Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2>C(O)(=O)C.C(OCC)C.[Pt]=O>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2
Reactant: Clc1cccc2ncccc12
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Clc1cccc2c1CCCN2
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
A mixture of 5-chloroquinoline (10.0 g) and platinum oxide (50 mg) in acetic acid was shaken under a hydrogen atmosphere at room temperature for 4 hours. The mixture was diluted with diethyl ether and filtered through Celite. The volatiles were removed under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate (3×300 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified over silica gel and the fractions containing product were combined and concentrated under reduced pressure to provide 7.0 g (69%) of the desired compound.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7]([CH3:34])[C:8]1[CH:33]=[CH:32][C:11]([CH:12]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:15]=2SC)=[CH:10][CH:9]=1.[NH2:35][CH:36]([CH2:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH3:37]>C(#N)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7]([CH3:34])[C:8]1[CH:33]=[CH:32][C:11]([CH:12]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([N:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[C:15]=2[NH:35][CH:36]([CH3:37])[CH2:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[CH:10][CH:9]=1
Reactant: CCN(CC)CCCC(C)N
Reactant: CSc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCN(CC)CCCC(C)Nc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.47 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-(methylthio)imidazolium tetrafluoroborate are suspended in 50 ml of absolute acetonitrile, whereupon the suspension is treated with 7.8 g of absolute 2-amino-5-(diethylamino)pentane. The mixture is stirred at room temperature under an argon atmosphere for about 24 hours. The insoluble constituents are removed by filtration and the filtrate is treated with 450 ml of diethyl ether. The pale yellow precipitate obtained is removed by filtration under suction, washed three times with diethyl ether and recrystallized from methanol/diethyl ether. There is obtained pale yellow 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-[[4-(diethylamino)-1-methylbutyl]amino]imidazolium tetrafluoroborate of melting point 187°-191° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[CH:30][C:25]=1[O:26][CH2:27]CO.[Na]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([O:16][CH2:17][CH2:27][O:26][C:25]3[CH:30]=[C:31]([Cl:35])[C:32]([Cl:34])=[CH:33][C:24]=3[Cl:23])=[O:15])=[CH:10][CH:9]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Reactant: OCCOc1cc(Cl)c(Cl)cc1Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CC(Oc1ccc(COc2ccc(Cl)cc2)cc1)C(=O)OCCOc1cc(Cl)c(Cl)cc1Cl
Reaction time: 4 h

Procedure:
A mixture consisting of 2.2 gm of methyl 2-[4-(4-chlorophenoxy-methyl)-phenoxy]-propionate, 2.4 gm of 2-(2,4,5-trichloro-phenoxy)-ethanol and 0.03 gm of sodium was heated at about 120°-150° C. and a pressure of 150 mm Hg for four hours. After cooling, the reaction mixture was briefly boiled with acetone, the cooled solution was filtered, and the solvent was removed from the filtrate in vacuo. The residue was recrystallized from ethanol/water, yielding 1.3 gm (36% of theory) of the compound of the formula ##STR19## which had a melting point of 83° C.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([CH2:11][NH:12]C(=O)OC(C)(C)C)[CH:9]=[CH:10][C:5]=2[C:4]([CH3:21])([CH3:20])[O:3]1.[ClH:22]>CO>[ClH:22].[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]2[C:4]([CH3:21])([CH3:20])[O:3][B:2]([OH:1])[C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)B(O)OC2(C)C
Agent: Cl
Solvent: CO
Product: CC1(C)OB(O)c2cc(CN)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
To a solution of tert-butyl ((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)carbamate (13.15 mmol) in methanol (100 mL) was added HCl (20 mL, 65.75 mmol). The reaction mixture was stirred for 16 h at rt. The solvent was removed to give 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (1.5 g; yield 50% over 4 steps). MS: m/z=192.1 (M+1, ESI+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[OH:22])[CH2:5][C@@H:6]([C:16]([OH:18])=[O:17])[NH:7][C:8](=[O:15])[CH2:9][CH2:10][S:11]C(=O)C.[OH-].[NH4+]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[OH:22])[CH2:5][C@@H:6]([C:16]([OH:18])=[O:17])[NH:7][C:8](=[O:15])[CH2:9][CH2:10][SH:11]
Reactant: CC(=O)SCCC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=C(CCS)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O

Procedure:
3-Hydroxy-N-(3-acetylthiopropanoyl)-L-tyrosine (280 mg.) is treated with concentrated ammonium hydroxide according to the procedure in Example 76. The crude product, 3-hydroxy-N-(3-Mercaptopropanoyl)-L-tyrosine is crystallized from acetonitrile, yield 157 mg., m.p. 89°-91°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[N:25]=[C:24](I)[CH:23]=[CH:22][N:21]=1>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]([C:22]3[CH:23]=[CH:24][N:25]=[C:20]([S:19][CH3:18])[N:21]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3nc(Cl)ccc3[nH]2)cc1
Reactant: CSc1nccc(I)n1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
KN(TMS)2 (1.42 g 7.16 mmol) in toluene (7 ml) is added at 0° C. to a solution of 5Chloro-2-(4fluorophenyl)imidazo[4,5-b]pyridine (1.9 g 6.66 mmol) in DMF (25 ml). After stirring 1 h at room temperature, 2-methylthio-4-iodopyrimidine (1.8 g 7.1 mmol) in toluene (7 ml) is added dropwise and heated for 20 h at 120° C. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crystalline crude product, which after recrystallisation from ethyl acetate yields the title compound as colorless crystals (1.76 g 67%).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:11](Cl)=[CH:10][C:7]=1[CH2:8][NH2:9]>C(O)C.[OH-].[OH-].[Pd+2]>[F:2][C:3]([F:15])([F:16])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][NH2:9]
Reactant: NCc1cc(Cl)ccc1OCC(F)(F)F
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: NCc1ccccc1OCC(F)(F)F
Reaction time: 4 h

Procedure:
A solution of 2-(2,2,2-trifluoroethoxy)-5-chlorobenzylamine hydrochloride (650 mg) in ethanol (200 mL) containing 20% Pd(OH)2/C (1 g) was hydrogenated at 50 psi for 4 h. The catalyst was removed via filtration through Celite and the filtrate then evaporated to dryness to give the title compound as a white powder: 1H NMR (CD3OD) δ7.47 (m, 2H), 7.19 (m, 2H), 4.69 (q, J=8.4 Hz, 2H), 4.16 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26](I)[CH3:27]>CN(C=O)C.C(OCC)(=O)C>[CH2:26]([N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[C@@H:12]([CH:17]([OH:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[CH3:27]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(C)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN([C@H](C(=O)OC)C(C)O)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Compound 9A (1 g, 3.0 mmol) dissolved in DMF (10 ml) was added with K2CO3 (1.1 equiv., 456 mg) and ethyl iodide (1.1 equiv., 0.316 ml) and the reaction was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed several times with water and finally with Brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by crystallization from ethyl ether and petroleum ether afforded 895 mg of a semisolid. Yield=93%. 1HNMR (DMSO, 200 MHz) δ 1.13 (3H, d, J=6.2 Hz), 1.26 (3H, t, J=7 Hz), 3.32 (3H, s), 3.41 (2H, q, J=7.8 Hz), 4.02 (1H, bs), 4.23 (1H, m), 5.13 (1H, d, J=4.6 Hz), 7.42 (2H, m), 7.84 (2H, m)
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N+]([O-])=O)=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:25])=O.O>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([Cl:25])=[N:10][C:9]=3[N:8]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2[nH]c(Cl)nc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,3-Di-cyclopropylmethyl-8-nitro xanthine (6 g, 0.023 mol) was dissolved in dimethylformamide (20 ml) and reacted with phosphorus oxychloride (14 g), for 1 hour at 120° C. The mixture was then treated with water and stirred for 1 hour at room temperature. The precipitate was filtered off, dissolved in ethyl acetate, dried over anhydrous sodium sulphate and the solvent was removed in vacuo, yield 2.5 g (40%), m.pt. 220° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=O.[BH4-].[Na+].Cl>CO>[Cl:1][CH2:2][CH2:3][CH:4]=[CH:5][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2cc(C=CCCCl)ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.0 Grams of 6-(4-chloro-1-oxobutyl)-3,4-dihydrocarbostyril was disposed in 200 ml of methanol, and the suspension was stirred at a room temperature. Then 2.0 g of sodium borohydride was added to the suspension gradually and the reaction was continued for 1 hour. Next, 3 ml of concentrated hydrochloric acid was added to the reaction mixture and the mixture was concentrated under a reduce pressure with heat-refluxing condition to obtain a residue. The residue was extracted with chloroform and the chloroform layer was washed with water and dried. Then colorform was removed by distillation under a reduced pressure to obtain a residue, and the residue was recrystallized from ethanol to obtain 2.4 g of 6-(4-chloro-1-butenyl)-3,4-dihydrocarbostyril in yellow needle-like crystals. Melting point: 153°-155° C.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(CCO)CC.[NH2:37][C:38]1[CH:39]=[N:40][C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:37][C:38]2[CH:39]=[N:40][C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:47]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Reactant: Nc1cnc2ccccc2c1
Agent: CCN(CC)CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2cnc3ccccc3c2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DEEA (0.19 mL, 1.09 mmol) and 3-aminoquinoline (260 mg, 1.80 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (24 mg, 12% yield).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=1)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[CH:16]1([C:19]2[N:20]=[CH:21][NH:22][CH:23]=2)[CH2:18][CH2:17]1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu-]=O.C(#N)CCC>[CH:16]1([C:19]2[N:20]=[CH:21][N:22]([C:2]3[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH:13]=3)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH:23]=2)[CH2:18][CH2:17]1
Reactant: c1nc(C2CC2)c[nH]1
Reactant: COc1ccc(I)cc1C(=O)OC(C)C
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCCC#N
Product: COc1ccc(-n2cnc(C3CC3)c2)cc1C(=O)OC(C)C
Temperature: 120 °C
Yield: 51 %

Procedure:
A suspension of isopropyl 5-iodo-2-methoxybenzoate (1.52 g, 4.75 mmol), 4-cyclopropyl-1H-imidazole (0.777 g, 7.13 mmol), copper(I) oxide (0.067 g, 0.047 mmol), 8-hydroxyquinoline (0.103 g, 0.71 mmol), cesium carbonate (2.41 g, 7.41 mmol), PEG-3350 (1.18 g) and butyronitile (60 ml) was placed in a sealed tube, which was flushed with nitrogen and heated at 120° C. for 16 hours. The solvent was removed under reduced pressure, and the residue was purified by reversed phase HPLC to provide isopropyl 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-methoxybenzoate. (0.720 g, 2.4 mmol). 51% yield. 301 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16])[CH3:13].C([O-])([O-])=O.[Na+].[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>O1CCOCC1.C(OCC)(=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-c2cnc(N)c([N+](=O)[O-])c2)c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 75.5 %

Procedure:
To a solution of 5-bromo-3-nitropyridin-2-amine (5.00 g, 23.97 mmol) in dioxane (115 mL) was added 3-(ethoxycarbonyl)phenylboronic acid (4.65 g, 23.97 mmol) and 1N Na2CO3 aqueous solution (92.2 mL, 92.2 mmol). The reaction mixture was degassed using Argon gas for 20 min followed by the addition of dichlorobis(triphenylphospine) palladium(II) (971 mg, 1.38 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (881 mg, 2.07 mmol). The reaction flask was put into the preheated oil-bath at 90° C. The reaction mixture was further stirred at 90° C. for a period of 10 h after which it was filtered and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 90:10 v/v hexane:ethyl acetate as solvent to afford ethyl 3-(6-amino-5-nitropyridin-3-yl)benzoate (5.2 g, 78% yield) as a tan solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([Cl:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccccn3)nc(NCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][N:6]=1)=[O:4].[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:31]=[C:30]([OH:32])[C:24]3[CH2:25][C:26]([CH3:29])([CH3:28])[O:27][C:23]=3[CH:22]=2)=[O:20])=[N:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:32][C:30]2[C:24]3[CH2:25][C:26]([CH3:28])([CH3:29])[O:27][C:23]=3[CH:22]=[C:21]([C:19](=[O:20])[NH:18][C:15]3[CH:16]=[CH:17][N:13]([CH3:12])[N:14]=3)[CH:31]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: COC(=O)c1ccc(F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1
Temperature: 160 °C
Yield: 56.4 %

Procedure:
A mixture of 5-fluoro-pyridine-2-carboxylic acid methyl ester (179a) (342 mg, 2.20 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (633 mg, 2.20 mmol), and Cs2CO3 (1.44 g, 4.40 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H2O, and extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage column chromatography with 75-90% EtOAc in hexanes to give a white solid (524 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=3.03 Hz, 2 H) 8.13 (d, J=8.59 Hz, 1 H) 7.22-7.36 (m, 2 H) 7.06 (d, J=5.05 Hz, 2 H) 6.77 (d, J=2.27 Hz, 1 H) 4.01 (s, 3 H) 3.78 (s, 3 H) 2.89 (s, 2 H) 1.49 (s, 6 H); LCMS for C22H22N4O5 m/z 423.20 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[I-:14].[K+].[K].S(=O)(=O)(O)O>O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([I:14])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: [I-]
Reactant: CC(C)(C)c1cc(C=O)ccc1O
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C=O)cc(I)c1O
Yield: 131.4 %

Procedure:
A slurry of 3-tert-butyl-4-hydroxybenzaldehyde (16 gm) sodium hydroxide (3.5 gm), potassium iodide (10.3 gm), potassium in distilled water (91 ml) was added dropwise during 20 mins to a stirred solution of ethanol (69 ml), water (15 ml) and and concentrated sulphuric acid (7.5 ml) at 50°-55° C. After addition, the mixture was refluxed for 1 hour. Sodium metabisulphite (1 gm) was added to the mixture and on cooling a precipitate formed. The precipitate was collected and recrystallised from petroleum ether to give 3-tert-butyl-4-hydroxy-5-iodobenzaldehyde (24.8 gm) m.p. 124°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]([O:17][CH2:18][CH3:19])=[CH2:16])CCC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[CH2:16])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CN(C)C=O
Product: C=C(OCC)c1nc(Cl)ncc1F
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dichloro-5-fluoro-pyrimidine (5.2 g, 31.14 mmol) in DMF (60 mL) was added tributyl-(1-ethoxy-vinyl)-stannane (12.37 g, 361.2 mmol), followed by dichlorobis(triphenylphosphine) palladium(II) (0.438 g, 0.623 mmol). The mixture was heated at 75° C. for 2 hours, cooled to rt and concentrated. The oily residue was dissolved in ethyl ether and a saturated solution of aqueous potassium fluoride was added and the mixture was stirred at room temperature for 18 hours. After dilution with EtOAc and filtration through Celite, the organic phase was washed with water, brine and concentrated. The crude material was purified by CombiFlash (0 to 10% EtOAc/Hex) to give desired product. LCMS-ESI+: calc'd for C8H9ClFN2O: 203.0 (M+H+); Found: 203.1 (M+H+); 1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J=2.8 Hz, 1H), 5.30 (d, J=3.1 Hz, 1H), 4.71 (d, J=3.1 Hz, 1H), 3.96 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[F:18][C:19]1[C:24](B(O)O)=[CH:23][C:22]([CH:28]=[CH2:29])=[CH:21][N:20]=1.C([O-])(=O)C.[K+].O>C(O)C.C(P([Pd](P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C)(Cl)Cl)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[F:18][C:19]1[C:24]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:23][C:22]([CH:28]=[CH2:29])=[CH:21][N:20]=1
Reactant: C=Cc1cnc(F)c(B(O)O)c1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C=Cc1cnc(F)c(-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (984 mg, 3.89 mmol), 2-fluoro-5-vinylpyridin-3-ylboronic acid (882 mg, 5.28 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphino)dichloropalladium (138 mg, 0.195 mmol), and potassium acetate (1.212 g, 12.35 mmol) were suspended in ethanol (12.0 mL) and water (2.4 mL) and the flask was fitted with a reflux condenser and nitrogen was bubbled through the suspension for about 15 seconds. Then, the flask was put in a preheated oil bath (80° C.) and stirred under nitrogen for 1 h. The reaction was cooled to room temperature, diluted with water (20 mL), and extracted with DCM. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (25:1 to 20:1 DCM/2 N ammonia in MeOH) to afford 6-(2-fluoro-5-vinylpyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine, which was taken on to the next step. MS (ESI pos. ion) m/z 340 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=2)[S:6]1(=[O:16])=[O:15]
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Reactant: OB(O)c1cccc(F)c1
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1cccc(F)c1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (400 mg) was coupled to m-fluorophenylboronic acid to provide 3-(3-chloropropyl)-1-(3-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (78 mg):
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28](O)=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)N2CCC(O)CC2)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 65.7 %

Procedure:
8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (130 mg, 0.29 mmol) was reacted with piperidin-4-ol (35.3 mg, 0.35 mmol) using a procedure similar to the one described in Example 2.00 to give 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-6-(4-hydroxypiperidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (101 mg, 65.5%) as a white solid. Mass Spectrum: M+H+ 530. NMR Spectrum: (DMSOd6) at 323° K: 1.24 (bs, 2H), 1.62 (d, 3H), 1.63 (bs, 2H), 2.99 (bs, 2H), 3.19 (bs partially hidden by H2O, 2H), 3.49-3.63 (m, 4H), 3.65-3.72 (m, 1H), 3.72-3.78 (m, 4H), 4.62 (d, 1H), 5.04-5.13 (m, 1H), 5.56 (s, 1H), 6.28 (d, 1H), 6.33 (dd, 1H), 6.64 (ddd, 1H), 6.82 (ddd, 1H), 7.57 (d, 1H), 7.77 (d, 1H).