Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:35])[C@@H:17]([NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH2:28]([O:27][C:25](=[O:26])[NH:24][C@@H:17]([CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)[C:16](=[O:35])[NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)[C@@H](NC(=O)OCc2ccccc2)C2CCCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H](C(=O)NCC1CCNCC1)C1CCCCC1)OCc1ccccc1
Reaction time: 15 h
Yield: 97 %

Procedure:
4-[(2-(S)-Benzyloxycarbonylamino-2-cyclohexyl-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (7.15 g, 14.66 mmol, example 223 a)) was solved in trifluoracetic acid (90% in water, 100 ml). The reaction mixture was stirred for 15 h and evaporated in vacuo to give 7.1 g of the desired product (97%). MS m/z: 388.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH3:26])[CH3:27])=[CH:20][CH:19]=2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Product: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 42.9 %

Procedure:
Following general procedure D, 1-(6-bromo-4-((4-((dimethylamino)methyl)phenyl)amino)quinolin-3-yl)butan-1-one (43 mg, 0.10 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.16 mmol) to afford the desired product (21.8 mg, 43%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.12 (s, 1H), 7.97-7.87 (m, 2H), 7.73 (d, J=1.8 Hz, 1H), 7.46-7.39 (m, 2H), 7.26-7.19 (m, 2H), 7.10 (s, 2H), 3.80 (s, 2H), 3.17 (t, J=7.3 Hz, 2H), 2.39 (s, 6H), 1.81 (h, J=7.4 Hz, 2H), 1.05 (t, J=7.4 Hz, 3H). ESI MS m/z 508 [C28H27Cl2N3O2+H]+; HPLC 99% (AUC), tR=11.22 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[N:5]2[CH:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.[O:23]1[CH2:26][CH:25]([N:27]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[N:28]2)[CH2:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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].O1CCOCC1>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[N:5]4[CH:20]=[CH:21][N:22]=[C:4]4[CH:3]=[C:2]([C:30]4[CH:29]=[N:28][N:27]([CH:25]5[CH2:26][O:23][CH2:24]5)[CH:31]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1
Reactant: CC1(C)OB(c2cnn(C3COC3)c2)OC1(C)C
Reactant: N#CCC(C1CC1)n1cc(-c2nc(Cl)cc3nccn23)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#CCC(C1CC1)n1cc(-c2nc(-c3cnn(C4COC4)c3)cc3nccn23)cn1
Temperature: 75 °C
Yield: 50.6 %

Procedure:
To a flask charged with 3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-cyclopropylpropanenitrile (Preparation M; 0.050 g, 0.16 mmol), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Table 2, compound f; 0.078 g, 0.21 mmol), and potassium phosphate (0.24 mL, 0.48 mmol) was added 2 mL of dioxane and argon was bubbled through for 5 minutes before dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.015 g, 0.032 mmol) and tris(dibenzylideneacetone)dipalladium (0.015 g, 0.016 mmol) were added. The reaction was fitted with a septum and argon was bubbled through for 10 minutes before it was sealed and then heated to 75° C. for 2 hours. The reaction mixture was diluted with dichloromethane and loaded directly onto a silica gel column pre-wetted and eluted with ethyl acetate containing 0.5% ammonium hydroxide to afford the title compound (0.034 g, 0.081 mmol, 50% yield). MS (apci) m/z=401.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[Cl-].Br[CH2:17][CH2:18]Cl.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17]2)=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: N#CCc1ccc(Br)cc1C(F)(F)F
Reactant: ClCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: N#CC1(c2ccc(Br)cc2C(F)(F)F)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 97.7 %

Procedure:
o a stirred solution of (4-bromo-2-trifluoromethyl-phenyl)-acetonitrile (3.33 g, 12.61 mmol) from step 2 of example A(141), benzyltriethylammoniym chloride (0.057 g, 0.25 mmol) and 1-bromo-2-chloroethane (1.57 g, 10.94 mmol), was added dropwise a solution of NaOH 40% ( 3 mL). The reaction mixture was stirred 6 hours at 50° C. After this time the reaction was quenched with 1 N HCl (30 mL) and extracted with EtOAC (3×30 mL). The organic phase was dried over Na2SO4 and evaporated. The crude organic product was purified by flash column chromatography (10% EtOAc in hexanes) to give the product (3.1 g, 86%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.4–1.44 (m, 2H), 1.76–1.80 (m, 2H), 7.44 (d, J=8.3 Hz, 1 H), 7.69 (dd, J=8.3, 2 Hz, 1 H), 7.84 (d, J=2 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH:35]([NH:38][C:39]([C:41]1[C:50](=[O:51])[C:49]2[C:44](=[N:45][CH:46]=[CH:47][CH:48]=2)[N:43]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54](Br)[CH:53]=2)[CH:42]=1)=[O:40])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:35]([NH:38][C:39]([C:41]1[C:50](=[O:51])[C:49]2[C:44](=[N:45][CH:46]=[CH:47][CH:48]=2)[N:43]([C:52]2[CH:53]=[CH:54][CH:55]=[C:56]([C:2]3[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=3)[CH:57]=2)[CH:42]=1)=[O:40])([CH3:37])[CH3:36]
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(-c2cccc(-n3cc(C(=O)NC(C)C)c(=O)c4cccnc43)c2)ccc1O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 5′-bromo-2′-hydroxyacetophenone, diboron pinacol ester (1.25 eq), potassium acetate (3 eq) and [1,1′-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) in N,N-dimethylformamide (10 mmol) was stirred at 80° C. for 3 hours and cooled down. A solution of N-Isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 1, Step 4 (0.75 eq) in N,N-dimethylformamide (7 ml/mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(1) (0.05 eq) and 2M aqueous sodium carbonate (8.5 eq) were added and the resulting mixture was stirred at 80° C. for 2.5 hours. The cooled mixture was partitioned between ethyl acetate and water and the product from the organic phase was chromatographed on silica gel eluting with 60% ethyl acetate in hexane to afford the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[C:14]2=O)[C:5]([O:7][CH3:8])=[O:6].[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14]2)[C:5]([O:7][CH3:8])=[O:6]
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)OC)c1cccc2c1NC(=O)C2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C(C(=O)OC)c1cccc2c1NC(=O)C2

Procedure:
A solution of 2,3-dihydro-2,3-dioxo-1H-indole-7-propandioic acid dimethyl ester (1.4 g, 0.0048 mole) is dissolved in acetic acid (100 ml) and in the presence of 20% Pd/C is treated with hydrogen gas at 50 psi. The solution is filtered and concentrated to yield 2,3-dihydro-2-oxo-1H-indole-7-propandioic acid dimethyl ester. This is purified by flash chromatography on silica (elution with 7:3 hexane:ethyl acetate) to give after concentration pure 2,3-dihydro-2-oxo-1H-indole-7-propandioic acid dimethyl ester, mp 161°-161.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.Cl.[NH2:37][OH:38]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]4=[N:37][OH:38])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCCC4=NO)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of (3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone (0.41 g, 0.81 mmol) in EtOH (8.2 mL) was added hydroxylamine hydrochloride (0.11 g, 1.61 mmol). The reaction mixture was stirred at room temperature overnight. Then the mixture was warmed to 70° C. for 15 min. The reaction mixture was concentrated in vacuo, suspended in EtOAc-DCM, washed with half saturated brine (2×) and filtered through a SiO2 plug. The resulting residue was azeotroped with CH3CN (2×) to provide an off white powder which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12](Cl)(Cl)=[O:13]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:5]([O:7][C:12](=[O:13])[NH:11][C:3]=12)=[O:6]
Reactant: O=C(Cl)Cl
Reactant: Nc1c(Cl)cccc1C(=O)O
Solvent: Clc1ccccc1
Product: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Temperature: 25 °C

Procedure:
171.6 g (1.0 mol) of 99.7% 3-chloroanthranilic acid are initially introduced, in 1,720.0 g of chlorobenzene, into a four-necked flask having a stirrer, a thermometer and a reflux condenser operated at -20° C., and 440.0 g of phosgene are gassed in at 100° C. over a period of about 3 h while stirring thoroughly. After that, the mixture is stirred at 100° C. for a further 1 h, and is subsequently blown free of phosgene at this temperature using nitrogen. After cooling to about 25° C., the crystals which have precipitated out are filtered off with suction and the filter cake is washed with 2×50 ml of chlorobenzene and dried at 100° C. in vacuo. 184.9 g of 3-chloroisatoic anhydride, having a purity by GC of >99%, are obtained, corresponding to 93.6% of theory.
Reaction SMILES: F[C:2]1[C:7](F)=[C:6](OCC)[CH:5]=[CH:4][C:3]=1[C:12]1[C:13](B(O)O)=[CH:14][CH:15]=[CH:16][CH:17]=1.Br[C:22]1[CH:27]=[CH:26][C:25](I)=[C:24](F)[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)C.O>[C:22]1([C:13]2[C:12]([C:3]3[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: CCOc1ccc(-c2ccccc2B(O)O)c(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)O
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1

Procedure:
0.047 mol of 2′,3′-difluoro-4′-ethoxybiphenylboronic acid (14), 0.05 mol of 1-bromo-3-fluoro-4-iodobenzene (15), 1 mmol of palladium acetate, 2 mmol of triphenylphosphine, 25 ml of saturated sodium carbonate solution, 20 ml of water and 100 ml of isopropanol are initially introduced and refluxed overnight. Conventional work-up gives the terphenyl compound (16).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1.[Cl-].[Ca+2].[Cl-]>C(O)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1
Reactant: Cn1ccnc1SCCSc1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: Cn1ccnc1SCCSc1ccc(N)cc1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
1-methyl-2-[[2-[(4-nitrophenyl)thio]ethyl]thio]imidazole (1.3 g) was dissolved in 85% ethanol (39 ml), calcium chloride (0.24 g) and reduced iron (1.23 g) were added to the mixture, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was filtered with. Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[2-[(1-methylimidazol-2-yl)thio]ethyl]thio]aniline (0.68 g).
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.F[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1>>[CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([O:11][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[C:4]=2[CH:3]=1
Reactant: Fc1ccc2ccccc2c1
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc2ccccc2c1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH2:1]([C@H:4]1[C:9](=[O:10])[O:8][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:2]=[CH2:3].C1OCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:56][CH:57]1[CH2:62][CH2:61][N:60]([C:63]([O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])=[O:64])[CH2:59][CH2:58]1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([C@:4]1([CH2:56][CH:57]2[CH2:62][CH2:61][N:60]([C:63]([O:65][CH2:66][CH2:67][Si:68]([CH3:69])([CH3:71])[CH3:70])=[O:64])[CH2:59][CH2:58]2)[C:9](=[O:10])[O:8][C@H:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C(=O)O[C@H](c2ccccc2)[C@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(CBr)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CC[C@]1(CC2CCN(C(=O)OCC[Si](C)(C)C)CC2)C(=O)O[C@H](c2ccccc2)[C@H](c2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
4.9 g of tert-butyl (3S,5S,6R)-3-allyl-2-oxo-5,6-diphenylmorpholine-4-carboxylate were dissolved in 100 ml of THF. 14.9 ml of 15-crown-5 were added, and the mixture was cooled to −78° C. Then 6.8 ml of a 2 M solution of NaHMDS in THF were added dropwise. The mixture was stirred for 10 min and then 8 g of 2-trimethylsilanylethyl 4-bromomethylpiperidine-1-carboxylate were added dropwise. The mixture was allowed to warm to 0° C. over the course of 6 h, and the reaction was then stopped by adding 500 ml of saturated ammonium chloride solution. The aqueous phase was extracted 3 times with 400 ml of ethyl acetate each time, and the combined organic phases were dried with MgSO4. The solvents were removed in vacuo, and the residue was chromatographed on silica gel.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1COCC1>[CH2:1]([O:8][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To 2.5 mL benzyl alcohol in 80 mL THF is added 1.87 g NaH. After one hour stirring at room temperature, 5.0 g of 2,4-Difluorobenzonitrile is added. After stirring one hour, the reaction is quenched with excess water and concentrated in vacuo. The residue is redissolved in ethyl acetate and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The product is recrystallizde in carbon tetrachloride to give 3.24 g (39.7%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:24][C@:25]12[CH2:42][CH2:41][C@H:40]3[C@@H:30]([CH2:31][CH2:32][C@@H:33]4[C@:38]3([CH3:39])[CH2:37][CH:36]=[CH:35][CH2:34]4)[C@@H:29]1[CH2:28][CH2:27][C:26]2=O>C(O)C>[CH3:24][C@:25]12[CH2:42][CH2:41][C@H:40]3[C@@H:30]([CH2:31][CH2:32][C@@H:33]4[C@:38]3([CH3:39])[CH2:37][CH:36]=[CH:35][CH2:34]4)[C@@H:29]1[CH2:28][CH2:27][C:26]2=[N:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C[C@]12CC=CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NN=C2CC[C@H]3[C@@H]4CC[C@H]5CC=CC[C@]5(C)[C@H]4CC[C@]23C)cc1

Procedure:
4-Methylbenzenesulphonic acid hydrazide (525 g) and 4-methylbenzenesulphonic acid (5.25 g) were added to a hot, stirred solution of (5α)-androst-2-en-17-one (700 g) in ethanol (5.6 l) and the solution was heated under reflux for 8 h. The stirred mixture was cooled and further ethanol (1 l) was added to give 4-methylbenzenesulphonic acid [(5α)-androst-2-en-17-ylidene]hydrazide as a crystalline solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([N:35]3[CH:47]=[CH:46][N:38]4[C:39]5[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=5[CH:45]=[C:37]4[C:36]3=[O:48])[N:30]=[CH:29][CH:28]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:34][CH2:33][C:32]1[C:31]([N:35]2[CH:47]=[CH:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:30][CH:29]=[CH:28][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
A mixture of 151g (89 mg, 0.14 mmol), NaBH4 (22 mg, 0.60), and methanol (10 mL) was stirred at 25° C. for 1 h. The mixture was quenched with water (8 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 151 (35 mg, 39%). MS-ESI: [M+H]+ 649. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=2.0 Hz, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.46 (s, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.50-7.48 (m, 2H), 7.38-7.36 (m, 1H), 7.26-7.24 (m, 2H), 6.83-6.80 (m, 2H), 4.98 (bs, 1H), 4.57-4.54 (m, 2H), 4.48-4.33 (m, 4H), 3.67-3.66 (m, 1H), 3.60 (s, 3H), 3.39-3.38 (m, 2H), 3.09-3.08 (m, 1H), 2.96-2.94 (m, 1H), 2.76-2.74 (m, 2H), 2.64-2.62 (m, 2H), 2.36-2.31 (m, 2H), 2.20-2.17 (t, J=7.5 Hz, 1H), 1.88-1.86 (m, 2H), 1.75-1.74 (m, 2H), 0.93 (d, J=6.5 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21][P:22]([OH:25])([OH:24])=[O:23])[C@@H:17]([O:26][P:27]([O:30][CH2:31][C@@H:32]3[C@@H:36]([O:37][C:38](=[O:62])[C@@H:39]([NH:54]C(OC(C)(C)C)=O)[CH2:40][CH2:41][C@@H:42]4[S:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43]4)[C@@H:35]([OH:63])[C@H:34]([N:64]4[CH:72]=[N:71][C:70]5[C:65]4=[N:66][CH:67]=[N:68][C:69]=5[NH2:73])[O:33]3)([OH:29])=[O:28])[CH2:16]2)[C:11](=[O:74])[N:10]=1>ClCCl>[NH2:54][C@H:39]([CH2:40][CH2:41][C@@H:42]1[S:46][CH2:45][NH:44][CH2:43]1)[C:38]([O:37][C@H:36]1[C@@H:35]([OH:63])[C@H:34]([N:64]2[CH:72]=[N:71][C:70]3[C:65]2=[N:66][CH:67]=[N:68][C:69]=3[NH2:73])[O:33][C@H:32]1[CH2:31][O:30][P:27]([O:26][C@H:17]1[CH2:16][C@H:15]([N:12]2[CH:13]=[CH:14][C:9]([NH2:8])=[N:10][C:11]2=[O:74])[O:19][C@@H:18]1[CH2:20][O:21][P:22]([OH:24])([OH:25])=[O:23])([OH:29])=[O:28])=[O:62]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC[C@H]1CN(C(=O)OC(C)(C)C)CS1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3OC(=O)[C@H](N)CC[C@H]3CNCS3)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 155.5 %

Procedure:
A 10% solution of trifluoroacetic acid in dichloromethane (0.16 mL) was added to a solution of (5S)-tert-butyl 5-((3S)-4-(((2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy) (hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl)Oxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)thiazolidine-3-carboxylate (Compound tk4) (8.5 mg, 8.43 μmol) in dichloromethane (0.2 mL), and the mixture was stirred at room temperature for 1.25 hours. Following concentration under reduced pressure, (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-4-((S)-thiazolidin-5-yl)butanoate (Ala(Tzm)-pdCpA) (Compound tk5) (10.6 mg, quant.) was obtained.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26]([CH2:28][C:29](O)=[O:30])#[N:27]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[CH2:28][C:26]#[N:27])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N#CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (14.9 mg, 53.5%), MS (ISP) m/z=398.1 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and 2-cyanoacetic acid.