Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].CN(C=O)C.[C:19]([C:23]1[C:24]([CH3:45])([CH3:44])[CH2:25][O:26][C:27]=1[C:28]1[CH:42]=[C:41]([OH:43])[C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:34][C:30]=2[CH:29]=1)([CH3:22])([CH3:21])[CH3:20].[Cl-].[Na+]>>[C:19]([C:23]1[C:24]([CH3:45])([CH3:44])[CH2:25][O:26][C:27]=1[C:28]1[CH:42]=[C:41]([O:43][Si:10]([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11])[C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:34][C:30]=2[CH:29]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)C1=C(c2cc(O)c3nc(-c4ccccc4)oc3c2)OCC1(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)C1=C(c2cc(O[Si](C)(C)C(C)(C)C)c3nc(-c4ccccc4)oc3c2)OCC1(C)C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
In nitrogen atmosphere at a room temperature, adding 43 mg (0.63 mmol) of imidazole and 64 mg (0.42 mmol) of TBDMSCl to 2.0 ml of DMF dissolving 102 mg (0.28 mmol) of 4-t-butyl-5-(4-hydroxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [63]), the mixture was stirred for 2 hours. The mixture was added to saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, then dried with magnesium sulfate anhydride and concentrated. The concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=7:1) to obtain 108 mg of 4-t-butyl-5-[4-(t-butyldimethylsiloxy)-2-phenylbenzo[d]oxazol-6-yl]-3,3-dimethyl-2,3-dihydrofuran (Compound [65]) as a colorless oil. Yield 80.6%
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CC#N>[CH3:20][S:21]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(-c2cccs2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)Oc1ccc(-c2cccs2)cc1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a mixture of 4-(2-thienyl)phenol (1.76 g) and triethylamine (1.50 g) in MeCN (10 ml) was added dropwise methanesulfonylchloride (1.26 g) with ice-cooling. The mixture was stirred for 1 hour, then for 1 hour at ambient temperature. The resulting mixture was concentrated and diluted with a mixture of AcOEt and H2O to separate solid. The separated solid was recovered and washed with H2O and AcOEt to give 1.62 g of 2-(4-methanesulfonyloxyphenyl)thiophene.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([OH:17])[CH:12]=1.C(Cl)Cl>COCCOC.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:1]1([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([OH:17])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cc(Br)ccn1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: Oc1cc(-c2ccccc2)ccn1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (164 mg, 0.14 mmol) was added to a stirred suspension of phenylboronic acid (345 mg, 2.84 mmol) and 4-bromo-2-hydroxypyridine (494 mg, 2.84 mmol) in DME (10 mL). The reaction mixture was stirred under an argon atmosphere for 90 min. Degassed 2N potassium carbonate solution (aq) (10 mL) was added and the reaction mixture stirred with heating at 90° C. for 72 h. The solvent was evaporated in vacuo, and the residue partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate (×2). The organics were combined, dried over Na2SO4 and the solvent evaporated in vacuo. The residue was purified by chromatography on silica gel. Elution with DCM with a gradient to 5:95 methanol:DCM afforded 4-phenylpyridin-2-ol (311 mg, 1.82 mmol, 64%) M.S. (ESI) (m/z): 172 [M+H]+.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH:20]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)([CH3:22])[CH3:21]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH:20]([CH3:22])[CH3:21])[CH2:28][CH2:27]4)=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 537.0 [M+H]+; single peak at tR=3.08 min (System 1); Rf=0.12 (CH2Cl2/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH3:18])[C:4](=[O:19])[CH:3]=1.[N:20]([O-])=[O:21].[Na+].C(O)(=O)C>O>[CH2:8]([N:7]1[C:2]([NH2:1])=[C:3]([N:20]=[O:21])[C:4](=[O:19])[N:5]([CH2:16][CH2:17][CH3:18])[C:6]1=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=N[O-]
Reactant: CCCn1c(=O)cc(N)n(Cc2ccccc2)c1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCn1c(=O)c(N=O)c(N)n(Cc2ccccc2)c1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
2.0 g (7.7 mmol) of 6-amino-1-benzyl-3-propyluracil are heated to 80° C. in 15 ml of water and mixed with a solution of 0.55 g of sodium nitrite in 3 ml of water. After the addition of 1 ml of glacial acetic acid, a red solid is precipitated. The pH is adjusted to 4 and the suspension is stirred for a further 30 minutes at 80° C. After cooling, the crystals are filtered under suction and washed with water. 1.9 g of the title compound are obtained in the form of reddish-violet crystals (86% of theory), m.p. 208°-212° C./decomposition.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[C@@H:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](CCCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To a stirring solution consisting of (S)-4-benzyl-3-(5-phenylpentanoyl)oxazolidin-2-one (21ma, 1.24 g, 3.68 mmol) in THF (20 mL) at −78° C. was slowly added lithium bis-(trimethylsilyl)amide solution (4.41 mL, 4.41 mmol, 1 M solution in THF). The reaction mixture was stirred at −78° C. for one hour, after which time iodomethane (0.27 mL, 4.2 mmol) was slowly added. The resulting reaction mixture was allowed to rise to room temperature with stirring overnight. The mixture was acidified with 5% KHSO4 and extracted twice with ethyl acetate. The organic layer was washed twice with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (25:75 v/v) afforded the title compound (563 mg, 43.6%) as a clear oil; TLC Rf 0.53 (solvent system: 25:75 v/v ethyl acetate-heptane; MS (ESI+) m/z 352.3 (M+H)+374.2 (M+Na)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].[NH2:17][CH2:18][C:19]1[O:20][CH:21]=[CH:22][CH:23]=1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:17][CH2:18][C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccco1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Solvent: CS(C)=O
Product: CCn1ncc2c(NCc3ccco3)c3ccccc3nc21
Yield: 34.2 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 0.0043 mol), DMSO (3 mL) and 2-aminomethylfuran (0.8 mL, 0.009 mol) was heated at 90° for 3 hours. The reaction mixture was then partitioned between CH2Cl2 (50 mL) and water (50 mL). The aqueous layer was separated and then extracted with CH2Cl2 (25 mL) and then the CH2Cl2 layers were combined, washed with water dried over Na2SO4 and reduced to a volume of about 3-5 mL. The solution was passed through a silica gel column eluting with ethyl acetate to afford the product which was recrystallized from ether/CH2Cl2 to afford 430 mg of 1-ethyl-N-(2-furanylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 156-158° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])=[CH:15][C:14]=4[F:31])[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.Cl.[C:35](OCC)(=[O:37])[CH3:36]>C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:35](=[O:37])[CH3:36])[CH3:22])=[CH:15][C:14]=4[F:31])[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl [(1S)-2-({6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate (101 mg), 4M hydrogen chloride/ethyl acetate (1 mL) and ethyl acetate (1 mL) was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was mixed with acetic anhydride (1 mL) and pyridine (1 mL), and the obtained mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol), and recrystallized (hexane/ethyl acetate) to give the title compound (53.1 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH:24]3[NH2:31])[CH2:22]1)[CH2:28]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:31][CH:24]2[CH:23]3[CH2:29][CH:27]4[CH2:28][C:21]([OH:20])([CH2:30][CH:25]2[CH2:26]4)[CH2:22]3)=[O:17])(=[O:11])=[O:12])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)NC(C)(C)C(=O)O)cc1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(S(=O)(=O)NC(C)(C)C(=O)NC2C3CC4CC2CC(O)(C4)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
2-(4-acetylphenylsulfonamido)-2-methylpropionic acid (109 mg, 0.38 mmol), 5-hydroxy-2-adamantanamine (127 mg, 0.76 mmol), and BOP (168 mg, 0.38 mmol) were charged, and CH2Cl2 (5 ml) was added thereto, followed by stirring for 30 minutes at room temperature. DIPEA (0.18 ml, 1.14 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated using CH2Cl2 and H2O, dried with MgSO4, and filtered. Then, through vacuum distillation, the solvent was removed, and the resultant product was purified with column chromatography to obtain 2-(4-acetylphenylsulfonamido)-N-(5-hydroxyadamantane-2-yl)-2-methylpropanamide (110 mg, 0.25 mmol, 69%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[NH:24]([C:26]([O:28][CH3:29])=[O:27])[NH2:25].O>CO>[Cl:1][CH:2]1[C:10](=[C:11]=[N:25][NH:24][C:26]([O:28][CH3:29])=[O:27])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reactant: COC(=O)NN
Solvent: CO
Solvent: O
Product: COC(=O)NN=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Yield: 84.9 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 122 mg, 0.32 mmol) was dissolved in MeOH (10 mL) to which was added methyl hydrazinocarboxylate (115 mg, 1.3 mmol). The resulting solution was heated on a 60 C oil bath for 16 h, then cooled to room temperature and poured into 100 mL of water, and the solvent evaporated to approx 50 mL. The resulting suspension was cooled to 4 C, then filtered and the solids rinsed with cold water (25 mL). The solids were recrystallized from boiling EtOAc/hexane to yield 123 mg (85%) of 4.31 as a pale pink crystalline solid: mp 217-219 C; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 11.17 (b, 1H, D2O exch.), 8.54 (s, 1H), 8.42 (s, 1H), 8.22 (b, 1H), 5.92 (d, 1H), 5.42-5.37 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.43 (q, 1H), 4.15 (d, 1H), 3.98 (d, 1H), 3.72 (b, 5H). 13C-NMR (125 MHz, DMSO-d6): δ 153.88, 133.17, 129.33, 126.08, 124.96, 124.06, 122.17, 115.34, 108.59, 88.76, 86.03, 71.30, 69.73, 69.62, 61.07, 52.04. HRMS (ES) m/z calcd. for C16H16Cl3N3O6.Na 474.0002. found 473.9999. Anal calcd for C16H16Cl3N3O6.¼H2O: C, 42.03; H, 3.64; N, 9.19. Found: C, 42.11; H, 3.92; N, 9.18.
Reaction SMILES: [Li].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:7]=[N:8][CH:9]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:43][C:44]1[CH:45]=[C:46]([NH:51][NH2:52])[CH:47]=[CH:48][C:49]=1[F:50]>>[Cl:43][C:44]1[CH:45]=[C:46]([N:51]2[C:10]([C:6]3[CH:7]=[N:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=3)=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[N:52]2)[CH:47]=[CH:48][C:49]=1[F:50]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(OC)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cncc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1

Procedure:
600 mg (1.33 mmol) of the compound of Example 16A is reacted analogously to the synthesis of the compound of Example 20A with 288 mg (1.46 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, the entire reaction mixture is reduced to the dry state i. vac. 712 mg (37% purity, 57% of theory) of the title compound, which is used without further purification, is obtained.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16]C)=[O:15])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([OH:16])=[O:15])[CH:9]=2)[N:4]([CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[N:3]=1
Reactant: COC(=O)c1cccc(-c2cnc3[nH]nc(I)c3c2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(I)c2cc(-c3cccc(C(=O)O)c3)cnc21
Temperature: 25 °C
Yield: 15.5 %

Procedure:
To a solution of methyl 3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate (988 mg, 2.61 mmol) in DMF was added sodium hydride (60% in mineral oil, 525 mg, 13.03 mmol) at −40° C. The mixture was stirred for 60 minutes before SEMCl (920 μl, 5.22 mmol) was added. The reaction was warmed to room temperature and quenched with methanol and water. Acetic acid was then used to adjust the pH to 4-5. The mixture was then extracted with ethyl acetate (3×) and the organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the resulting crude product afforded 3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoic acid (200 mg, 15% yield) as solids. MS: m/z 517.9 (M+Na+).
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:29])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:32])=O>>[CH2:22]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=2)[C:19]([Cl:32])=[C:10]([C:8]#[N:7])[C:11]1=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2Cc1ccccc1
Yield: 38 %

Procedure:
A solution of Compound 18 (5 g, 12.80 mmol) in 30 mL neat phosphorus oxychloride was heated at 100° C. for 3 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 1.51 g (38%) of yellow solids. M.P. 219° C. 1H NMR (DMSO-d6): δ 2.40 (s, 3H), 5.54 (s, 2H), 7.23-7.26 (m, 3H), 7.29-7.32 (m, 2H), 7.45 (d, J=8.8 Hz, 1H), 7.61 (dd, J=1.5, 8.8 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H). EIMS m/z 309 (M+1), 331 (M+23).
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].[I-].[K+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1>>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][N:32]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: ClCc1ccncn1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccncn1
Yield: 77.1 %

Procedure:
Using an analogous procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (560 mg) was reacted in the presence of catalytic potassium iodide with 4-(chloromethyl)pyrimidine (375 mg) to give 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(pyrimidin-4-ylmethoxy)quinazoline (496 mg, 74%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]([C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([NH2:72])[CH:67]=2)=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[O:53]([C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([NH:72][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:67]=2)=[CH:62][CH:61]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc(Oc3ccccc3)cc2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 78 %

Procedure:
DIEA (0.011 mL, 0.063 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.016 g, 0.057 mmol) and HATU (0.024 g, 0.063 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-phenoxy-biphenyl-3-ylamine (0.015 g, 0.057 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.023 g of product in 78% yield: LCMS (ESI) m/z 518 (MH+).
Reaction SMILES: CO.Cl[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[N:8][CH:9]=1.[CH3:13][S-:14].[Na+]>O>[CH3:13][S:14][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[N:8][CH:9]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1ccc([N+](=O)[O-])nc1
Reaction time: 13 h
Yield: 45.3 %

Procedure:
A methanol (40 mml) solution of 5-chloro-2-nitropyridine (2.0 g. 12.6 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (1.02 g, 13.9 mmol) while being cooled with ice, and after the mixture was stirred for 13 hours while raising its temperature to the room temperature, water added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was recrystalized with ethyl acetate-hexane to obtain 972 mg (yield 45%) of 5-methylthio-2-nitropyridine.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.O>C(Cl)(Cl)Cl>[Br:1][C:12]1[C:6]2[C:7](=[N:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[NH:10][CH:11]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1cnc2[nH]cc(Br)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of bromine (3.5 ml) in chloroform (40 ml) was added dropwise to an ice-cold solution of the 5-chloro-1H-pyrrolo[2,3-b]pyridine (3) (10 g, 65 mM) in chloroform (260 ml). The reaction mixture was stirred for 60 minutes at 0° C. The reaction mixture was then hydrolysed with water and the pH of the solution was adjusted to 10. The resulting solid was removed by filtration, and the aqueous was extracted with dichloromethane. The organic was washed with water, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (10.5 g, 69%). 1H NMR (DMSO-d6) 7.8 (1H, s), 7.9 (1H, s), 8.3 (1H, s)
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:18]=1[C:19]([NH2:21])=[O:20]>>[CH2:1]([N:8]1[C:12]([C:13]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[C:18]=2[C:19](=[O:20])[NH2:21])=[O:14])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1nnnn1Cc1ccccc1
Reactant: NC(=O)c1c(N)cccc1N1CCOCC1
Product: NC(=O)c1c(NC(=O)c2nnnn2Cc2ccccc2)cccc1N1CCOCC1

Procedure:
In a manner similar to Example I, 1-benzyl-1H-tetrazole-5-carbonyl chloride is condensed with 2-amino-6-(4-morpholinyl) benzamide to give 1-benzyl-N-[2-carbamoyl-3-(4-morpholinyl)phenyl]-1H-tetrazole-5-carboxamide.