Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=[C:8]2[CH:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ncccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ncccc2n1-c1ccccc1
Temperature: 90 °C
Yield: 36.2 %

Procedure:
A mixture of (S)-1-(1-phenyl-1H-imidazo[4,5-b]pyridin-2-yl)ethylamine (330 mg, 1.38 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (460 mg, 1.94 mmol) and DIPEA (440 μL, 2.49 mmol) in n-butanol (2 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) and then crystallised from EtOAc and MeOH to afford 199 as a white solid (178 mg, 36%). LCMS (Method K): RT 2.72 min [M+H]+ 357.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.42 (1H, dd, J=4.73, 1.53 Hz), 8.20-7.94 (3H, m), 7.68 (2H, d, J=7.55 Hz), 7.63-7.48 (4H, m), 7.23 (1H, dd, J=8.06, 4.74 Hz), 5.51 (1H, br s), 1.60 (3H, d, J=6.85 Hz)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[C:15]([O:24][CH3:25])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]([O:24][CH3:25])=[O:23])=[O:14])=[CH:2]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: COC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(=O)CCc1c[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 3-(3-indolyl)propionic acid (6.0 g, 32 mmol) in 100 ml THF at room temperature was added 1,1-carbonyldiimidazole (5.14 g, 32 mmol). The reaction mixture was stirred under a dry atmosphere for 30 minutes, after which methyl anthranilate (4.79 g, 32 mmol) was added, and the reaction mixture was stirred at reflux for 30 minutes. No reaction was detected by thin layer chromatography (TLC). Pyridinium p-toluenesulfonate (PPTS) [6.36 g, 25 mmol] was added, and the mixture was stirred at reflux for two days. The reaction mixture was allowed to cool, and the solvent was removed in vacuo. The resulting product was taken up in ethyl acetate and washed (1N HCl, H2O, saturated NaHCO3, and brine) and dried over anhydrous magnesium sulfate. Concentration in vacuo provided a light yellow solid which, when triturated with ethyl acetate/hexane, gave, upon filtration, 7.19 g (70% yield) of 3-(3-indolyl)-N-(2-methoxycarbonylphenyl)propionamide as an off white granular solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13](O)=[O:14])[CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CO>O1CCCC1>[C:1]([NH:8][C@H:9]([CH2:13][OH:14])[CH2:10][CH2:11][CH3:12])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of Boc-norvaline (25.0 g, 0.115 mol) in tetrahydrofuran (461 mL), cooled to 0° C., was added borane/tetrahydrofuran complex (461 mL of a 1.0M solution in tetrahydrofuran) dropwise. After 1 h at 0° C., the solution was warmed to room temperature over a period of 1.5 h. TLC indicated that the reaction was complete. Methanol was added to quench the reaction. The solution was concentrated to yield the title compound (22.56 g, 96%) as a foamy syrup. TLC of the products indicated satisfactory purity. Rf=0.34 (40% ethyl acetate/hexanes).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:6](=[C:19](OCC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:29])(=O)C.[CH3:30][N:31]([CH3:46])[CH2:32][CH2:33][N:34]([S:42]([CH3:45])(=[O:44])=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1>>[CH3:30][N:31]([CH3:46])[CH2:32][CH2:33][N:34]([C:35]1[CH:36]=[CH:37][C:38]([NH:41]/[C:19](=[C:6]2\[C:5](=[O:29])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=3)/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:39][CH:40]=1)[S:42]([CH3:45])(=[O:44])=[O:43]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3)ccc21)c1ccccc1
Product: CN(C)CCN(c1ccc(N/C(=C2\C(=O)Nc3cc(-c4ccccc4)ccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:30][C:31](O)=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][NH2:41].C1CCC(N=C=NC2CCCCC2)CC1.CCOC(C)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:27])([F:29])[F:28])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:30][C:31]([NH:41][O:40][CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][O:34]1)=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(N2CCN(CC(=O)NOC3CCCCO3)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reaction time: 3 h
Yield: 74.3 %

Procedure:
A solution of (S)-2-(2-benzyl-4-(8-methoxy-2-(trifluoromethyl)quinolin-5-yl)piperazin-1-yl)acetic acid (184 mg, 0.40 mmol) in CH2Cl2 (4 mL) at 0-5° C. was treated with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (49 mg, 0.42 mmol), catalytic DMAP, and finally DCC (87 mg, 0.42 mmol). The reaction mixture was stirred for 3 h after which time the mixture was treated with EtOAc (5 mL), filtered and evaporated. The residue was purified by silica gel flash chromatography with 100% EtOAc, as eluant to afford intermediate 2-((S)-2-benzyl-4-(8-methoxy-2-(trifluoromethyl)quinolin-5-yl)piperazin-1-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acetamide as an oil (166 mg, 74%). LC/MS (Method A) 5.76 min, [M+1]+ 559.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[N+:7]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)([O-:9])=[O:8]>C([O-])(O)=O.[Na+].C(O)C>[N+:7]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])([O-:9])=[O:8]
Reactant: NCCC(=O)O
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
To a solution of beta-alanine (1.0 g, 11.1 mmole) in 50 ml of 1M NaHCO3 was added 2,4-dinitrofluorobenzene (10.4 g, 56 mmole) in 100 ml of ethanol. The reaction mixture was stirred at room temperature for 2 hours and evaporated to remove the volatile in vacuo. The residue was transferred to a separatory funnel with water and washed twice with ethyl ether. The aqueous layer was acidified with 1N HCl until precipitation was complete. The mixture was filtered and the wet cake washed with ether. This purification process, starting from dissolving the solid in 1M NaHCO3, washing the ether, and precipitating with 1N HCl, was repeated in the same manner to give yellow solid (1.6 g, 77%). e(MeOH)=7900 (260 nm), 15900 (350 nm). NMR spectral analysis was consistent with the structure.
Reaction SMILES: [C:1]([C:3]([C:23](=O)[CH3:24])=[CH:4][C:5]1[O:13][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7]=2[CH:6]=1)#[N:2].[NH2:26][C:27]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[CH:28][C:29]#[N:30]>C(O)(=O)C>[C:29]([C:28]1[CH:4]([C:5]2[O:13][C:12]3[CH:11]=[CH:10][N:9]=[C:8]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:7]=3[CH:6]=2)[C:3]([C:1]#[N:2])=[C:23]([CH3:24])[NH:26][C:27]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)#[N:30]
Reactant: CC(=O)C(C#N)=Cc1cc2c(NC(=O)c3ccccc3)nccc2o1
Reactant: N#CC=C(N)c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2cc3c(NC(=O)c4ccccc4)nccc3o2)C(C#N)=C(c2ccc(Cl)cc2)N1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 200 mg (0.604 mmol) N-{2-(2-cyano-3-oxobut-1-en-1-yl)furo[3,2-c]pyridin-4-yl}benzamide (Example 4A) and 129 mg (0.724 mmol) 3-amino-3-(4-chlorophenyl)prop-2-enenitrile (Example 6A) in acetic acid (2 ml) was stirred for 30 min at 110° C. Upon cooling, the mixture was concentrated under reduced pressure, and the residue was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient, final mixture 90:10 v/v) to yield 197 mg (64% of th.) of the racemic title compound.
Reaction SMILES: CN(C)C=O.[Cl:6][CH2:7][C:8]([CH2:10]Cl)=[CH2:9].[CH:12]([C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[OH:24])[C:17]([O:19][CH3:20])=[O:18])=[O:13].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:6][CH2:7][C:8](=[CH2:9])[CH2:10][O:24][C:23]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH:12]=[O:13]
Reactant: C=C(CCl)CCl
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(CCl)COc1ccc(C(=O)OC)cc1C=O
Reaction time: 26 h
Yield: 52.4 %

Procedure:
45 ml of dimethylformamide and then 1.15 ml (9.95 mmol) of 2-chloromethyl-3-chloro-1-propene are added under argon to 717 mg (3.98 mmol) of methyl 3-formyl-4-hydroxybenzoate as a mixture with 1.055 g (9.95 mmol) and 440 mg (1.195 mmol) of tetrabutylammonium iodide. The solution is stirred for 26 hours and then water is added. In order to break the emulsion, the pH is brought to 7 using a 1N hydrochloric acid solution. The aqueous phase is extracted several times with ether and then the combined organic phases are washed several times with water and with brine. After drying over magnesium sulfate and concentrating under vacuum, the crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 20/80) to give 560 mg (52%) of methyl 4-{[2-(chloromethyl)-2-propenyl]oxy}-3-formylbenzoate in the form of a white solid; 1H NMR (300 MHz, CDCl3): 10.44 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.18 (dd, J=2.4 Hz and 8.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 5.44 and 5.39 (2s, 2H), 4.79 (s, 2H), 4.19 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:32])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][C:13]=1[O:21][CH3:22])=[CH:8][C:7]([CH2:23][CH:24]([NH:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH3:25])=[CH:6][CH:5]=2.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40]([NH2:43])(=[O:42])=[O:41]>>[Cl:1][C:2]1[N:3]([CH3:32])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:43][S:40]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[Cl:33])(=[O:42])=[O:41])=[O:17])=[CH:14][C:13]=1[O:21][CH3:22])=[CH:8][C:7]([CH2:23][CH:24]([NH:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH3:25])=[CH:6][CH:5]=2
Reactant: COc1cc(C(=O)O)ccc1Cc1c(Cl)n(C)c2ccc(CC(C)NC(=O)N(C)C)cc12
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2Cl)ccc1Cc1c(Cl)n(C)c2ccc(CC(C)NC(=O)N(C)C)cc12

Procedure:
Using a similar procedure to that described in Example 2, part c, except starting from 4-[2-chloro-5-[2-(N',N'-dimethylureido)propyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoic acid, and using 2-chlorophenylsulfonamide instead of 2-methylphenylsulfonamide, the title compound was obtained (47%) as a white solid; mp 126°-136° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:27]([C:25]2[N:24]=[CH:23][N:22]([CH3:21])[CH:26]=2)(=[O:29])=[O:28])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cnc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To N-Boc-piperazine (500 mg) in DCM (10 ml) was added triethylamine (450 μl) and 1-methylimidazole-4-sulfonyl chloride (524 mg). The reaction mixture was stirred at room temperature overnight, then partitioned between dichloromethane and water, washed with brine, organics were dried over MgSO4, filtered and volatiles removed in vacuo to give 4-(1-methylimidazole-4-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (730 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]3[N:20]=[C:21]([NH:31][CH:32]4[CH2:36][O:35][C@@H:34]5[C@H:37]([O:40][Si](C(C)(C)C)(C)C)[CH2:38][O:39][C@H:33]45)[N:22](COCC[Si](C)(C)C)[C:17]3=[CH:16][C:15]=2[Cl:48])=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]3[N:20]=[C:21]([NH:31][CH:32]4[C@H:33]5[O:39][CH2:38][C@@H:37]([OH:40])[C@H:34]5[O:35][CH2:36]4)[NH:22][C:17]3=[CH:16][C:15]=2[Cl:48])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(Nc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4n3COCC[Si](C)(C)C)CO[C@@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O[C@@H]1CO[C@@H]2C(Nc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TFA (0.1 mL) was added to a stirred mixture of 5-([1,1′-biphenyl]-4-yl)-N-((3aR,6R,6aS)-6-((tert-butyldimethylsilyl)-oxy)hexahydrofuro[3,2-b]furan-3-yl)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-amine (minor isomer) (3.2 mg, 4.61 μmol) in DCM (0.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.1% TFA, to give title compound. LC-MS: calculated for C24H21ClN4O3 448.13 observed m/e: 449.16 (M+H)+ (Rt 1.10/2 min); 1H NMR δ (ppm) (CD3OD): 7.72 (m, 5H), 7.61 (m, 1H), 7.49 (m, 3H), 7.54 (m, 1H), 4.61 (m, 3H), 4.31 (m, 1H), 4.14 (m, 1H), 4.03 (d, 1H), 3.91 (dd, 1H), 3.62 (dd, 1H).
Reaction SMILES: C(OC[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][C:16]=2[OH:20])[N:11]=[CH:10]1)(=O)C(C)(C)C.[O:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[CH3:22][O:21][C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[NH:9][CH:10]=[N:11]2)=[C:16]([O:20][CH:26]2[CH2:27][CH2:28][O:23][CH2:24][CH2:25]2)[CH:15]=1
Reactant: OC1CCOCC1
Reactant: COc1cc(O)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(OC2CCOCC2)c2c(=O)[nH]cnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of (5-hydroxy-7-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (2.50 g, 8.16 mmol), tetrahydro-4H-pyran-4-ol (1.02 g, 10 mmol), and Ph3P (3.41 g, 13 mmol) in CH2Cl2 (40 mL) at 0° C. was added di t-butyl azodicarboxylate (3.993 g, 13 mmol). It was stirred at room temperature for 2 hour. After solvent was evaporated under reduced pressure, to the residue was added 7 N NH3/MeOH (80 mL) and stirred at room temperature overnight. A solid was precipitated. It was filtered, washed with MeOH, and dried under vacuum to afford 7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4(3H)-one as solid (1.091 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ 10.6 (br, 1H), 7.98 (s, 1H), 6.74 (d, 1H), 6.69 (d, 1H), 4.79 (m, 1H), 3.97 (m, 2H), 3.91 (s, 3H), 3.57 (m, 2H), 1.98 (m, 2H), 1.74 (m, 2H); LC-MS (ESI) m/z 277 (M+H)+.
Reaction SMILES: [C:1](OCC#N)(=[O:5])[CH2:2][CH:3]=[CH2:4].C([N+](CCCC)(CCCC)CCCC)CCC.[P:27]([O:31][CH2:32][C@@H:33]1[C@@H:37]([O:38][P:39]([O:42][CH2:43][C@@H:44]2[C@@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([N:51]3[CH:59]=[N:58][C:57]4[C:52]3=[N:53][CH:54]=[N:55][C:56]=4[NH2:60])[O:45]2)([OH:41])=[O:40])[CH2:36][C@H:35]([N:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[N:63][C:62]2=[O:68])[O:34]1)([OH:30])([OH:29])=[O:28].C(O)(C(F)(F)F)=O>CN(C=O)C>[C:1]([O:49][C@H:48]1[C@@H:47]([OH:50])[C@H:46]([N:51]2[CH:59]=[N:58][C:57]3[C:52]2=[N:53][CH:54]=[N:55][C:56]=3[NH2:60])[O:45][C@@H:44]1[CH2:43][O:42][P:39]([O:38][C@H:37]1[CH2:36][C@H:35]([N:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[N:63][C:62]2=[O:68])[O:34][C@@H:33]1[CH2:32][O:31][P:27]([OH:30])([OH:29])=[O:28])([OH:41])=[O:40])(=[O:5])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(=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
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyanomethyl but-3-enoate (Compound 86) (0.050 g, 0.400 mmol) was added to a solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate tetrabutylammonium salt (Compound 1h) (0.20 g, 0.150 mmol) in DMF (1.0 ml), and the mixture was stirred at room temperature for 1 hour. A 0.05% aqueous TFA solution was added to the reaction solution, the mixture was lyophilized, and the resulting residue was purified by preparative HPLC (0.05% aqueous TFA solution:acetonitrile) to prepare the title compound 85 (0.010 g, 10%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].P(Br)(Br)[Br:15]>C(OCC)C.O>[Br:15][CH2:12][C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([F:1])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: CS(=O)(=O)c1ccc(CO)cc1F
Solvent: CCOCC
Solvent: O
Product: CS(=O)(=O)c1ccc(CBr)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of (3-fluoro-4-methanesulfonyl-phenyl)-methanol (0.269 g, 1.31 mmol) in diethyl ether (5 ml) under an inert atmosphere of Argon is added dropwise phosphorus tribromide (46 μl, 0.434 mmol). After stirring at room temperature overnight, the reaction mixture is diluted with water (2 ml) and the diethyl ether layer separated. This organic portion is placed over NaOH pellets and after 20 minutes, is used as a reagent in solution in diethyl ether.
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][NH:3]1.O=P(Cl)(Cl)[Cl:18].P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:18][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(-c2ccccc2)c[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(-c2ccccc2)cnc1Cl
Temperature: 25 °C

Procedure:
2-Oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile (2.50 g, 12.7 mmol) was added to a suspension of POCl3 (1.5 ml) and PCl5 (7.35 g) at room temperature. The suspension was then stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature and added cautiously to iced water. The solution was then adjusted to pH 11 with sodium carbonate and the resulting white solid was filtered, washed with water, then dried in vacuo to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:32]=[CH:31][C:23]3[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=3[CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:11]=[C:9]1[NH:8][C:7]2[C:2]([C:20]3[CH:32]=[CH:31][C:23]4[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=4[CH:21]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[S:10]1
Reactant: O=c1[nH]c2c(Br)cccc2s1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(=O)Nc1nc2ccc(-c3cccc4sc(=O)[nH]c34)cc2s1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
4-Bromobenzo[d]thiazol-2(3H)-one (69.9 mg, 0.304 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (124.9 mg, 3.925 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (39.7 mg, 56.6 μmol), and sodium carbonate (0.30 mL, 2.0 M in water, 0.60 mmol) were suspended in 1,2-dimethoxyethane (1.4 mL) and ethanol (0.39 mL). The reaction flask was fit with a reflux condensor and the solution was heated in a preheated oil bath (85° C.) and stirred under nitrogen for 7 hours, at which time the reaction was slowly allowed to cool to RT. After sitting at RT for 4 days, more PdCl2(PPh3)2 (37.3 mg) was added, and stirring was resumed at 85° C. for 4 hours. Then, the reaction was cooled to RT and filtered through a silica gel plug with 10:1 DCM/MeOH. The filtrate was concentrated and purified on HPLC (10-95% MeCN/water with 0.1% TFA over 40 minutes) to provide N-(6-(2-oxo-2,3-dihydrobenzo[d]thiazol-4-yl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 342 (MH+). Calculated exact mass for C16H11N3O2S2: 341.
Reaction SMILES: [OH-:1].[Na+].OO.[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:24]=1)#[N:6]>O1CCCC1>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH3:17])([CH3:16])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11]=2[CH:24]=1)(=[O:1])[NH2:6]
Reactant: [OH-]
Reactant: CC1(C)N=C(c2ccccn2)c2cc(C#N)ccc2O1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)N=C(c2ccccn2)c2cc(C(N)=O)ccc2O1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Aqueous 2N sodium hydroxide solution (6 ml) and 30% hydrogen peroxide solution (8 ml) were added dropwise over 20 minutes to a solution of 6-cyano-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.40 g) in tetrahydrofuran(16 ml). The mixture was stirred at room temperature for 40 minutes. The reaction mixture was extracted by addition of ethyl acetate. The organic layer was successively washed with an aqueous sodium bicarbonate solution, an aqueous sodium bisulfite and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was washed with diethyl ether to obtain 6-carbamoyl-2,2-dimethyl-4-(2-pyridyl)-2H-1,3-benzoxazine (0.30 g) (compound 9).