Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][P:2]([O:5][P:6]([O:9][P:10]([O:13][P:14]([OH:17])([OH:16])=[O:15])([OH:12])=[O:11])([OH:8])=[O:7])(=[O:4])[OH:3].[Si]([O:25][C@@H:26]1[C@@H:30]([CH2:31][OH:32])[O:29][C@@H:28]([N:33]2[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]2=[O:35])[C@@H:27]1[OH:41])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CC(O)=O.[SiH3]O[SiH3]>CC#N>[OH:17][P:14]([O:13][P:10]([O:9][P:6]([O:5][P:2]([OH:4])([OH:3])=[O:1])([OH:8])=[O:7])([OH:12])=[O:11])(=[O:15])[OH:16].[C@@H:28]1([N:33]2[CH:40]=[CH:39][C:37](=[O:38])[NH:36][C:34]2=[O:35])[O:29][C@H:30]([CH2:31][OH:32])[C@@H:26]([OH:25])[C@H:27]1[OH:41]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1[C@@H](O)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P(O)(O)OP(=O)(O)OP(=O)(O)OP(=O)(O)O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CC(=O)O
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94 %

Procedure:
The 3′-O-TBDMS-Uridine Tetraphosphate [8] (2.55 mg, 0.00376 mmol) was taken up in CH3CN (Aldrich anhydrous, 160 μL). Tetrabutylammonium fluoride in THF (1.0 M, Aldrich, 113 μL, 0.113 mmol) and HOAc (glacial, Aldrich, 2.2 μL, 0.0376 mmol) were added to the solution. The resulting reaction mixture was allowed to stir for 21 hours at ambient temperature. HPLC analysis of the reaction at this time showed no remaining silyl ether. The volatile materials were removed on a rotary evaporator. The product mixture was resuspended in H2O, and the product was purified by reversed phase HPLC. (Column: Zorbax SB-C18, 9.4 mm×25 cm. Solvent A: 0.1 M TEAA, 2.5% CH3CN, pH=7.0; Solvent B: CH3CN. Flow rate: 4.0 mL/minute. Gradient: t=0 minutes, 100% A; t=15 minutes, 75% A/25% B; t=15.01 minutes, 100% B; t=20 minutes, 100% A; t=27 minutes, 100% A. Retention time: 7.05 minutes). The purified material was lyophilized. The resulting material was resuspended and lyophilized a total of 5 times to ensure complete removal of TEAA salts. Before the final lyophilization, the material was quantified by UV (2.00 mg, 94% yield). The compound [9] obtained in this manner was a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([C:31](=[O:33])[CH3:32])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:10]2[CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=[CH:37][C:9]1=2)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[F:26][C:23]([F:24])([F:25])[C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([C:27]([F:29])([F:30])[F:28])[CH:20]=1)[CH2:16][N:15]([CH:11]1[CH2:12][CH2:13][CH2:14][NH:8][C:9]2[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][C:10]1=2)[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2ccc(C(F)(F)F)cc21

Procedure:
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.118 g, 0.197 mmol) was treated with 1:1 TFA/DCM (2.00 ml) at room temperature. Evaporation of solvents provided the titled compound, which was used directly for the next step without further purification. MS (ES+): 499 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:11](=[O:13])[CH:12]=1.P(Br)(Br)(Br)(Br)[Br:21].P(Br)(Br)(Br)=O.C([O-])([O-])=O.[K+].[K+]>>[Br:21][C:11]1[CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:10]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:11](=[O:13])[CH:12]=1
Reactant: BrP(Br)(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: O=P(Br)(Br)Br
Agent: O=c1cc(-c2ccccn2)[nH]c(-c2ccccn2)c1
Product: Brc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A 500 mL flask was charged with 2,6-bis-pyridyl-4-(1H)-pyridone (2.47 g, 9.9 mmol), phosphorus pentabromide (6.6 g, 15.4 mmol), and phosphorus oxybromide (30 g) and heated to 100° C. with stirring for 12 h, giving a black oily residue. The reaction was cooled to room temperature; ice was added cautiously to the reaction until the evolution of gas subsided. The reaction mixture was neutralized with K2CO3 (aq), extracted with CH2Cl2 (3×300 mL), dried over MgSO4, and filtered. Removal of solvent gave a tan colored solid which was purified by column chromatography on neutral alumina using 2:1 CH2Cl2:hexanes as the eluant, providing 2.65 g of pure 4′-bromo-2,2′;6′,2″-terpyridine (86% yield, based on 2.47 g of the 2,6-bis-pyridyl-4-(1H)-pyridone starting material). 1H-NMR (250 MHz, CDCl3): 8.68 (dq, 2 H, J=4.7 Hz, 0.8 Hz), 8.62 (s, 2 H), 8.56 (dt, 2 H, J=8.0 Hz, 1.0 Hz), 7.84 (td, J=7.7 Hz, 1.7 Hz), 7.33 (ddd, 2 H, J=7.6 Hz, 4.9 Hz, 1.2 Hz). HRMS (ESI+) m/z: 333.9955 (calcd for C15H10N3BrNa (M+Na)+ 333.9956).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:32]=[CH:31][C:14]3[C:15]4[N:16]=[C:17]([C:23]5[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=5)[S:18][C:19]=4[CH2:20][CH2:21][O:22][C:13]=3[CH:12]=2)[CH:8]=[N:7]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:28]([N:24]1[C:23]([C:17]2[S:18][C:19]3[CH2:20][CH2:21][O:22][C:13]4[CH:12]=[C:11]([C:9]5[CH:8]=[N:7][N:6]([CH2:5][CH2:4][OH:3])[CH:10]=5)[CH:32]=[CH:31][C:14]=4[C:15]=3[N:16]=2)=[N:27][CH:26]=[N:25]1)([CH3:30])[CH3:29]
Reactant: CCOC(=O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCO)c3)ccc1-2
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of {4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-acetic acid ethyl ester in THF (200 mL) was cooled to 0° C. and treated dropwise with a solution of 1M LiAlH4 (in THF, 23 mL, 23 mmol, 2.5 eq). After 1 h, LCMS indicated consumption of starting material. A solution of saturated sodium sulfate was added slowly until H2 evolution ceased. ˜30 g of solid magnesium sulfate was added and the whole was stirred for 20 min. Filtration over celite (EtOAc and DCM) follwed by concentration of the filtrant gave a crude residue that was purified by reverse-phase HPLC to give 1.4 g of 105 (43%). LCMS: 423.1. 1HNMR (400 MHz, DMSO) δ 8.32 (d, J=8.3 Hz, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.43 (dd, J=8.3, 1.6 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 5.84 (dt, J=13.2, 6.6 Hz, 1H), 4.91 (t, J=5.3 Hz, 1H), 4.39 (t, J=4.9 Hz, 2H), 4.16 (t, J=5.6 Hz, 2H), 3.77 (q, J=5.5 Hz, 2H), 3.44 (t, J=4.9 Hz, 2H), 1.56 (d, J=6.6 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]=[C:7]2[OH:18].[Cl-].[Li+].[CH2:21](C([SnH3])=C(CCCC)CCCC)[CH2:22]CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]1([C:9]2[CH:8]=[C:7]([OH:18])[C:6]3[C:11](=[C:2]([CH:21]=[CH2:22])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCC([SnH3])=C(CCCC)CCCC
Reactant: Oc1cc(-c2ccccc2)nc2c(Br)cccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1cccc2c(O)cc(-c3ccccc3)nc12
Temperature: 90 °C
Yield: 43.1 %

Procedure:
A suspension of 500 mg (1.67 mmol) 8-bromo-2-phenyl-quinoline-4-ol (commercially available from Ubichem Research Ltd, Budapest, Hungary), 97 mg (0.09 mmol) Pd(PPh3)4, 71 mg (1.67 mmol) lithium chloride and 528 mg (1.67 mmol) tributylvinyl stannane in 20 ml dioxane was heated at 90° C. for 16 h. The resulting yellow suspension was filtered and the filtrate evaporated to dryness. The residue was suspended in ethyl acetate, filtered and the filtrate extracted with water. The organic layer was evaporated to dryness and the isolated crude product purified by silica gel chromatography (ethyl acetate) to yield 178 mg (43%) of the title compound as yellowish crystals. 1H-NMR (300 MHz, CDCl3): 5.59 (d, J=11.1 Hz, 1H); 5.75 (d, J=17.4 Hz, 1H); 6.42 (s, 1H); 7.04 (dd, J=17.4, 11.1 Hz, 1H); 7.23 (t, J=8.1 Hz, 1H); 7.40-7.60 (m, 6H); 8.21 (d, J=8.1 Hz, 1H); 8.70 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[I:11]N1C(=O)CCC1=O>C(Cl)Cl.C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([I:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2cn[nH]c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CC#N
Product: Clc1ccc2c(I)n[nH]c2n1
Yield: 96.3 %

Procedure:
A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyridine (0.40 g, 2.6 mmol)(Ark Pharm Cat. No. AK-32412) and N-iodosuccinimide (0.64 g, 2.9 mmol) in methylene chloride (6 mL) and acetonitrile (3 mL) was stirred at 70° C. for 3 h. After cooling it was concentrated and the residue was treated with water. The precipitate was collected by filtration to afford the desired product (0.70 g). LCMS (M+H)+=279.9.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[I:28]I>CCO.CCOC(C)=O.S([O-])([O-])(=O)=O.[Ag+2]>[OH:1][C:2]1[C:7]([I:28])=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of the title compound from Example 1 Step B (2.00 g, 5.30 mmol) and silver sulfate (1.653 g, 5.30 mmol) in EtOH (53 mL) was added iodine (1.35 g, 5.30 mmol). The resulting suspension was stirred vigorously at ambient temperature. After 4 h, the reaction mixture was diluted with EtOAc, and the organic phase was washed successively with water, sat. aq. sodium bisulfate, and sat. aq. NaHCO3. The organic phase was then concentrated in vacuo. The title compound was separated from the para-iodo isomer upon purification by flash chromatography on silica gel (0 to 15% EtOAc in hexanes, then 15% EtOAc in hexanes, then 15 to 100% EtOAc in hexanes; the title compound is the later eluting isomer): LCMS m/z 504.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 13.08 (s, 1H), 8.17 (s, 1H), 8.10 (t, J=8.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.86 (dd, J=7.5, 1.5 Hz, 1H), 7.82 (dd, J=8.0, 1.5 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 6.75 (t, J=8.0 Hz, 1H), 4.33 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([CH2:14]OS(C)(=O)=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[C-:20]#[N:21].[Na+].C(OCC)(=O)C>CS(C)=O.CCCCCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([CH2:14][C:20]#[N:21])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CS(=O)(=O)OCC1(c2cc(Cl)ccc2Cl)CCCC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCC1(c2cc(Cl)ccc2Cl)CCCC1
Temperature: 140 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
To a stirred solution of methanesulfonic acid 1-(2,5-dichlorophenyl)-cyclopentylmethyl ester (201) (24 g, 74.53 mmol) in dimethyl sulfoxide (200 mL) KI (1.237 g, 7.453 mmol) and NaCN (5.478 g, 111.801 mmol) were added. The mixture was heated to 140° C. and stirred for 5 h. Silica TLC was performed (10% ethyl acetate in hexane, Rf=0.6). The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with brine, dried, concentrated. The obtained crude product was purified using normal silica gel (100-200 mesh) column chromatography using a gradient eluent of 2 to 10% ethyl acetate in hexane to get pure [1-(2,5-dichlorophenyl)-cyclopentyl]-acetonitrile (202) (10.5 g, 55.43%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C@@H:7]([F:8])[CH2:6][C@@H:5]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:5]4[CH2:4][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[C@@H:7]([F:8])[CH2:6]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1C[C@H](N)[C@@H](F)C1
Agent: Cl
Product: CCC(=O)N[C@H]1C[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1F

Procedure:
Starting from N-[(1S*,3S*,4S*)-3-amino-4-fluorocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f70) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[C-:16]#[N:17].[K+]>CN(C=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[O:6][N:5]=[C:4]([CH3:15])[C:3]=2[CH2:2][C:16]#[N:17])=[CH:9][CH:10]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1CC#N
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To 4-bromomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole (10.74 mmol) in DMF (30 mL) was added potassium cyanide (0.729 g, 10.74 mmol), and the reaction was stirred at 65° C. overnight. After aqueous workup, the crude material was purified by silica gel chromatography (0-70% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Br[C:2]1[N:3]([CH2:12][CH2:13][CH2:14][CH3:15])[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[CH:6][N:5]=2.NC(N)=[S:18]>C(O)CCC>[NH2:11][C:8]1[N:7]=[CH:6][N:5]=[C:4]2[C:9]=1[NH:10][C:2](=[S:18])[N:3]2[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NC(N)=S
Reactant: CCCCn1c(Br)nc2c(N)ncnc21
Solvent: CCCCO
Product: CCCCn1c(=S)[nH]c2c(N)ncnc21
Yield: 101.1 %

Procedure:
A suspension of 8-bromo-9-butyl-9H-purin-6-ylamine (0.50 g, 1.85 mmol) and thiourea (1.49 g, 19.6 mmol) in n-butanol (10 ml) was heated to reflux for 14 h. Dilution with CH2Cl2 (70 ml), washing with water and concentration afforded 6-amino-9-butyl-7,9-dihydro-purine-8-thione as a white powder (0.42 g, 1.87 mmol, 100%). 1H NMR (DMSO-d6) δ 12.35-12.25 (br. s, 1H), 8.13 (s, 1H), 6.92-6.72 (br. s., 2H), 4.09 (t, J=7.6 Hz, 2H), 1.71 (quint., J=7.5 Hz, 2H), 1.29 (sext., J=7.5 Hz, 2H), 0.87 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:12]1[N:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[N:13]=1)[CH2:9][C:10]#[CH:11])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]([C:12]1[N:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:29])[C:19]2[C:14](=[CH:15][C:16]([Cl:30])=[CH:17][CH:18]=2)[N:13]=1)[CH2:9][C:10]#[CH:11]
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C#CC[C@@H](N)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Yield: 111.3 %

Procedure:
To a mixture of (R)-[1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynyl]-carbamic acid tert-butyl ester (5.35 g, 12.2 mmol) in methanol (65 ml) was added HCl in dioxane (4M, 20 ml). The resulting solution was stirred and the reaction completion was monitored using HPLC/LCMS. The solvent was then removed and the mixture was triturated with diethyl ether to afford 2-((R)-1-amino-but-3-ynyl)-7-chloro-3-phenylamino-3H-quinazolin-4-one (4.60 g, 100%) as off-white solid. M.p. 175-180° C. LCMS: m/e 339 [M+H]. 1H NMR: (DMSO d6) δ 9.27 (s, 1H), 8.73 (s, br, 3H), 8.15 (d, J=8.4 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.70 (dd, J=2.0 and 8.4 Hz, 1H), 7.32 (t, J=8.0 Hz, 2H), 6.92 (t, J=7.6 Hz 1H), 6.68 (m, 2H), 4.90, 4.58 (m, 1H, rotomers), 3.18 (m, 1H), 3.08 (m 2H).
Reaction SMILES: [C:1]1([O:7][P:8]([O:17][C@@H:18]2[C@@H:30]([CH2:31][O:32][C:33]([O:35][C:36]([CH3:42])([CH3:41])[C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])[O:29][C@@H:21](OCC[Si](C)(C)C)[C@H:20]([NH:43][C:44]([O:46][CH2:47][C:48]([Cl:51])([Cl:50])[Cl:49])=[O:45])[C@H:19]2[O:52][C:53](=[O:83])[CH2:54][C@H:55]([O:67][C:68](=[O:82])[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC(Cl)[Cl:87]>C(Cl)(Cl)Cl.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[C:1]1([O:7][P:8]([O:17][C@@H:18]2[C@@H:30]([CH2:31][O:32][C:33]([O:35][C:36]([CH3:41])([CH3:42])[C:37]([Cl:38])([Cl:40])[Cl:39])=[O:34])[O:29][C@H:21]([Cl:87])[C@H:20]([NH:43][C:44]([O:46][CH2:47][C:48]([Cl:50])([Cl:49])[Cl:51])=[O:45])[C@H:19]2[O:52][C:53](=[O:83])[CH2:54][C@H:55]([O:67][C:68](=[O:82])[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH3:81])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(Cl)Cl
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O[C@@H]1[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@H](OCC[Si](C)(C)C)O[C@H](COC(=O)OC(C)(C)C(Cl)(Cl)Cl)[C@H]1OP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O[C@@H]1[C@@H](NC(=O)OCC(Cl)(Cl)Cl)[C@@H](Cl)O[C@H](COC(=O)OC(C)(C)C(Cl)(Cl)Cl)[C@H]1OP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A solution of the compound 8 (6.5 g, 4.84 mmol) and dichloromethyl methyl ether (2.18 ml, 24.2 mmol) in CHCl3 (60 ml) at 0°C. was treated with ZnCl2 (1.0 M in ether; 2.41 ml, 2.41 mmol) and then allowed to warm slowly and stir at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated aq. NaHCO3, dried (Na2SO4) and then concentrated. The light yellow oil obtained was purified by flash chromatography on silica gel eluting with 10% EtOAc-hexanes to give 5.4 g (88%) of 2-deoxy-4-O-diphenylphosphono-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]-6-O-(2,2,2-trichloro-1,1-dimethylethoxycarbonyl)-2-(2,2,2-trichloroethoxycarbonylamino)-α-D-glucopyranosyl chloride (compound 9) as an amorphous solid: 1H NMR (CDCl3) δ 0.88 (~t, 6H), 1.1-1.6 (m, 42H), 1.78 (s, 3H), 1.88 (s, 3H), 2.18 (t, 2H, J=7.6 Hz), 2.34-2.52 (m, 2H), 4.2-4.4 (m, 4H), 4.70 (d, 1H, J=12 Hz), 4.73 (d, 1H J=12 Hz), 4.83 (~q, 1H, J=9 Hz), 5.09 (m, 1H), 5.51 (~t, 1H, J=10 Hz), 5.79 (d, 1H, J=8.0 Hz), 6.26 (d, 1H, J=3.6 Hz), 7.1-7.4 (m, 10H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>N1C=CC=CC=1>[N:1]1([C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1ccc(-n2ccnn2)cc1

Procedure:
A mixture of 1,2,3-triazole (3.4 ml, 58.7 mmol), potassium carbonate (9.03 g, 65.4 mmol), and 4-fluorobenzaldehyde (6.3 ml, 58.7 mmol) in pyridine (30 ml) is heated under nitrogen atmosphere at reflux overnight. After pyridine is distilled, the mixture is diluted with methylene chloride, filtered and washed with chloroform. The combined filtrate is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude material is purified by column chromatography on silica with hexane/ethyl acetate (5:1) to give 4-(1,2,3-triazol-1-yl)-benzaldehyde and with hexane/ethyl acetate (1:2) to give 4-(1,2,3-triazol-1-yl)-benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][C:16]2[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=2)[C@@H:9]([CH3:14])[C:10]([O:12]C)=O)[C:5]([N+:26]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[NH:26][C:10](=[O:12])[C@H:9]([CH3:14])[N:8]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)[C:6]=2[N:7]=1
Reactant: COC(=O)[C@H](C)N(Cc1ncc(C)c(OC)c1C)c1nc(N)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1c(C)cnc(CN2c3nc(N)ncc3NC(=O)[C@@H]2C)c1C
Temperature: 70 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Methyl (2S)-2-[(2-amino-5-nitro-pyrimidin-4-yl)-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl]amino]propanoate (Intermediate 1)(500 mg, 1.28 mmol) was dissolved in acetic acid (4 mL) and heated to 70° C., then iron powder (144 mg, 2.58 mmol) was added. The mixture was stirred at 70° C. for 1 hour, then 100° C. for 30 minutes. The dark mixture was filtered through Celite®, and the filter media was washed with DCM. The filtrate was concentrated under reduced pressure, then purified by column chromatography (eluting with 5-20% methanol in DCM) to yield the title product as a cream foam (354 mg, 84%);
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>[Pd].CO>[OH:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11](=[O:20])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=C(/C=C/c1ccccn1)c1ccc2c(c1O)OCO2
Agent: [Pd]
Solvent: CO
Product: O=C(CCc1ccccn1)c1ccc2c(c1O)OCO2
Yield: 59.6 %

Procedure:
(E)-1-(4-hydroxybenzo[d][1,3]dioxol-5-yl)-3-(pyridin-2-yl)prop-2-en-1-one (0.5 g, 1.857 mmol) was added to methanol (50 ml) to give a yellow solution. Palladium on carbon (0.05 g) was added. Product was hydrogenated while stirring till conversion was completed (checked by TLC). The reaction mixture was filtered, evaporated and the solid residue was washed with diethylether, and dried to yield 0.3 g (57%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)=[CH:15][C:10]=3[N:9]=[CH:8]2)[S:4][C:3]=1[C:22]([O:24][CH3:25])=[O:23].O[CH:27]([C:29]1[CH:30]=[C:31]([O:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[CH:32]=[CH:33][CH:34]=1)[CH3:28].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>C(Cl)Cl>[CH3:25][O:24][C:22]([C:3]1[S:4][C:5]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:6][C:2]=1[O:1][CH:27]([C:29]1[CH:30]=[C:31]([O:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:43])[CH2:38][CH2:37]2)[CH:32]=[CH:33][CH:34]=1)[CH3:28])=[O:23]
Reactant: CC(O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(-c4cnn(C)c4)ccc32)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(-c4cnn(C)c4)ccc32)cc1OC(C)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 249.1 %

Procedure:
Methyl 3-hydroxy-5-[5-(1-methyl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]-2-thiophenecarboxylate (0.300 g, 0.847 mmol), (+/−)-1,1-dimethylethyl 4-{[3-(1-hydroxyethyl)phenyl]oxy}-1-piperidinecarboxylate (0.285 mmol), and triphenylphosphine (0.667 g, 2.54 mmol) were dissolved in 25 mL of DCM with stirring. Diisopropyl azodicarboxylate was added slowly dropwise via syringe. The reaction was stirred overnight, and the mixture was adsorbed onto silica gel. Purification by flash chromatography afforded 0.467 g (84%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.56 (s, 2H), 7.48 (s, 1H), 7.26 (dd, J=8.1, 7.9 Hz, 1H), 7.08 (m, 1H), 7.01 (d, J=7.9 Hz, 1H), 6.87 (dd, J=8.1, 2.2 Hz, 1H), 5.69 (q, J=6.0 Hz, 1H), 4.50 (m, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.65-3.56 (m, 2H), 3.18-3.05 (m, 2H), 1.91-1.78 (m, 2H), 1.58 (d, J=6.2 Hz, 3H), 1.53-1.40 (m, 2H), 1.35 (s, 9H).