Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][NH2:11].O1CCOCC1>C(OCC)(=O)C>[NH:10]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[C:8]([NH2:9])=[N:11]1
Reactant: NN
Reactant: N#Cc1cccnc1Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1n[nH]c2ncccc12
Temperature: 150 °C

Procedure:
2-Chloro-3-cyanopyridine (2.77 g), hydrazine (5 mL), and dioxane (100 mL) were combined in a sealed tube and heated at 150° C. for 16 hr. The reaction mixture was cooled to room temperature and concentrated in vacuo to provide a crude residue. The resultant residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaCl solution (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1H-pyrazolo[3,4-b]pyridin-3-ylamine as a yellow solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.C1C(=O)N([Cl:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:16][CH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1cnc(C)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cnc(CCl)cn1
Temperature: 80 °C
Yield: 20.2 %

Procedure:
To a solution of 2,5-dimethylpyrazine (500 mg, 4.62 mmol) in carbon tetrachloride (7 mL) was added NCS (679 mg, 5.09 mmol) followed by BPO (20 mg) and the mixture was heated to 80° C. for 6 hours. The mixture was diluted with DCM and extracted with saturated aqueous sodium sulfite solution and brine. The organic layer was dried and concentrated to give a crude product which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (1:0 to 15:1) to give 2-(chloromethyl)-5-methylpyrazine (133 mg, 20.19% yield) as yellow oil. LCMS retention time 0.557 min; LCMS MH+ 143.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=[O:12])[CH2:3]1)[CH2:9]2.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.CO>C1COCC1>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([C:5]4=[O:12])[CH2:3]2)[CH2:9]3)=[CH:24][CH:23]=1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C2CC3CC1CC(OCc1ccc(-c4nc5ccccc5o4)cc1)(C3)C2
Reaction time: 1 h

Procedure:
To KH (35%; 1.38 g; 0.012 mole) in THF (20 ml) under N2 and cooled to 0° C. is added 5-hydroxytricyclo[3.3.1.13,7 ]decan-2-one (2 g; 0.012 mole) all at once. The reaction mixture is stirred for 5 min. in an ice bath and 1 hr. at room temperature. To the reaction mixture is then added 4-(benzoxazol-2-yl)benzyl bromide (3.4 g; 0.012 mole) dissolved in THF (60 ml) at a fast drip rate. A bright yellow mixture forms and the mixture is stirred overnight at room temperature. The mixture is next cooled in an ice bath, MeOH added to quench any KH and filtered. The filtercake is washed with THF and evaporated to dryness. The product is purified using a gradient flash chromatography (eluting with 10%-25% ethyl acetate/hexane) to obtain 5-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]decan-2-one (m.p. 159°-160° C.) which is used directly in Step C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:27][C:28]([NH:30][C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:34]([O:41][C:42]3[CH:43]=[CH:44][C:45]4[N:46]([C:48]([N:51]5[CH2:55][CH2:54][CH2:53][C@@H:52]5[CH3:56])=[N:49][N:50]=4)[CH:47]=3)[CH2:33][CH2:32]2)=[O:29])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][O:20]C3CCCCO3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:27][C:28]([NH:30][C@@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:34]([O:41][C:42]3[CH:43]=[CH:44][C:45]4[N:46]([C:48]([N:51]5[CH2:55][CH2:54][CH2:53][C@@H:52]5[CH3:56])=[N:49][N:50]=4)[CH:47]=3)[CH2:33][CH2:32]2)=[O:29])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH2:18][CH2:19][OH:20])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(Cl)c(OCCO)c4)c4ccccc43)cn12
Yield: 75.1 %

Procedure:
A solution of Intermediate 78c (60.0 mg, 0.08 mmol) and pyridinium p-toluene sulphonate (58.0 mg, 0.23 mmol) in MeOH (1 mL) was heated at 45° C. for 18 h. The reaction mixture was cooled and diluted with DCM (5 mL). This was washed with sat. aq. NaHCO3 (2×5 mL). The organic layer was passed through a phase separator and concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to afford the title compound (42 mg, 78%). LCMS (Method 3): Rt: 3.47 min, m/z 699/701 [MH+].
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].[CH:12]1C=CC=CC=1.CI.CCCCCC.C(OCC)(=O)C>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[CH3:12][O:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1
Reactant: c1ccccc1
Reactant: O=c1ccc2c([nH]1)CCCC2
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: COc1ccc2c(n1)CCCC2
Temperature: 25 °C

Procedure:
A mixture of 5,6,7,8-tetrahydro-2-quinolone [Meyers, A. I. and Garcia-Munoz, G., J. Org. Chem. (1964) 29, 1435] (7.20 g, 48.32 mmol) and silver carbonate (9.33 g, 33.82 mmol) in THF (100 ml)-benzene (20 ml) was treated with methyl iodide (4.67 ml, 10.28 g, 72.48 mmol) and then heated at reflux for 18 h. On cooling to room temperature the mixture was filtered and the filtrate concentrated to give a brown oil which was subjected to column chromatography (silica, hexane-ethyl acetate, 2:1) to afford the title compound (4.40 g) as yellow oil MS (ES+) 164 (MH+). δH (CDCl3) 7,23 (1H, d, J 8.3 Hz), 6.47 (1H, d, J 8.3 Hz), 3.88 (3H, s), 2.78 (2H, t, J 5.9 Hz), 2.65 (2H, t, J 5.9 Hz) and 1.88-1.71 (4H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:24]#[CH:25])[C:21]=1[O:22]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:24]#[CH:25])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: C#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C#N)c1OC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C#N)c1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
3-(3-cyano-5-ethynyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (197 mg) was dissolved in N,N-dimethylformamide (2 mL), and lithium chloride (239 mg) was added to the solution, and then the mixture was stirred at 100° C. for 1 hour. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), and then crystallized from n-hexane-acetone to obtain the title compound (102 mg) as a pale yellow crystal.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([OH:23])[CH:6]=[C:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:8]=1.Cl.[CH3:25][N:26]([CH3:33])[CH2:27]/[CH:28]=[CH:29]/[C:30](O)=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([OH:23])[CH:6]=[C:7]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][N:21]([C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:8]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Oc1cc(Cl)cc(Nc2ncnc3sc4c(c23)CCNC4)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)N1CCc2c(sc3ncnc(Nc4cc(O)cc(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-chloro-5-(5,6,7,8-tetrahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-ylamino)phenol hydrochloride from Example 65A (150 mg, 0.41 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (94 mg, 0.57 mmol) in a mixture of DMF (2 mL) and THF (4 mL) was treated with DIPEA (263 mg, 2.03 mmol) and TBTU (197 mg, 0.61 mmol). The mixture was stirred at rt overnight and then directly purified by preparative HPLC. The product was triturated with tert-butyl methyl ether and collected by suction filtration to yield 52 mg (29%) as tan crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[C:13](=[O:16])([O-])[O-].[K+].[K+].O>C(COC)OC>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:2]2[CH:3]=[CH:4][C:13]([OH:16])=[CH:9][CH:10]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(-c2ccc(O)cc2)c2c1C(=O)NC2
Yield: 181.6 %

Procedure:
In a similar manner to Step 1 of Example 152, 7-amino-4-bromoisoindolinone (200 mg, 0.880 mmol) was dissolved in dimethoxyethane (14 mL); and the solution was treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (387 mg, 1.76 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (57.4 mg, 0.0704 mmol), potassium carbonate (607 mg, 4.40 mmol) and water (0.32 mL), followed by purification by slurry using chloroform to obtain 7-amino-4-(4-hydroxyphenyl)isoindolinone (192 mg, yield 91%).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([NH:19][C@@H:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Fmoc-Cl (27.6 g, 107.2 mmol) in 1,4-dioxane (950 mL) was added dropwise to a solution of (S)-methyl 2-amino-3-(4-nitrophenyl)propanoate (3A; 20 g, 89.3 mmol) and K2CO3 (14.8 g , 107.2 mmol) in water (80 mL) and 1,4-dioxane (150 mL) on an ice bath. After being stirred for 2 hours at room temperature, the mixture was poured into 1.2 L of water to precipitate a white solid, which was filtered and washed with cold water. The solid was dried under vacuum for 3 hours to give 40 g of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoate 3B, which was directly used in step 2.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([SH:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28]I.[OH-].[K+].CO>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([S:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(S)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1nc(SC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of 4′-[(4-butyl-6-oxo-2-sulfanyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.6 g), methyl iodide (0.83 mL), potassium hydroxide (0.68 g) and methanol (30 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (3.5 g, 95%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+].Cl.[CH2:15](O)[CH3:16]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:15][CH3:16]
Reactant: CCO
Reactant: CCCCCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCBr
Temperature: 75 °C

Procedure:
The ground polymer of Example 23 (5 g) was placed in a 500-mL 3-neck round-bottom flask and suspended in 100 mL of deionized water. The suspension was stirred with a mechanical stirrer. To this swollen gel was added a solution of 15 g of 1-bromodecane in 100 mL of ethanol, and the reaction mixture was stirred for 10 minutes. Aqueous sodium hydroxide (2 g of 50% w/w) was then added and the reaction mixture was stirred at room temperature for 40 minutes followed by heating to 75° C. Subsequently, an additional 4 g of 50% NaOH was added in 1 g batches at an interval of 1.5 hr. The reaction mixture was allowed to stir at 75° C. for a total period of 20 hr. After cooling to 30° C., 2 mL concentrated HCl was added and the mixture was stirred for 30 minutes. The polymer was filtered off and washed with 500 mL of deionized water and 500 mL of methanol. The filtered polymer particles were slurried in methanol (400 mL), stirred for 40 minutes, and reisolated by filtration. This process was then repeated. The polymer was suspended in 500 mL of 2M NaCl solution and the suspension was stirred for 40 minutes. The polymer was filtered off and this NaCl treatment was repeated two more times. The fitered polymer cake was washed with 500 mL of deionized water and suspended in 500 mL of deionized water. After stirring the suspension for 30 minutes, the polymer was filtered off and resuspended in 500 mL of deionized water. The resulting suspension was stirred for 30 minutes. Concentrated HCl (1 mL) was added to the suspension, which was then stirred for 35 minutes. The polymer was then filtered off and dried at 60° C. in a forced air oven, yielding 13.3 g of the alkylated polymer as a pale white solid. The polymer was ground and passed through a 140 mesh sieve.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][CH:41]=[CH:40][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][CH2:35][C:36]([O:38]C)=[O:37])=[CH:13][CH:12]=1>O1CCOCC1.[OH-].[Na+].O>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][CH:41]=[CH:40][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:15][CH:16]=1
Reactant: COC(=O)CCCc1ccccc1OCCOC1CNCCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1COCCCOc1ccc(C2CCNCC2OCCOc2ccccc2CCCC(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 0.30 g of methyl 4-{2-[2-(4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidin-3-yloxy)ethoxy]phenyl}butyrate (Example 137) in 5 ml of dioxane and 2 ml of 2N NaOH is stirred at 80° C. over 7 hours. The reaction mixture is cooled to room temperature, diluted with water and washed with tert-butyl methyl ether. The combined organic phases are acidified to pH 6 with 1N HCl and subsequently extracted with ethyl acetate (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.08 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.37.
Reaction SMILES: C(O[CH:5]1[O:19][C@H:18]([CH2:20][O:21]C(=O)C2C=CC(Cl)=CC=2)[C@@H:7]([O:8]C(=O)C2C=CC(Cl)=CC=2)[CH2:6]1)(=O)C.C[Si]([NH:35][C:36]1[N:41]=[C:40]([O:42][Si](C)(C)C)[N:39]=[CH:38][N:37]=1)(C)C.S(O)(C(F)(F)F)(=O)=O.CO[Na]>CO.CS(C)=O.CC#N>[CH2:6]1[C@H:5]([N:39]2[C:40](=[O:42])[N:41]=[C:36]([NH2:35])[N:37]=[CH:38]2)[O:19][C@H:18]([CH2:20][OH:21])[C@H:7]1[OH:8]
Reactant: C[Si](C)(C)Nc1ncnc(O[Si](C)(C)C)n1
Reactant: CC(=O)OC1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Agent: CO[Na]
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Solvent: CC#N
Solvent: CS(C)=O
Product: Nc1ncn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of MeCN (45 mL), 1-O-acetyl-3,5-di-O-(4-chlorobenzoyl)-2-deoxy-D-ribofuranose (3.0 g), 2-[(trimethylsilyl)amino]4-[(trimethylsilyl)oxy]-s-triazine (1.78 g) and TfOH (0.5 g) were stirred at about 0° C. for 24 hours. DMSO (6 mL) was added and the mixture was evaporated at 30˜50° C. under reduced pressure to remove the MeCN. A 29% solution of MeONa in MeOH (1.8 g, 9.9 mmol, 1.5 eq.) was added with stirring at about 20˜25° C. After the reaction was complete, MeOH was added to effect precipitation and the solid was filtered, washed and dried to give crude decitabine. API grade decitabine (>99.0 HPLC purity) is prepared by the recrystallization of crude decitabine from MeOH, followed by three washes with MeOH and drying at 40° C. under vacuum.
Reaction SMILES: [CH3:1][S:2][CH2:3]Cl.[H-].[Na+].[CH2:7]([CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[CH2:7]([C:14]([CH2:3][S:2][CH3:1])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSCCl
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CSC)(Cc1ccccc1)C(=O)OCC
Temperature: 23 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
Chloromethyl methyl sulfide (1.4 mL, 17 mmol, 1.0 equiv) and 60% sodium hydride in mineral oil (750 mg, 19 mmol, 1.1 equiv) were sequentially added to a stirred solution of diethyl 2-benzylmalonate (4.0 mL, 17 mmol, 1.0 equiv) in N,N-dimethylformamide (34 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 18 h. The reaction mixture was concentrated under vacuum. The residue was diluted with water (150 mL) and extracted with diethyl ether (4×70 mL). The combined organic layers were dried (MgSO4), gravity-filtered, and concentrated by rotary evaporation to afford a yellow oil (5.3 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.13-7.30 (m, 5H), 4.22 (q, J=7 Hz, 4H), 3.36 (s, 2H), 2.94 (s, 2H), 2.11 (s, 3H), 1.27 (t, J=7 Hz, 6H).
Reaction SMILES: O[CH2:2][C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:5][C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([O:44][C:45]([NH:47][O:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[C:40]([O:44][C:45]([N:47]([CH2:2][C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[S:5][C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[O:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CO
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1CN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 23 h
Yield: 35.6 %

Procedure:
To a stirred solution of 3-hydroxymethyl-2,5-di(4-pyridyl)-4-methylthiophene (0.282 g), triphenylphosphine(0.446 g), and N,O-di-(tert-butoxycarbonyl)hydroxylamine (0.224 g), in THF (20 mL) was added diethylazodicarboxylate (0.296 g) under nitrogen. After stirring for 23 hours, the reaction mixture was poured into water (50 mL) and the whole was extracted with CH2Cl2 (100 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-CH2Cl2 -MeOH (1:1:0.04). The resulting product was purified by column chromatography on silica(NH-silica gel, FUJI SILISIA CHEMICAL LTD. DM203 5)(ethyl acetate-CH2Cl2 --MeOH=1:1:0.04) to give the subtitle compound (0.17 g)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:70]1[CH:75]=[CH:74][C:73]([OH:76])=[C:72]([CH3:77])[CH:71]=1)([C:55]1[CH:60]=[CH:59][C:58](B2OC(C)(C)C(C)(C)O2)=[CH:57][CH:56]=1)[CH2:53][CH3:54])[CH3:51].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:58]2[CH:57]=[CH:56][C:55]([C:52]([CH2:53][CH3:54])([C:70]3[CH:75]=[CH:74][C:73]([OH:76])=[C:72]([CH3:77])[CH:71]=3)[CH2:50][CH3:51])=[CH:60][CH:59]=2)[CH:10]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(CC)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(O)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(O)c(C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
(5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 181 mg, 0.789 mmol), palladium acetate (12 mg, 0.053 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (22 mg, 0.053 mmol), potassium phosphate (335 mg, 1.578 mmol) and water (0.6 mL) were added to a solution of 4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenol (Example 143-(3); 200 mg, 0.526 mmol) in toluene (6 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (130.0 mg, 61%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1COCC1.[Cu](I)I>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[O:28][C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]4[CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[N:15][C:12]2=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ncc(OCc2ccccc2)cc1Br)c1ccc(OCC2CC2)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(COc2cnc3nc(-c4ccc(OCC5CC5)cc4)oc3c2)cc1
Temperature: 70 °C
Yield: 24.5 %

Procedure:
To a solution of N-(5-(benzyloxy)-3-bromopyridin-2-yl)-4-(cyclopropylmethoxy)benzamide (780 mg) in THF (10 mL) were added copper iodide (49.2 mg), 1,10-phenanthroline (93.0 mg) and cesium carbonate (1.12 g), and the mixture was stirred with heating overnight at 70° C. The reaction mixture was allowed to cool to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (157 mg).