Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:7]([O:13][CH3:14])=[N:8][CH:9]=[CH:10][C:11]=1I.[NH2:15][CH2:16][C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[OH:18].C(O)CO.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(O)C.[Cu]I.CO.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:17]([OH:18])[CH2:16][NH:15][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([O:13][CH3:14])[C:6]=2[CH:2]2[O:3][CH2:4][CH2:5][O:1]2)[CH:24]=[CH:23][CH:22]=1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: COc1nccc(I)c1C1OCCO1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)O
Product: COc1nccc(NC[C@@H](O)c2cccc(Cl)c2)c1C1OCCO1
Temperature: 75 °C
Yield: 36.2 %

Procedure:
A suspension of 3-[1,3]dioxolan-2-yl-4-iodo-2-methoxy-pyridine (3.07 g, 10.0 mmol), (S)-2-amino-1-(3-chloro-phenyl)-ethanol (1.71 g, 10 mmol), CuI (190 mg, 1.0 mmol), ethylene glycol (1.86 g, 30 mmol) and K3PO4 (6.3 g, 30 mmol) in 2-propanol (200 mL) was sealed and heated at 75° C. for 22 h (CuI and K3PO4 were crushed into powders before added). After cooled down to room temperature, the reaction mixture was loaded on silica gel. The chromatography with eluant CH2Cl2: MeOH=100:1 afforded the title product (1.27 g, 38%). 1H NMR (CDCl3) δ 3.30 (m, 1H) 3.45 (m, 1H), 3.87 (s, 3H), 3.96-4.05 (4H), 4.85 n (m, 1H), 6.09 (s, 1H), 6.15-6.30 (2H), 7.21-7.35 (2H), 7.41 (s, 1H), 7.82 (d, J=6 Hz, 1H). ESI-MS m/z 351.4 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH:36]2[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCC2CCN(C)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCC2CCN(C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-((1-methylpiperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate (0.11 g) in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.11 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. Chloroform was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.070 g of methyl 2-(2-hydroxy-5-((1-methylpiperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Br[CH2:26][CH2:27][CH:28]=[CH2:29].C(=O)(O)[O-].[Na+]>CS(C)=O>[CH2:29]([NH:15][C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)[CH2:28][CH:27]=[CH2:26]
Reactant: C=CCCBr
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCCNc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reaction time: 40 h
Yield: 16.7 %

Procedure:
A solution of 0.20 g (0.0007 mol) 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine in 17.5 ml dimethylsulfoxide was treated with 0.69 g (0.001 mol) potassiumhydroxide(85%) for 20 minutes at room temperature. Then 0.10 g(0.0007 mol) 4-bromo-1-butene were added and stirring was continued for 40 hours. Saturated aqueous sodiumbicarbonate was added and the mixture was extracted with ethylacetate. Evaporation of the solvent and chromatography on silicagel with dichloromethane/methanol 97/3 gave 0.04 g(17%) but-3-enyl-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-amine as beige crystals. MS m/e (%): 341 (M+, 21), 300 (100), 287 (65).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)=[N:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>CN(C=O)C>[F:30][C:26]1[CH:25]=[C:24]([NH:23][C:20]2[N:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:31])=[O:2])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)=[CH:22][N:21]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4cccc(F)c4)nc3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)CC1CCC(c2ccc(-c3cnc(Nc4cccc(F)c4)nc3)cc2)CC1
Temperature: 60 °C

Procedure:
To a solution of (4-{4-[2-(3-fluorophenylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester (crude from above) in DMF (2.5 mL) is added LiOH (10% solution, 1 mL) and the reaction mixture is heated at 60° C. for 1.5 h. The mixture is then subjected to HPLC purification to give the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.15 (m, 1H) 1.50 (td, J=12.44, 9.98 Hz, 1H) 1.63 (d, J=5.31 Hz, 6H) 2.37 (d, J=7.58 Hz, 2H) 6.76 (td, J=8.21, 2.27 Hz, 1H) 7.28-7.39 (m, 4H) 7.52 (dd, J=8.34, 1.26 Hz, 1H) 7.65 (s, 1H) 7.63 (t, J=4.04 Hz, 2H) 7.87 (d, J=12.38 Hz, 1H) 8.84-8.86 (m, 2H) 9.99 (s, 1H); (M+H)+=406.2.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:18])=[CH:4][C:3]=1[C:19]([OH:21])=[O:20].S(Cl)(Cl)=O.N1C=C[CH:29]=[CH:28][CH:27]=1.ClC1C=CC=CC=1Cl>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1.ClC1C=CC=CC=1>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([Br:18])=[CH:4][C:3]=1[C:19]([O:21][CH:28]([CH3:29])[CH3:27])=[O:20]
Reactant: c1ccncc1
Reactant: Nc1c(C(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1cc(Br)c2c(c1N)C(=O)c1ccccc1C2=O
Reaction time: 2 h

Procedure:
The starting 1-amino-4-bromoanthraquinone-2-carboxylic acid is reacted with 1.5 to 3 molar equivalents of a chlorinating agent such as thionyl chloride at a temperature of 80 to 100° C. for a period of about 1 to 3 hours in the presence of 0.01 to 5 molar equivalents (based on the raw material) of pyridine in 3 to 7-fold weight an amount of an inert solvent such as orthodichlorobenzene, chlorobenzene, toluene or xylene so as to be converted into an acid chloride. After the excess chlorinating agent has been removed therefrom under reduced pressure, 1.5 to 5 molar equivalents of isopropyl alcohol is added thereto and esterification is then performed at 60 to 80° C. for 1 to 3 hours. Afterward, the product is allowed to stand, thereby obtaining crystals of isopropyl 1-amino-4-bromoanthraquinone-2-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1S(Cl)(=O)=O)#[N:2].[F-:13].[K+].S1(CCCC1)(=O)=O>>[F:13][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: [F-]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: N#Cc1ccccc1F

Procedure:
20.15 grams(0.l mole) of the product prepared in Example 1 above, 12 grams(0.21 mole) spray-dried potassium fluoride, and 45 milliliters sulfolane were heated under nitrogen to 230°-248° C. for one hour. The product was distilled directly through a 5-inch(12.7 centimeters) vigreaux column to give 6.9 grams 2-fluorobenzonitrile having a boiling point of 91°-92° C. at 27 mm Hg. The infrared spectrum was identical with that of the published spectrum. Based on 2-cyanobenzenesulfonyl chloride, the per cent yield of 2-fluorobenzonitrile was 57. Based on saccharin, the overall yield was 52.
Reaction SMILES: ClCCOC1C=C(C=CC=1)C#N.Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].N1C=NC(S)=N1.[CH3:32][C:33]1[NH:37][N:36]=[C:35]([SH:38])[N:34]=1>>[CH3:32][C:33]1[NH:37][N:36]=[C:35]([S:38][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])[N:34]=1
Reactant: Cc1nc(S)n[nH]1
Reactant: N#Cc1cccc(OCCCCl)c1
Agent: N#Cc1cccc(OCCCl)c1
Agent: Sc1nc[nH]n1
Product: Cc1nc(SCCCOc2cccc(C#N)c2)n[nH]1

Procedure:
By a method similar to that in Reference Example 2, and using, instead of 3-[(2-chloroethyl)oxy]benzonitrile, 3-[(3-chloropropyl)oxy]benzonitrile obtained in Reference Example 4 and using, instead of 1H-1,2,4-triazole-3-thiol, 5-methyl-1H-1,2,4-triazole-3-thiol, the title compound was obtained as a yellow oil (643.0 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[C:4]([CH2:7][C:8]([N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)=O)[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[S:6][CH:5]=[C:4]([CH2:7][CH2:8][N:10]2[CH2:15][CH:14]3[CH:12]([C:13]3([C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:11]2)[CH:3]=1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)Cc3csc(Cl)c3)CC21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCc3csc(Cl)c3)CC21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
To a solution of N-(3-{3-[2-(5-chloro-3-thienyl)acetyl]-6-methyl-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide (Preparation 121, 45 mg, 0.11 mmol) in anhydrous tetrahydrofuran (1 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.22 ml, 0.22 mmol) and the mixture was stirred at room temperature for 3 h. The rapidly stirred reaction mixture was treated sequentially with water (0.22 ml), sodium hydrogen carbonate (200 mg) and ethyl acetate (10 ml). After 30 min the reaction mixture was filtered and concentrated in vacuo to afford a pale yellow oil. This was purified by preparative HPLC (condition 8) to give a very pale yellow oil which was partitioned between dichloromethane (10 ml) and aqueous potassium carbonate solution (4% w:v, 5 ml). The layers were separated and the organic layer was washed with water (3 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (14 mg, 33%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:11][CH2:12]Cl)(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]>O.CCOC(C)=O>[C:5]([O:11][CH2:12][N:1]=[N+:2]=[N-:3])(=[O:10])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C(=O)OCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
Sodium azide (1.942 g, 29.9 mmol) was added to a suspension of chloromethyl pivalate (3.00 g, 19.92 mmol) in water (5 mL) and stirred vigorously at 90° C. for 16 h. The reaction mixture was diluted with water (20 mL) and EtOAc (20 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated to afford azidomethyl pivalate as a liquid (2 g, 64% yield). 1H NMR (400 MHz, Acetone-d6): δ 5.23 (s, 2H), 1.22 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:21]([O-])=O)=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C@H:15]([CH3:16])[N:8]3[CH:7]=[C:6]([C:17]([NH2:19])=[O:18])[C:5]2=[O:20])[C:11]=1[F:12].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>O.CO>[NH2:21][C:3]1[C:2]([F:1])=[C:11]([F:12])[C:10]2[O:13][CH2:14][C@H:15]([CH3:16])[N:8]3[C:9]=2[C:4]=1[C:5](=[O:20])[C:6]([C:17]([NH2:19])=[O:18])=[CH:7]3
Reactant: C[C@H]1COc2c(F)c(F)c([N+](=O)[O-])c3c(=O)c(C(N)=O)cn1c23
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C(N)=O)cn1c23
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
To a suspension of 3 (1 g, 3.07 mmol) in a mixture of water/methanol (1:1 v/v, 30 mL) was added sodium hydrosulfite (Na2S2O4, 4.3 g, 24.6 mmol). The suspension was refluxed for 5 h until all starting material has disappeared. Upon completion, the reaction mixture was cooled to room temperature and 50 mL of water were added. After 20 minutes, a light yellow solid was collected by filtration and washed with water. The solid was dried under vacuo to give 4 (725 mg, 74% yield), which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.O.NN>CCO.O.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)[NH:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2nc3cc(N)cnc3[nH]2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a stirred suspension of 6-Nitro-2-(4-nitrophenyl)-3H-imidazo [4,5-b]pyridine (4) (0.5 g, 1.75 mmol) in EtOH (40 mL) was added Raney Ni° (1 g, slurry in H2O) followed by hydrazine hydrate (2 mL) dropwise over 5 minutes. The reaction mixture was stirred at room temperature until the reaction subsided and was then heated at 100° C. for 1 h. The hot solution was filtered through celite and the filtrate concentrated under reduced pressure. Water was added to the residue resulting in the formation of an off white solid that was collected by filtration, rinsed with H2O and air dried. The solid was then dried in vacuuo at room temperature to give 5 as a light tan solid (0.318 g, 1.4 mmol, 81%) 1H NMR (500 MHz, DMSO-d6) δ12.27 (apparent d, 1H), 7.77 (br s, 2H), 7.70 (br s, 1H) 6.97 (br s, 1H), 6.63 (d, J=8.51 Hz, 2H), 5.57 (br s, 2H), 4.97 (br s, 2H)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[CH2:18][O:17][C:8]3([CH2:13][CH2:12][CH2:11][N:10]4[CH:14]=[N:15][CH:16]=[C:9]34)[C:6]=2[CH:7]=1.[CH3:19][N:20](C)C(=O)C>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].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].[C-]#N.[Zn+2].[C-]#N>[CH:16]1[N:15]=[CH:14][N:10]2[CH2:11][CH2:12][CH2:13][C:8]3([C:6]4[CH:7]=[C:2]([C:19]#[N:20])[CH:3]=[CH:4][C:5]=4[CH2:18][O:17]3)[C:9]=12
Reactant: Clc1ccc2c(c1)C1(CCCn3cncc31)OC2
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ccc2c(c1)C1(CCCn3cncc31)OC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 22 ml Supelco vial under Argon is loaded with 0.231 mmol of tris(dibenzylidene-acetone)dipalladium(0) (Pd2(dba)3) and 0.463 mmol of 1,1′-bis(diphenyl-phosphino)ferrocene (dppf). 5 ml of dry N,N-dimethyl acetamide is added and the dark solution is stirred at room temperature for 10 minutes. 1.388 mmol of zinc cyanide, and then a solution of 2.313 mmol of 6-chloro-6′,7′-dihydro-3H,5′H-spiro[2-benzofuran-1,8′-imidazo[1,5-a]pyridine] in 2.5 ml of dry N,N-dimethyl acetamide are successively added. The reaction mixture is briefly degassed, put under an atmosphere of Argon then directly placed in an oil bath pre-heated to 80° C. The dark brown mixture is then stirred for 15 hours at 140° C. If the conversion is not complete (HPLC check), a fresh solution of Pd2(dba)3 and dppf in N,N-dimethyl acetamide, previously stirred at room temperature for 10 minutes, is added and the stirring is continued at 140° C. till no more starting material is detected. The reaction mixture is cooled to room temperature and evaporated to dryness. The residue is diluted with 30 ml of dichloromethane and 100 ml of tert-butyl-methyl ether and washed with aqueous HCl 2N (2×50 ml). The combined aqueous phases are basified with 75 ml of 4N aqueous NaOH and extracted with dichloromethane (3×200 ml). The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a beige solid. Rf=0.13 (EtOAc-methanol 10:1); Rt=2.59 (gradient I).
Reaction SMILES: [CH2:1]([N:3]([Zr:6](N(CC)CC)([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH2:4][CH3:5])[CH3:2].[Cl-:22].[Cl-].[Cl-].[Cl-].[Zr+4]>O1CCCC1>[Cl:22][Zr:6]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CCN(CC)[Zr](N(CC)CC)(N(CC)CC)N(CC)CC
Reactant: [Cl-]
Agent: [Zr+4]
Solvent: C1CCOC1
Product: CCN(CC)[Zr](Cl)(N(CC)CC)N(CC)CC
Reaction time: 1 h

Procedure:
A 0.1M stock solution of chlorotris(diethylamino)zirconium in tetrahydrofuran (THF) was prepared in a dry box by the addition of 1.14 g (3 mmol) of tetrakis(diethylamino)zirconium to 233 mg (1 mmol) of zirconium tetrachloride. After standing for 1 h, the mixture was diluted to 40 mL with tetrahydrofuran, and the resulting 0.1M stock solution was stored at -23° in a refrigerated dry box.
Reaction SMILES: C[CH:2]([C:13]([CH:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)C)=O)C1C=CC(OC)=C(OC)C=1.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[OH:30].C(OC(C)C)(C)C>[Pt]=O.C(O)(C)C>[Cl:37][C:33]1[CH:32]=[C:31]([C@@H:29]([OH:30])[CH2:28][NH:27][C@H:13]([CH3:2])[CH2:15][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(C(C)C(=O)C(C)c2ccc(OC)c(OC)c2)cc1OC
Reactant: NC[C@H](O)c1cccc(Cl)c1
Agent: O=[Pt]
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: COc1ccc(C[C@@H](C)NC[C@H](O)c2cccc(Cl)c2)cc1OC
Reaction time: 24 h
Yield: 62 %

Procedure:
To a mixture of 5.83 g of methyl-3,4-dimethoxyphenylmethyl ketone, 5.15 g of (R)-2-amino-1-(3-chlorophenyl)ethanol and 50 mg of platinum oxide were added 15 ml of isopropyl alcohol and 30 ml of diisopropyl ether, and the reducing reaction was carried out at room temperature, at 1 atm under hydrogen atmosphere for 24 hours. After removing off platinum oxide by filtration, the solvent was distilled off under reduced pressure to give 6.51 g of white oil of (R,R)-1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol (yield 62%). The optical purity of the (R,R)-isomer was 65%.
Reaction SMILES: N#N.[C@@H:3]1([N:12]2[C:21](=[O:22])[C:20]3[NH:19][CH:18]=[N:17][C:16]=3[N:15]=[C:13]2[NH2:14])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@@H:4]1[OH:5].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>>[C@@H:3]1([N:12]2[C:21](=[O:22])[C:20]3[NH:19][CH:18]=[N:17][C:16]=3[N:15]=[C:13]2[NH:14][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@@H:4]1[OH:5]
Reactant: Nc1nc2nc[nH]c2c(=O)n1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(C)C(=O)Cl
Agent: N#N
Product: CC(C)C(=O)Nc1nc2nc[nH]c2c(=O)n1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
introducing an acyl group at the N2 position of 1-β-D-arabinofuranosyl guanine with an acylating agent, for example, using isobutyryl chloride under conditions suitable for obtaining 1-β-D-arabinofuranosyl-N2-isobutyryl guanine,
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:28])[N:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[N:17][CH:18]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.[NH3:29]>O1CCOCC1>[NH2:29][C:2]1[C:7]2[C:8](=[O:28])[N:9]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[N:17][CH:18]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)C(C)(C)COc1ccc(N2CCOc3ncnc(Cl)c3C2=O)cn1
Reactant: N
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)COc1ccc(N2CCOc3ncnc(N)c3C2=O)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
Methyl 3-(5-(4-chloro-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-20 was dissolved in a 0.5 M solution of ammonia in 1,4-dioxane and stirred at room temperature for 20 h. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica gel (7 N ammonia solution in methanol:CH2Cl2 gradient) to give methyl 3-(5-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-21 (55.0 mg, Yield=57% from B-19). MS (ESI) [M+1]+ 388.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20](CC=C)[C:19]([CH3:27])=[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]3=[O:33])=[O:13])[N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2>O>[CH3:1][O:2][C:3]1[C:4]([CH3:34])=[C:5]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([CH3:27])=[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]3=[O:33])=[O:13])[N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C=CCn1c(C)c(C(=O)OCC)c(=O)c2cc(C(=O)c3c(C)c(OC)c4ccccn34)ccc21
Solvent: O
Product: CCOC(=O)c1c(C)[nH]c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Temperature: 120 °C

Procedure:
6.7 mg (0.02 mmol) of dichloro(2,6,10-dodecatriene)-1,12-diyl ruthenium(IV) are added, at ambient temperature under an inert atmosphere, to 0.307 (0.67 mol) of ethyl 6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-2-methyl-4-oxo-1-prop-2-en-1-yl-1,4-dihydroquinoline-3-carboxylate in 12 ml of a mixture of DMFt-butanol and water (1/1). The reaction medium is microwave-heated for 30 minutes at 120° C. and then extracted with ethyl acetate. The organic phase obtained is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The precipitate obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 94 mg of a yellow solid are obtained.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:28](=[O:40])[N:29]([C:33]6[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=6)[N:30]=[CH:31][CH:32]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([NH:42][C@H:43]3[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][C@H:44]3[F:51])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>>[CH2:49]([N:46]1[CH2:47][CH2:48][C@H:43]([NH:42][C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:28](=[O:40])[N:29]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)[N:30]=[CH:31][CH:32]=4)=[O:26])=[CH:20][C:19]=3[F:41])[NH:8][N:9]=2)[C@H:44]([F:51])[CH2:45]1)[CH3:50]
Reactant: CCN1CC[C@H](Nc2nn(Cc3ccc(OC)cc3)c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Product: CCN1CC[C@H](Nc2n[nH]c3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c23)[C@H](F)C1
Yield: 66.2 %

Procedure:
Prepared from ±N-(4-(1-(4-methoxybenzyl)-3-((3R*,4S*)-1-ethyl-3-fluoropiperidin-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (8 mg, 0.01 mmol) and 2,2,2-trifluoroacetic acid (0.43 mL, 5.5 mmol) according to the procedure described for Example 145, Step C. The product was obtained as a pale yellow powder (4 mg, 51%). HPLC: 95% purity (220 nm); LRMS (ESI+): 97% purity, 220 nm, m/z 605 (M+1) detected; 1H NMR (400 MHz, MeOD-d3) δ 11.98 (s, 1H), 8.35 (m, 3H), 8.09 (d, J=13 Hz, 1H), 7.67 (m, 2H), 7.53 (m, 2H), 7.29 (t, J=9 Hz, 2H), 6.42 (d, J=5 Hz, 1H), 5.37 (d, J=47 Hz, 1H), 4.26 (m, 1H), 3.97 (m, 1H), 3.66 (m, 1H), 3.52 (m, 1H), 3.28 (m, 2H), 2.34 (m, 2H), 1.39 (t, J=7 Hz, 3H).