Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([CH3:18])=[N:4][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=1.C1COCC1.C([Mg]Cl)(C)C.CO[B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1>>[CH3:18][C:3]1[C:2]([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)=[CH:6][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)[N:4]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2cc(I)c(C)n2)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](n2cc(B3OC(C)(C)C(C)(C)O3)c(C)n2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl trans-4-(4-iodo-3-methyl-1H-pyrazol-1-yl)cyclohexanecarboxylate (120.0 mg, 0.3313 mmol) in THF (6 mL, 80 mmol) was added 2 M isopropylmagnesium chloride in THF (0.66 mL, 1.3 mmol) at rt, and the mixture was stirred for 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.27 mL, 1.7 mmol) was added, and the mixture stirred at rt for 2 h. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:34])[CH:22]([N:24]([CH:31]3[CH2:33][CH2:32]3)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23])[N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].C([N:38](C(C)C)CC)(C)C.C(OC(=O)CBr)C>C(#N)C>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:34])[CH:22]([N:24]([CH:31]3[CH2:33][CH2:32]3)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23])[N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)(=[NH:38])[NH2:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CN(C1CC1)C(C)C(=O)N1CCC[C@H]1CCc1cc2ccc(C#N)cc2n1CC
Agent: CCOC(=O)CBr
Solvent: CC#N
Product: CCOC(=O)CN(C1CC1)C(C)C(=O)N1CCC[C@H]1CCc1cc2ccc(C(=N)N)cc2n1CC
Temperature: 70 °C
Reaction time: 4 h

Procedure:
467 mg of ethyl 2-[[2-[(S)-2-[2-(6-cyano-1-ethylindol-2-yl)ethyl]pyrrolidinyl]-1-methyl-2-oxoethyl]cyclopropylamino]acetate was dissolved in 15 ml of acetonitrile, and diisopropylethylamine and ethyl-2-bromoacetate were added thereto. The reaction mixture was heated to 70° C. and stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain the residue, which was then purified with silica gel column chromatography [eluent: dichloromethane/methanol (20:1)] to obtain 538 mg of the title compound as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.FC1C=CC(C#N)=CC=1.[Br:21]N1C(=O)CCC1=O>CN(C)C=O>[Br:21][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2[nH]ncc2c1
Agent: N#Cc1ccc(F)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]nc(Br)c2c1
Reaction time: 24 h

Procedure:
To a solution of 300 mg of a compound 1H-5-indazolecarbonitrile (synthesized from 4-fluorobenzonitrile according to the procedures described in literature, Tetrahedron Lett., 33, 7499 (1992) and Synthetic commun., 27, 1199 (1997)) in 3 ml dimethylformamide was added 392 mg of N-bromosuccinimide at room temperature, and the mixture was stirred at the same temperature for one day. After removing the solvent by distillation, the residue was added with 25 ml of ethyl acetate. The mixture was sequentially washed with half-saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 440 mg of the title compound as pale red crystals.
Reaction SMILES: [F:1][C:2]([C:17]([F:20])([F:19])[F:18])([O:6][C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3](F)=[O:4].C[Si](C)(C)[O-:23].[Na+:26]>O1CCCC1>[F:1][C:2]([C:17]([F:18])([F:19])[F:20])([O:6][C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:12])([F:10])[F:11])[C:3]([O-:4])=[O:23].[Na+:26]
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C([O-])C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 69.3 %

Procedure:
The procedure of Example 1 was followed using perfluoro-2-methyl-3-oxahexanoyl fluoride (16.6 g, 50 mmol), sodium trimethylsilanolate (5.6 g, 50 mmol), and dry tetrahydrofuran (100 mL), and a 2 h reaction time. Sodium perfluoro-2-methyl-3-oxahexanoate (12.2 g, 69% yield) was isolated as a white solid: The 19F NMR data were the same as reported in Example 15.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:3]([OH:16])[CH2:4][N:5]([CH2:14][CH3:15])[NH:6][C:7]([O:9]C(C)(C)C)=O.C(O)(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH3:33][S:34]([NH:37][C:38]1[S:39][CH:40]=[C:41]([C:43](O)=[O:44])[N:42]=1)(=[O:36])=[O:35]>>[C:7]([NH:6][N:5]([CH2:4][C@@H:3]([OH:16])[C@@H:2]([NH:1][C:43]([C:41]1[N:42]=[C:38]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])[S:39][CH:40]=1)=[O:44])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:14][CH3:15])(=[O:9])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)Nc1nc(C(=O)O)cs1
Reactant: O=C(O)c1ccccc1
Reactant: CCN(C[C@@H](O)[C@@H](N)Cc1ccccc1)NC(=O)OC(C)(C)C
Product: CCN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)c1csc(NS(C)(=O)=O)n1)NC(=O)c1ccccc1

Procedure:
Synthesized as described above from tert-butyl 2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate, benzoic acid and 2-methanesulfonylamino-thiazole-4-carboxylic acid. MS (ESI+) for C24H29N5O5S2 m/z 532.7 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37](O)=[O:38])[N:27]=1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:40]([NH2:44])[CH:41]([CH3:43])[CH3:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(N(CC)CC)C.O>[C:1]([O:5][C:6]([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37]([NH:44][CH2:40][CH:41]([CH3:43])[CH3:42])=[O:38])[N:27]=1)=[N:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: Cc1ccc2nc(C(=O)O)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(C(=O)NCC(C)C)nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 400 mg of 4-{[(1S,2R)-2-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)cyclohexyl]amino}-6-methylquinazoline-2-carboxylic acid, 0.15 ml of isobutylamine, 285 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 200 mg of 1-hydroxybenzotriazole in 7 ml of N,N′-dimethylformamide, 0.41 ml of triethylamine was added, and then the mixture was stirred at room temperature for 24 hours. The reaction solution was mixed with water and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform) to obtain 242 mg of the desirable compound as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[Br-:13].[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N+:10]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8]1
Reactant: BrCCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: [Br-]
Product: c1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Yield: 84.1 %

Procedure:
A mixture of 1-(2-pyrimidinyl)piperazine (32.8 g; 0.2 mole), 1,4-dibromobutane (108 g; 0.5 mole) and finely powdered sodium carbonate (21.2 g, 0.2 mole) in 400 mL isopropanol was stirred and refluxed for a 16 hr period. The hot reaction mixture was filtered and the filtrate, on standing at room temperature, provided 50.3 g (84% yield) of product. Crystallization of this material from isopropanol affords analytically pure product, m.p. 241.5°-242.5° C. (corr.).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.C(O)(=O)C>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:9]1[CH:8]=[C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][C:4]=1[OH:3]
Reactant: BrBr
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(O)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Bromine (16.59 g, 104 mmol) in chloroform (25 mL) was added dropwise to a stirred, cooled (0° C.) mixture of methyl 4-hydroxyphenylethanoate (17.25 g, 104 mmol) and acetic acid (10 mL) in chloroform (140 mL). The mixture was stirred at 0° C. for 1 h., diluted with dichloromethane (100 mL), washed with water (2×200 mL) and brine (200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (25.43 g, 100%). 1H NMR (360 MHz, CDCl3) δ7.39 (1 H, d, J 2.0 Hz), 7.12 (1 H, dd, J 8.3, 2.0 Hz), 6.96 (1 H, d, J 8.3 Hz), 5.54 (1 H, br s), 3.70 (3 H, s), and 3.54 (2 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:21]([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18](=[O:20])C)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:24](O)[CH2:25][OH:26].[OH-].[Na+].O>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:12]([N:21]([CH3:22])[CH3:23])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][C:18]([O:26][CH2:25][CH3:24])=[O:20])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)COCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 16 h

Procedure:
A mixture of 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}-N,N-3-oxapentamethyleneacetamide (4.9 g prepared as described in Example 214), ethylene glycol (30 ml) and 18N aqueous sodium hydroxide solution (10 ml) was heated under reflux for 21/2 hours and then cooled. Water (30 ml) was added and the aqueous mixture washed with ether. The ether extracts were washed with 5N aqueous sodium hydroxide solution and the alkaline washings combined with the aqueous reaction mixture and the resulting mixture neutralised by addition of concentrated hydrochloric acid. The neutralised mixture was evaporated and the residue dried by azeotropic distillation with methanol and then propan-2-ol. The residue was mixed with propan-2-ol and the mixture filtered. The filtrate was evaporated and the residue was heated at 63°/0.7 mm to remove excess ethyleneglycol and then dissolved in ethanol (50 ml). Thionyl chloride (3.5 ml) was added dropwise with stirring and the mixture allowed to stand for 16 hours under anhydrous conditions. The reaction mixture was then poured into a mixture of ice and excess aqueous sodium bicarbonate solution. The mixture was extracted with ether and the extracts were dried and evaporated to give an oil which was mixed with ether. The mixture was filtered and a solution of maleic acid in ether was added to the filtrate to produce a gum. The supernatent was decanted and the residual gum washed with ether, which was decanted, several times and then basified with sodium bicarbonate. The product was extracted with ether and the extracts were dried and evaporated to give ethyl 2-{4-[1-(4-chlorophenyl)-cyclobutyl]-4-dimethylaminobutoxy}acetate. A sample of this material (2.8 g) was dissolved in methanol (300 ml). Ammonia gas was bubbled into the solution which was cooled in ice, saturated with ammonia gas and then evaporated and heated at 90°/20 mm to leave 2-{4-[1-(4-chlorophenyl)cyclobutyl]-4-dimethylaminobutoxy}acetamide a residual oil the boiling point of which was not determined.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12](C(C)(C)C)[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].S(Cl)([Cl:28])(=O)=O.S(=O)=O>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([Cl:28])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCC
Reactant: O=S(=O)(Cl)Cl
Agent: O=S=O
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(Cc1cc(Cl)c(O)c(C(C)(C)C)c1)OCC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
71.2 g of 3,5-di-tert. butyl-4-hydroxybenzyl-phosphonic acid diethyl ester are dissolved in 200 ml of carbon tetrachloride. After addition of a few drops of pyridine, 40.5 g of sulphuryl chloride are added dropwise, with stirring, at about 0° C in the course of 45 minutes. The reaction mixture is then further stirred for 10 hours at room temperature, in the course of which the formation of sulphur dioxide is observed. After the reaction is terminated, the solvent is removed as far as possible completely in vacuo. The semi-crystalline residue is digested with water and washed neutral and finally recrystallised from aqueous isopropanol in order to purify it. Instead of isopropanol it is also possible to use ethylene glycol monomethyl ether. Toluene is also suitable for effecting recrystallisation, but the crude product must in this case be freed from water beforehand. The 3-chloro-5-tert. butyl-4-hydroxybenzyl-phosphonic acid diethyl ester is obtained in the form of colourless crystals (stabiliser 1) with a melting point of 116° C.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[C:43]([O:54][CH2:55][CH3:56])(=[O:53])[CH:44]([CH:46]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[OH:47])[OH:45]>CCOCC>[F:31][C:30]([F:32])([F:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:45][CH:44]([CH:46]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[OH:47])[C:43]([O:54][CH2:55][CH3:56])=[O:53])=[O:11])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCC(F)(F)F)C(=O)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C(O)C(OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)OCC

Procedure:
A mixture of 4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino)benzoyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartarate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3]SC1C=CC=CC=1.Cl[C:12]1[CH:13]=[C:14](C(OO)=O)[CH:15]=[CH:16][CH:17]=1.[S:22]([O-:25])([O-])=[O:23].[Na+].[Na+]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][S:22]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:25])=[O:23]
Reactant: BrCCSc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
A mixture of (2-bromo-ethylsulfanyl)-benzene (273 mg, 1.26 mmol) and 3-chlorobenzenecarboperoxoic acid (650 mg, 3.77 .mmol) in methylene chloride (5 mL) were stirred at room temperature for 16 h. A saturated sodium sulfite solution was added and the mixture was extracted with methylene chloride. The organic layers were washed by saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated in vacuo to provide (2-bromo-ethanesulfonyl)-benzene (0.24 g, 76%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:47])[C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[O:39][Si](C(C)(C)C)(C)C)[CH:23]=1>C1COCC1>[CH3:19][O:20][C:21](=[O:47])[C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[OH:39])[CH:23]=1
Reactant: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2O)c1
Reaction time: 0.5 h

Procedure:
The solution of tetrabutyl ammonium fluoride (42.8 g, 0.13 mol) in THF (350 mL) was added dropwise to a solution of compound of Example 1g (35 g, 0.068 mol) in THF (150 mL) under nitrogen at 5° C. and stirred for 30 min. Solvent was removed from the reaction mixture and ice water (200 mL) was added. The solid separated was filtered, and washed with water (3×100 ml). The crude obtained was purified by column chromatography (silica gel, ethyl acetate/pet. ether) to obtain the title compound. Yield: 24 g, (88%); 1H NMR (CDCl3, 300 MHz): δ 2.44 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 4.26 (s, 2H, CH2), 6.81 (t, 1H, Ar), 7.20-7.26 (m, 2H, Ar), 6.81 (t, 1H, Ar), 7.70 (s, 1H, Ar); MS: m/e (EI) 401 (M+).
Reaction SMILES: C(O[C:4]([O:6][NH:7]/[C:8](=[N:42]/[H])/[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[CH:21]=[C:22]([CH:24]=[CH:25][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=[C:19]3[C:18]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:17][CH:16]=2)=[CH:11][N:10]=1)=[O:5])C.C1CCN2C(=NCCC2)CC1.O.Cl>CC1C=CC=CC=1C>[O:39]1[CH2:40][CH2:41][N:36]([C:18]2[C:19]3[N:20]([CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:8]4[N:42]=[C:4]([OH:5])[O:6][N:7]=4)=[N:10][CH:11]=3)=[CH:16][N:17]=2)[CH2:37][CH2:38]1
Reactant: [H]/N=C(/NOC(=O)OCC)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=Cc4ccc5ccccc5n4)cn23)cn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: Cc1ccccc1C
Product: Oc1nc(-c2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cn2)no1
Temperature: 25 °C
Yield: 27.2 %

Procedure:
To a solution of compound 4b (200 mg, 0.350 mmol) in o-xylene (4 mL) was added DBU (300 mg, 1.97 mmol). The reaction mixture was stirred in a 10 mL sealed tube at 120° C. for 2 h. After cooling to rt, water (20 mL) was added, and the pH of the solution was adjusted to 7 using 1N HCl solution. The solids were collected by filtration and washed with DCM/MeOH (50:1 v/v, 3×10 mL) to obtain the title compound 95 as an orange solid (49.4 mg, 26% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 13.32 (s, 1H), 9.06 (s, 1H), 8.82-8.60 (m, 1H), 8.44-8.40 (m, 2H), 8.30-8.05 (m, 5H), 8.05-7.92 (m, 1H), 7.82 (s, 1H), 7.75 (d, J=9.9 Hz, 1H), 7.65 (s, 1H), 4.55-4.30 (m, 4H), 4.00-3.80 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H22N8O3: 519.2 (M+H). Found 519.2.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([O:12]/[CH:13]=[CH:14]/B1OC(C)(C)C(C)(C)O1)[CH3:11]>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[C:7](/[CH:11]=[CH:10]/[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccc(I)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCO/C=C/c1ccc(Cl)nc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a degassed solution of 2,6-dichloro-3-iodopyridine (3.0 g, 11 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 g, 11 mmol) in 1,4-dioxane (20 mL) and water (1.0 mL) was added CS2CO3 (7.1 g, 22 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (357 mg, 0.54 mmol) under N2 protection. The resulting mixture was heated to 70° C. and stirred at this temperature overnight. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-20% EtOAc/DCM) to provide (E)-2,6-dichloro-3-(2-ethoxyvinyl)pyridine (1.96 mg, yield: 86%). MS (M+H)+: 218.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:59])[C@H:41]([CH:56]([CH3:58])[CH3:57])[NH:42][C:43]([N:45]([CH2:47][C:48]1[N:49]=[C:50]([CH:53]([CH3:55])[CH3:54])[S:51][CH:52]=1)[CH3:46])=[O:44])[CH2:9][C@H:10]([O:29][CH:30](SCCCC)[CH2:31][CH2:32][CH3:33])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:60](=[O:64])([OH:63])([OH:62])[OH:61].IN1C(=O)CCC1=O.C([O-])([O-])=O.[Na+:77].[Na+]>CN(C=O)C.CO>[CH2:1]([C@H:8]([NH:39][C:40](=[O:59])[C@H:41]([CH:56]([CH3:58])[CH3:57])[NH:42][C:43]([N:45]([CH2:47][C:48]1[N:49]=[C:50]([CH:53]([CH3:54])[CH3:55])[S:51][CH:52]=1)[CH3:46])=[O:44])[CH2:9][C@H:10]([O:29][CH:30]([O:64][P:60]([O-:63])([O-:62])=[O:61])[CH2:31][CH2:32][CH3:33])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:77].[Na+:77]
Reactant: O=P(O)(O)O
Reactant: CCCCSC(CCC)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1I
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCC(O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)OP(=O)([O-])[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution containing the product from Example 12A (1.2 g, 1.4 mmol), molecular sieves (4 Å, 6.0 g), and phosphoric acid (0.85 g) in DMF (28 mL) at 0° C. was added N-iodosuccinimide (0.406 g), and the mixture was stirred at 0° C. for 1 hour. To the cold reaction was added 10% Na2CO3 to adjust the pH to 9, and the mixture was diluted with methanol and filtered. The filtrate was treated with 1 M Na2S2O3 until it was clear, diluted with methanol and filtered again. The solvent was evaporated, and the crude product was purified by HPLC on a C18 column, eluting with a gradient starting with water and ending with methanol to give the title compound (0.605 g, 47% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH2:27][C:28]1[CH:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[CH:30][N:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:27][C:28]1[CH:33]=[C:32]([CH:31]=[CH:30][N:29]=1)[C:34]([NH:13][C:10]1[N:9]2[CH2:14][CH2:15][N:16]=[C:8]2[C:7]2[CH:6]=[CH:5][C:4]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[C:3]([O:2][CH3:1])[C:12]=2[N:11]=1)=[O:35]
Reactant: Nc1cc(C(=O)O)ccn1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1ccnc(N)c1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (100 mg, 0.28 mol) was dissolved in DMF (3 mL), and 2-aminopyridine-4-carboxylic acid (38 mg, 0.28 mmol) was added. PYBOP (217 mg, 0.42 mmol) and diisopropylethylamine (0.15 mL, 0.83 mmol) were subsequently added, and the mixture was stirred at rt overnight. The mixture was purified by HPLC to give the title compound (50 mg, 37%). LC MS RT=1.02 min, MH+=480.3. 1H NMR (DMSO-d6) δ: 13.25 (1H, br s), 10.15 (1H, br s), 8.42 (1H, br s), 8.08 (1H, s), 8.06 (1H, d), 7.43 (1H, d), 7.75 (1H, s), 7.50 (1H, d), 7.38 (1H, dd), 4.50 (2H, dd), 4.35 (2H, br t), 4.27 (2H, dd), 4.01 (3H, s), 3.99 (2H, br s), 3.66 (2H, t), 3.50 (2H, d), 3.31 (2H, br t), 3.13 (2H, m), 2.25 (2H, m).