mg) were added, the mixture was stirred at 150° C. for 2 hours. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 1.00 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[C:9]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)=[O:13])[CH:8]=[N:7][C:6]=12.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CN1CCCC1=O>[CH2:26]([NH:33][C:10]1[N:5]2[N:4]=[CH:3][C:2]([Br:1])=[C:6]2[N:7]=[CH:8][C:9]=1[C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(c1cnc2c(Br)cnn2c1Cl)N1CCC(c2ccccc2)CC1
Reactant: NCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
3-Bromo-7-chloro-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (3.0 g, 7.2 mmol) obtained in step 3 was dissolved in N-methylpyrrolidinone (30 mL), benzylamine (2.0 mL, 17.9 mmol) was added, and the mixture was stirred at 70° C. for 2 hr. 10% Aqueous citric acid solution (10 mL) and water (100 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, and washed with water (50 mL) to give the title compound (3.2 g, 90%).
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[C:9]([C:20]4[CH:25]=[CH:24][C:23]([S:26](=[O:35])(=[O:34])[NH:27][C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])=[CH:22][N:21]=4)[N:10]3[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:42](Br)[CH:43]=[CH2:44]>CN(C=O)C>[CH2:44]([N:27]([C@@H:28]([CH3:33])[C:29]([F:31])([F:30])[F:32])[S:26]([C:23]1[CH:24]=[CH:25][C:20]([C:9]2[N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:12]=3)=[N:21][CH:22]=1)(=[O:35])=[O:34])[CH:43]=[CH2:42]
Reactant: C=CCBr
Reactant: C[C@H](NS(=O)(=O)c1ccc(-c2cc3ccc(C4CC4)cc3n2C(=O)OC(C)(C)C)nc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN([C@@H](C)C(F)(F)F)S(=O)(=O)c1ccc(-c2cc3ccc(C4CC4)cc3n2C(=O)OC(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 6-cyclopropyl-2-(5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-1H-indole-1-carboxylate (503 mg, 0.99 mmol) and K2CO3 (276 mg, 2 mmol) in DMF (5 mL) was added allyl bromide (0.11 mL, 1.30 mmol). The mixture was stirred at room temperature for 2 hrs, and quenched with water (60 mL). The mixture was extracted with CH2Cl2 (3×20 mL). The solvent was then evaporated and (S)-tert-butyl 2-(5-(N-allyl-N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-6-cyclopropyl-1H-indole-1-carboxylate was obtained as a light yellow oil (500 mg, 92% yield). MS m/z 550.3 M+H+. This material was used in the next step without further purification.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[NH:13][C:12]([C:14]([C:46]4[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=4)=[C:15]4[N:45]=[C:18]([C:19]([C:38]5[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=5)=[C:20]5[NH:37][C:23](=[C:24]([C:30]6[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=6)[C:25]6[CH:26]=[CH:27][C:28]=2[N:29]=6)[CH:22]=[CH:21]5)[CH:17]=[CH:16]4)=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.[C:53](=[O:56])([O-])[O-].[K+].[K+].[Br-]>CN(C=O)C>[OH:52][C:49]1[CH:48]=[CH:47][C:46]([C:14]2[C:12]3[NH:13][C:9]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([O:56][CH2:53][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH3:8])=[CH:7][CH:6]=4)=[C:28]4[N:29]=[C:25]([C:24]([C:30]5[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=5)=[C:23]5[NH:37][C:20](=[C:19]([C:38]6[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=6)[C:18]6[CH:17]=[CH:16][C:15]=2[N:45]=6)[CH:21]=[CH:22]5)[CH:26]=[CH:27]4)=[CH:10][CH:11]=3)=[CH:51][CH:50]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2c3nc(c(-c4ccc(O)cc4)c4ccc([nH]4)c(-c4ccc(O)cc4)c4nc(c(-c5ccc(O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
5,10,15,20-tetrakis-(4-Hydroxy-phenyl)-porphyrin (200 mg, 0.294 mmol) is dissolved and potassium carbonate (487 mg, 3.53 mmol, 12 eqv.) is suspended under argon in absolute DMF (50 mL) and the mixture is heated to 55° C. A solution of octal bromide (35.8 μl, 0.206 mmol, 0.7 eqv.) in absolute DMF (10 mL) is added dropwise during 30 min. and the mixture is stirred at 55° C. for 2 h. The solvent is removed in vacuo at 50° C., water (80 mL) is added and the mixture is extracted with ethyl acetate (3×40 mL). The combined organic fraction is dried (Na2SO4) and the solvent evaporated. The residue is purified by chromatography on a column (300 g) of silica gel. Tetra-alkylated and tri-alkylated compounds are eluted with toluene:ethyl acetate (30:1 by vol.). The third fraction (di-substituted compound, trans-isomer) is eluted with toluene:ethylacetate (15:1 by vol.). The fourth fraction (di-substituted compound, cis-isomer) is eluted with toluene:ethyl acetate (10:1 by vol.) and the desired product (mono-alkylated compound) is eluted with toluene:ethylacetate (5:1 by vol.). The solvent is removed under reduced pressure and the residue dried under high vacuum to give the product as a violet solid.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH2:7]1[C@@H:11]2[CH2:12][NH:13][CH2:14][C@@H:10]2[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Br[C:23]1[CH:32]=[C:31]2[C:26]([C:27]([NH:33][C:34]([NH:36][C:37]3[CH:42]=[N:41][CH:40]=[CH:39][N:38]=3)=[O:35])=[CH:28][CH:29]=[N:30]2)=[CH:25][CH:24]=1>C1COCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:38]1[CH:39]=[CH:40][N:41]=[CH:42][C:37]=1[NH:36][C:34](=[O:35])[NH:33][C:27]1[C:26]2[C:31](=[CH:32][C:23]([N:13]3[CH2:12][C@@H:11]4[CH2:7][N:8]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C@@H:10]4[CH2:14]3)=[CH:24][CH:25]=2)[N:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Reactant: O=C(Nc1cnccn1)Nc1ccnc2cc(Br)ccc12
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc4c(NC(=O)Nc5cnccn5)ccnc4c3)C[C@@H]2C1
Yield: 91.8 %

Procedure:
A solution of sodium tert-butoxide (98 mg, 1.017 mmol) and (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (95 mg, 0.436 mmol) in THF (3 mL) was stirred under nitrogen. To this was added 1,1′-bis(diphenylphosphino)ferrocene (25 mg, 0.05 mmol), Pd2(DBA)3 (12 mg, 0.02 mmol) and 1-(7-bromoquinolin-4-yl)-3-(pyrazin-2-yl)urea (100 mg, 0.291 mmol). The mixture was then heated at reflux for 12 h before partitioning between CH2Cl2 and water. The mixture was filtered through Celite and the organic phase was separated. The water phase was extracted twice with CH2Cl2 and the combined extracts dried (Na2SO4), filtered and concentrated in vacuo to provide the crude material, which was purified by flash chromatography to give the title compound (127 mg, 83%) as a white solid.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].I[C:19]1[C:20]([OH:29])=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([CH:26]=1)[CH:24]=[O:25]>>[OH:15][C:10]1[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]2[O:4][C:3]([C:1]#[C:2][C:19]3[CH:26]=[C:23]([CH:22]=[C:21]([O:27][CH3:28])[C:20]=3[OH:29])[CH:24]=[O:25])([CH3:17])[CH2:8][CH2:7][C:6]=2[C:9]=1[CH3:16]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: COc1cc(C=O)cc(I)c1O
Product: COc1cc(C=O)cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)c1O

Procedure:
Rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 2.3 g, was reacted with 4.17 g (15 mmol) of 5-iodovanilline as described in example 1, but extending the reaction time to 4.5 hours. After the usual workup, the residue was chromatographed over 150 g of silica gel using 10% (V/V) of ethyl acetate in methylene chloride. Crystallization from ether/hexane and recrystallization from ethyl acetate/hexane yielded colorless crystals with m.p. 158°-160°.
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].O.[NH4+].[Cl-]>CO.[Zn]>[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc(N)cc2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
A solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-(4-nitro-benzyl)-piperazine (as prepared in the previous step, 279 mg, 0.735 mmol) in MeOH (4 mL) and water (4 mL) was treated with solid NH4Cl (393 mg, 7.35 mmol) and Zn powder (240 mg, 3.67 mmol). The mixture was stirred at 50° C. for 2 h and at RT for 16 h. The mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 20-g Isolute SPE column on a FlashMaster system with EtOAc afforded the title compound (204 mg, 79%) as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C19H35N3OSi, 350.3 (M+H). found 350.2.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH2:5](Cl)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:16]([NH:3][CH2:2][CH2:1][NH2:4])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5]
Reactant: CCCCCCCCCCCCCl
Reactant: NCCN
Solvent: CCO
Product: CCCCCCCCCCCCNCCN
Reaction time: 1.5 h

Procedure:
N-propylol-N'-lauryl ethylenediamine is prepared by dissolving 2 kmol ethylenediamine in 500 liters absolute ethanol and then, while constantly stirring, 2 kmol laurylchloride is added while the temperature is maintained not to exceed 100°C and then the reaction mixture is held for 1.5 hours at that temperature. N'-lauryl-ethylenediamine is formed. Subsequently the reaction mixture is cooled to 30°C, the chloride is precipitated with ammonia and the precipitate is filtered off. The pH value of the pure solution is adjusted to 8.5 and 2 kmol propionaldehyde ia added. The temperature is maintained at 40°C during a subsequent 3 hour period while stirring. Then the alcohol is driven off under vacuum and the unreacted products are washed out with water. The end product has a molecular weight of about 300 and the formula ##EQU12##
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:23])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[CH3:15].[H-].[Na+].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CCCCCC>CCOC(C)=O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2([CH3:15])[C:3](=[O:24])[C:4]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][C:9]=3[Cl:10])[NH:12][C:13]2=[O:23])=[CH:17][CH:18]=1
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1NC(=O)C(C)c1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(Br)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 16.2 %

Procedure:
The objective compound was prepared by the same procedure for the example 1, using a 2-[2-(4-bromo-phenyl)-propionyl amino]-4,6-dichloro-benzoic acid methyl ester (400 mg, 0.93 mmol) and NaH (78 mg, 1.95 mmol) as a base instead of LiHMDS. After normal workup, the objective compound (60 mg, 18%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=5:1): 1H NMR (200 MHz, CDCl3+CD3OD) δ 1.69 (s, 3H, CH3), 6.91-7.48 (m , 6H, ArH); m.p. 237-238° C.; MS(EI) m/e 397 [M+].
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:23]1[N:28]=[C:27]([NH2:29])[N:26]=[C:25]2[NH:30][N:31]=[CH:32][C:24]=12.C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[C:1]1([S:7]([N:10]2[CH2:16][CH2:15][CH:14]([NH:17][C:23]3[N:28]=[C:27]([NH2:29])[N:26]=[C:25]4[NH:30][N:31]=[CH:32][C:24]=34)[CH2:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: NC1CCN(S(=O)(=O)c2ccccc2)c2ccccc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(NC2CCN(S(=O)(=O)c3ccccc3)c3ccccc3C2)c2cn[nH]c2n1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-amine in anhydrous dimethylacetamide (1 mL) was added 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (135 mg, 1.0 mmol) and diisopropylethylamine (0.4 mL, 2.30 mmol). The mixture was stirred at 120° C. for 20 hours. After cooling to room temperature the mixture was poured into water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organics were dried over sodium sulfate and concentrated to a residue which was purified by reverse phase chromatography on a preparative LC/UV/MS system using a mass triggered fractionation. Compounds were eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 ml/min with 5-95 acetonitrile/water gradient using 0.1% TFA as modifier to yield N4-(1-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (13.4 mg).
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[N-:15]=[N+]=[N-].[Na+]>CS(C)=O>[NH:15]1[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[CH:8]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C=CC1=C(Cl)CCCC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2c([nH]1)CCCC2
Temperature: 105 °C
Yield: 93.1 %

Procedure:
To a mixture of ethyl 3-(2-chlorocyclohex-1-enyl)acrylate (21.4 g, 100 mmol) in DMSO (100 mL) was added sodium azide (9.75 g, 150 mmol). The reaction mixture was heated at 105° C. for 4 h. After cooling to room temperature, the mixture was poured into ice water. The resulting precipitate was collected by filtration to afford 121a (18.0 g, 93.3%). MS-ESI: [M+H]+ 194.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1)[NH2:18]
Reactant: Clc1cc2c(nn1)-c1ccccc1CCC2
Reactant: NN
Solvent: CCO
Product: NNc1cc2c(nn1)-c1ccccc1CCC2

Procedure:
Alternatively, 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6 g) was heated with anhydrous hydrazine (4 mL) in ethanol (50 mL) at 100° C. for 4.75 h. The solvent was removed under vacuum. The residue was partitioned between chloroform and 1M saturated aqueous potassium carbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine as a brown solid; 1H NMR (CDCl3, 300 MHz) 7.74 (m, 1H), 7.30 (m, 2H), 7.17 (m, 1H), 6.92 (s, 1H), 2.49 (m, 2H), 2.39 (m, 2H), 2.12 (m, 2H) ppm; MS (ES) 227 (M+H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:34][O:35][C:36]([C:38]1([N:46]([OH:59])[C:47](=[O:58])[CH2:48][C:49]2[C:54]([CH3:55])=[CH:53][C:52]([CH3:56])=[CH:51][C:50]=2[CH3:57])[CH2:43][CH2:42][N:41]([O:44][CH3:45])[CH2:40][CH2:39]1)=[O:37].[CH3:60][O:61][N:62]1[CH2:67][CH2:66][CH:65](O)[CH2:64][CH2:63]1>C1COCC1>[CH3:34][O:35][C:36]([C:38]1([N:46]([O:59][CH:65]2[CH2:66][CH2:67][N:62]([O:61][CH3:60])[CH2:63][CH2:64]2)[C:47](=[O:58])[CH2:48][C:49]2[C:50]([CH3:57])=[CH:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])[CH2:39][CH2:40][N:41]([O:44][CH3:45])[CH2:42][CH2:43]1)=[O:37]
Reactant: CON1CCC(O)CC1
Reactant: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(N(OC2CCN(OC)CC2)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (1.11 g, 4.23 mmol) in THF (20 ml) at 0° C. was added diisopropyl azodicarboxylate (0.83 ml, 0.85 g, 4.24 mmol) dropwise and the resulting precipitate was stirred at 0° C. for 30 minutes. 4-{Hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (compound P3ii.3 obtained in analogy to preparation example 11, step 4) (1.3 g, 3.57 mmol) was further added in one portion, followed by a solution of 1-methoxy-piperidin-4-ol (0.53 g, 4.04 mmol) in THF (6 ml) dropwise at 0° C. The reaction mixture was stirred at room temperature for two hours and concentrated in vacuo. The residue was triturated with hexane and filtered to remove part of the insoluble triphenylphosphine oxide. The filtrate was evaporated and the residue purified by chromatography on silica gel (gradient ethyl acetate/heptane 3:7→ethyl acetate). Yield: 861 mg of pure 1-methoxy-4-{(1-methoxy-piperidin-4-yloxy)-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (title compound P3ii.26) as a colorless gum, followed by a second fraction of compound P3ii.26 (701 mg) slightly contaminated with triphenylphosphine oxide.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[NH4+:18].[OH-]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([NH2:18])=[O:11]
Reactant: O=C(O)CC1CC2CCC1C2
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)CC1CC2CCC1C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A solution of 2-(bicyclo[2.2.1]heptan-2-yl)acetic acid (0.50 g, 3.24 mmol) in DCM (30 mL) was treated with oxalyl chloride (0.426 mL, 4.86 mmol), followed by a catalytic amount of DMF (1 drop) and stirred at RT for 2 h. A solution of NH4OH (˜15M, 2 mL, ˜30 mmol) in THF (5 mL) was added drop wise and the mixture stirred at RT overnight. The mixture was concentrated to dryness and the residue was dissolved in EtOAc, washed with brine, dried over MgSO4 and concentrated to dryness to afford 2-(bicyclo[2.2.1]heptan-2-yl)acetamide (480 mg, 97%). 1H NMR (400 MHz, DMSO-d6): δ 7.19 (s, 1H), 6.65 (s, 1H), 2.14 (s, 1H), 1.91 (m, 3H), 1.75 (m, 1H), 1.35 (m, 4H), 1.11 (m, 4H); MS (ESI) m/z: 154.2 (M+H+).
Reaction SMILES: [Cl:1]C(OCC)=O.[CH3:7][C:8]1[CH2:9][C:10]([CH2:23]N2CCOCC2)=[C:11]([CH2:15][O:16][N:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH2:12][C:13]=1[CH3:14]>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[CH:18]=[N:17][O:16][CH2:15][C:11]1[CH2:12][C:13]([CH3:14])=[C:8]([CH3:7])[CH2:9][C:10]=1[CH2:23][Cl:1]
Reactant: COC(=O)C=NOCC1=C(CN2CCOCC2)CC(C)=C(C)C1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)C=NOCC1=C(CCl)CC(C)=C(C)C1

Procedure:
1.4 ml of ethyl chloroformate are added to a solution of 2.3 g methyl (4,5-dimethyl-2-morpholin-4-ylmethylcyclohexa-1,4-dienyl)methoxyiminoacetate in 25 ml of THF. The mixture is now heated for 20 hours at 70°. After the mixture has been evaporated, the residue is chromatographed on silica gel (ether/hexane 1:2). This gives 1.5 g of crystals of the title compound of melting point 65-68°.
Reaction SMILES: N([C@@H:4]1[C@H:8]([OH:9])[C@@H:7]([CH2:10][OH:11])[O:6][C@H:5]1[N:12]1[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]1=[O:14])=[N+]=[N-].[N-]=[N+]=[N-].[Li+]>CN(P(N(C)C)(N(C)C)=O)C>[CH:18]1[C:16](=[O:17])[N:15]=[C:13]2[N:12]([C@@H:5]3[O:6][C@H:7]([CH2:10][OH:11])[C@@H:8]([OH:9])[C@@H:4]3[O:14]2)[CH:19]=1
Reactant: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: [Li+]
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Yield: 50 %

Procedure:
The synthesis of 2′-azido-2′-deoxyuridine (ADU) has been previously published (Moffat et al. (1971) J. Org. Chem. 36:250). According to this procedure, anhydrouridine is treated with 7.1 equivalents of lithium azide in HMPA at 150° C. The desired product is obtained in only 50% yield after separation from a number of by-products. It is desirable to have a process by which ADU is synthesized in high yield without the necessity of further purification by chromatographic processes. Furthermore, it is desirable to avoid the use of HMPA, a known carcinogen.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([O-])(O)=[O:12].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]=[C:11]=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(N=C=O)c1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of (S)-1-(4-bromophenyl)ethanamine (240 g, 1.2 mol) in methylene chloride (3 L) and satd aq NaHCO3 (3 L) solution was added triphosgene (118 g, 0.396 mol) at 0° C. The mixture was stirred for 15 min. The organic phase was separated, dried over Na2SO4 and concentrated to give 1-bromo-4-(1-isocyanato-ethyl)-benzene (170 g, 63%).