Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)=[N:10][CH2:9][CH:8]2[OH:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCCl>[C:1]1([CH:7]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=3)=[N:10][CH2:9][CH:8]2[O:24][C:32](=[O:33])[NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: OC1CN=C(c2ccc(OC(F)(F)F)cc2)OC1c1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccc(OC(F)(F)F)cc2)OC1c1ccccc1
Temperature: 60 °C
Yield: 13.5 %

Procedure:
A mixture of (5RS, 6RS)-6-phenyl-2-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-4H-1,3-oxazin-5-ol (6 g) and phenyl isocyanate (2.4 g) in 1,2-dichloroethane (100 cc) is heated to a temperature in the region of 60° C. for 5 hours. After being cooled, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue obtained is purified by chromatography on silica (0.063-0.2 mm; 200 g) contained in a column 3.5 cm in diameter, eluting in 20-cc fractions with an ethyl acetate/cyclohexane mixture (30:70 by volume). Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in diisopropyl ether (5 cc). (5RS, 6SR)-6-Phenyl-5-phenylcarbamoyloxy-2-[4-(trifluoromethoxy)phenyl]-5,6-dihydro-4H-1,3-oxazine (1.1 g), m.p. 128° C., is thereby obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[OH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2.C(N(CC)CC)C>CC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Oc1cccc2cccnc12
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Oc2cccc3cccnc23)c([N+](=O)[O-])c1

Procedure:
D. Reinheimer, et al, disclose (J. Org. Chem., 1957, vol. 22, p. 1743) that 2,4-dinitrofluorobenzene reacts with 8-hydroxyquinoline in acetone, in the presence of triethylamine, to form 8-(2,4-dinitrophenoxy)quinoline.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:13]=[CH:14][CH:15]=2.[N:16]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][N:18]=[CH:17]1>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6]([NH:24][CH2:23][CH2:22][CH2:21][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[C:5]=3[CH:13]=[CH:14][CH:15]=2
Reactant: SC1=Nc2c(Cl)cc(Cl)c3cccc1c23
Reactant: NCCCn1ccnc1
Solvent: CN(C)C=O
Product: Clc1cc(Cl)c2cccc3c2c1N=C3NCCCn1ccnc1
Yield: 43.4 %

Procedure:
A mixture of 5.0 g of 6,8-dichloro-benz(cd) indole-2-thiol, 35 ml of dimethylformamide, 2.6 g of 3-(1H-imidazol-yl)propanamine and 6.3 g of mercuric acetate was reacted as described in Example 1, giving 2.95 g of the desired product, mp 182° C.-183° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([O:20][C:21]([N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28](O)[CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(N(CC)CC)C>[C:16]([O:20][C:21]([N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:29]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (9.6 ml) was added to a solution of 2-(tert-butyloxycarbonyl)-5-hydroxy-2,3-dihydro-1H-isoindole (12.2 g) and triethylamine (8.7 ml) at −20° C. under argon. The reaction was stirred overnight at room temperature, then the crude product isolated by extraction and chromatographed to give 2-(tert-butyloxycarbonyl)-5-trifluoromethanesulfonyloxy-2,3-dihydro-1H-isoindole (12.7 g), which was dissolved in DMF (180 ml). To this solution was added zinc cyanide (3.7 g) and tetrakis-triphenylphosphine palladium (0) (3.7 g) and the mixture was heated at 100° C. for 4 h. Work-up and chromatography on silica gel gave the title compound as a solid (7.6 g, 83%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](OC)=[CH2:4].[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([S:29][CH2:30][C:31]=1[CH3:32])[CH:27]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]2=[O:41])=[O:23])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH:8]([O:21][C:22]([C:24]1[N:25]2[CH:28]([S:29][CH2:30][C:31]=1[CH:32]=[C:3]([N:2]([CH3:7])[CH3:1])[CH3:4])[CH:27]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]2=[O:41])=[O:23])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Reactant: C=C(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1)N(C)C

Procedure:
1-Dimethylamino-1-methoxyethylene (218 g) is added dropwise, in the course of 55 minutes, to a solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (345 g) in anhydrous dimethylformamide (1,600 cc) at 80° C. This yields a solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylaminoprop-1-en-1-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene, which is poured into a stirred mixture of distilled water (2 liters), ice (2 kg) and ethyl acetate (2.5 liters). The organic phase is decanted, washed with distilled water (3×1 liter), dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 30° C. The residue is divided into 2 equal parts which are each chromatographed separately on a column of Merck silica gel (0.06-0.2) (1,500 g) (diameter of the column: 8.5 cm; height: 70 cm). Each column is eluted with a 23/77 (by volume) ethyl acetate/cyclohexane mixture (20 liters), 1 liter fractions being collected. Fractions 7 to 15 from each column are concentrated to dryness at 30° C. under reduced pressure (20 mm Hg; 2.7 kPa). This yields 3-acetonyl-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (149 g) in the form of a hard yellow foam.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH3:37]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[CH3:37])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(F)ccc1CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2ccc(F)cc2C)cc1

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-4-fluoro-2-methylbenzene in a manner similar to that described in Example 25 as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) d=7.65 (d, J=7.0 Hz, 1 H), 7.41 (d, J=7.0 Hz, 1 H), 7.37-7.30 (m, 2 H), 7.03 (dd, J=6.0, 8.3 Hz, 1 H), 6.96-6.83 (m, 3 H), 6.22 (d, J=3.5 Hz, 1 H), 5.58-5.49 (m, 2 H), 5.44-5.37 (m, 1 H), 2.76 (s, 3 H), 2.47 (s, 3 H), 2.32 (s, 3 H), 0.95 (s, 9 H); LCMS (m/z) ES+=475 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:8][C:7](=O)[C@@H:6]([CH3:10])[NH:5][C:4]1=O.B.C1COCC1.[ClH:18]>CO>[ClH:18].[CH3:10][C@@H:6]1[CH2:7][NH:8][C@@H:3]([CH2:2][OH:1])[CH2:4][NH:5]1
Reactant: C[C@H]1NC(=O)[C@H](CO)NC1=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN[C@@H](CO)CN1
Temperature: 70 °C

Procedure:
To (3S,6R)-3-hydroxymethyl-6-methyl-piperazine-2,5-dione (34 g, 0.215 mol) was added a solution of borane in THF (1 M, 1.6 L, 1.6 mol) and the mixture was heated to 70° C. for 18 h. The solution was cooled in ice, then MeOH (425 mL) was gradually added, followed by 5 M hydrochloric acid (113 mL). The mixture was heated to 70° C. for 2 h and then cooled to ambient temperature. The resulting solid was filtered, cake washed with THF (200 mL) and dried in vacuo at 40° C., to give the title compound (39.3 g) as a colourless solid. 1H NMR (DMSO-d6): 9.79 (3H, s), 5.59 (1H, s), 3.76-3.40 (5H, m), 3.19-2.94 (2H, m), 1.28 (3H, d).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH2:11][N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:23])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1.O>[Cl:23][C:4]1[CH:3]=[C:2]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[O:9][C:8]([CH2:11][N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(Br)c2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(-c3ccccc3)c2o1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a suspension of the 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (0.500 g, 1.28 mmol), dichlorobis(tro-o-tolylphosphine)palladium(II) (0.101 g, 0.128 mmol), and potassium carbonate (0.531 g, 3.84 mmol) in dioxane (20 mL) and water (1 mL) heated to 90° C. was added phenylboronic acid (0.390 g, 3.20 mmol) and the reaction allowed to stir for 1 h. The reaction was cooled to room temperature, filtered (celite), and the solvent removed in vacuo to provide a crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4) gave 0.422 g (85%) of 2-[(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white solid. mp 163-166° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[CH3:14][Si:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][OH:18]>C1COCC1>[CH3:14][Si:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][O:18][C:12](=[O:13])[NH:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C=Nc1cc([N+](=O)[O-])ccc1F
Reactant: C[Si](C)(C)CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOC(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 50 °C
Reaction time: 11 h
Yield: 75.8 %

Procedure:
To a solution of 1-Fluoro-2-isocyanato-4-nitro-benzene (9.82 g, 54 mmol) in THF (40 ml) at 23° C. under an atmosphere of argon was added 2-Trimethylsilanyl-ethanol (7.72 ml, 54 mmol). The resulting mixture was stirred for 11 hours then heated to 50° C. for 2 hours. The reaction mixture was allowed to cool to 23° C. quenched with saturated NaHCO3 (aq) and extracted with EtOAc (3×100 ml). The pooled ethyl acetate was washed with 1N HCl (aq) (2×90 ml) water (90 ml) and brine (90 ml), dried with Na2SO4, filtered and concentrated to a yellow solid. Silica gel chromatography (2:8 ethyl acetate-hexane) provided (2-Fluoro-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester (12.3 g, 77%). 1H NMR (300 MHz, CDCl3) δ 9.06 (dd, 1H, J=6.89 Hz, J=2.63 Hz), 7.89 (m, 1H), 7.20 (m, 1H), 6.91 (bs, 1H), 4.31 (t, 2H, J=8.67 Hz), 1.06 (t, 2H, J=8.67 Hz), 0.05 (s, 9H). LCMS (ESI−) [M+H]/z Calc'd 299. found 299.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[OH-].[Na+].[CH2:21](O)[CH3:22]>>[CH2:21]([O:12][C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:22]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Yield: 98 %

Procedure:
To a stirred solution of (4-nitro-phenyl)-acetic acid (3 g, 16.4 mmol) in ethanol (30 mL) was added sulphuric acid (1 mL) and the reaction mixture was heated to reflux for 16 hours. The reaction mixture was neutralized with 2N aq. NaOH solution and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a light yellow oil in 98% yield, 3.4 g.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[C:17]2[S:22][CH2:21][S:20][CH2:19][S:18]2)[CH2:15][CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:17]2[S:18][CH2:19][S:20][CH2:21][S:22]2)[CH2:15][CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=C1SCSCS1)c1ccc(Oc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(c1ccc(Oc2ccccc2)cc1)C1SCSCS1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
In 10 ml of anhydrous dichloromethane were dissolved 1.0 g of 2-{1-(4-phenoxyphenyl)propan-1-ylidene}-1,3,5-trithiane and 0.67 g of triethylsilane, and a solution prepared by diluting 1 ml of trifluoroacetic acid with 5 ml of dichloromethane was added dropwise at room temperature. The resulting solution was stirred overnight. After sodium carbonate powder was added, the resulting mixture was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation, and then the residue was purified by a silica gel column chromatography (chloroform:hexane=2:1) to give 0.91 g of the desired compound.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:6]=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:16][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: C=CCOC(=O)c1cccc(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CCOC(=O)c1cccc(CBr)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of allyl 6-(hydroxymethyl)pyridine-2-carboxylate (1.0 g, 5.17 mmol) in 20 mL of CH2Cl2 is cooled to 0° C. under argon and 3.43 g (10.3 mmol) of CBr4 is added. Then, 1.5 g (5.69 mmol) of triphenyl phosphine is added in several portions over 20 min. The reaction is allowed to stir at 0° C. for 3 h and is then concentrated in vacuo and applied to a short silica gel column. Elution with 1:1 EtOAc-hexane yields allyl 6-(bromomethyl)pyridine-2-carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[N:4][C:3]=1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([N:7]2[C:8]([CH3:12])([CH3:11])[CH2:9][O:10][C:29]2=[O:31])=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CO)Nc1nc(-c2ccc(C#N)cc2)c(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)c(Cl)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
4-{5-Chloro-2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (0.93 g, 3.0 mmol), prepared in the previous step, was dissolved in methylene chloride (25 mL), triethylamine (4.15 mL, 30 mmol) was added and the mixture was cooled to 0° C. Triphosgene (1.79 g, 6.0 mmol) was added and the mixture was stirred for 2 h. The mixture was then diluted with methylene chloride, washed with 2N HCl, saturated NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone/hexane) afforded the title compound (220 mg, 22%) as a pale yellow solid. HRMS: calcd for C15H12ClN3O2S+H+, 334.04115; found (ESI, [M+H]+), 334.04; HPLC purity 100% at 210-370 nm, 10.6 min; 100% at 244 nm, 10.6 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 mm.
Reaction SMILES: [CH3:1][N:2]([CH:18]([CH3:20])[CH3:19])[C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[K+]>CO.O>[CH3:1][N:2]([CH:18]([CH3:20])[CH3:19])[C:3]1[C:4](=[O:17])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N(C)C(C)C)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2[nH]c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (2.5 g, 9.08 mmol) in methanol (20 ml) was added potassium hydroxide (2.5 g, 44.56 mmol) in water (5 ml). The resulting solution was stirred overnight at 50° C. and then concentrated in vacuo. The reaction was quenched water (100 ml). The pH was adjusted to 5 with HCl (3N). The product was precipitated from water and collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-oxo-1,2-dihydroquinoxaline-6-carboxylic acid as a white solid (2.1 g, 88%).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:37][CH3:38])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:33][CH:32]([C:34]#[N:35])[CH2:31]3)=[O:29])=[C:24]([F:36])[CH:23]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]3[CH2:33][CH:32]([C:34]#[N:35])[CH2:31]3)=[O:29])=[C:24]([F:36])[CH:23]=2)[C:15]([O:37][CH3:38])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(C(=O)N2CC(C#N)C2)c(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1ccc(C(=O)N2CC(C#N)C2)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (11 mg, 0.057 mmol), 1-{[3′-(1-aminoethyl)-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-yl]carbonyl}azetidine-3-carbonitrile (21 mg, 0.052 mmol), and N,N-diisopropylethylamine (0.018 mL, 0.10 mmol) in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C26H24ClFN7O2 (M+H)+: m/z=520.2. found: 520.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:9])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH2:10](OC(OCC)OCC)C>>[Cl:8][C:7]1[C:2]2[N:1]=[CH:10][S:9][C:3]=2[N:4]=[CH:5][N:6]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1c(S)ncnc1Cl
Product: Clc1ncnc2scnc12
Temperature: 25 °C

Procedure:
5-Amino-6-chloropyrimidine-4-thiol (E-3) (14.0 g, 86.9 mmol) is dissolved in triethoxy methane (180 mL) and the resulting mixture is stirred at reflux for 3 h. The mixture is allowed to cool to RT and then concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (5-10% ethyl acetate-petro ether) to afford the product, 7-chlorothiazolo[5,4-d]pyrimidine (E-4).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:22])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: COc1nc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C(C)=O)cc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 77 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 46 to obtain the titled compound.
Reaction SMILES: [P:1](OC)(OC)[O:2][CH3:3].[CH3:8][CH:9]([OH:13])[CH:10]([OH:12])[CH3:11]>CO>[CH3:3][O:2][P:1]1[O:13][CH:9]([CH3:8])[CH:10]([CH3:11])[O:12]1
Reactant: COP(OC)OC
Reactant: CC(O)C(C)O
Solvent: CO
Product: COP1OC(C)C(C)O1
Temperature: 100 °C

Procedure:
A mixture of 300 g of trimethyl phosphite and 200 ml of 2,3-butanediol was heated to 100° C. and the methanol formed was distilled off to obtain 170 g of 2-methoxy-4,5-dimethyl-1,3,2-dioxaphospholane with a boiling point of 66° C. at 20 mm Hg, 37 g of the said product were added over two hours to 62.5 g of tert.-butyl bromoacetate heated to 115° C. under reduced pressure of 140 mm Hg and the volatile products were removed under reduced pressure to obtain 59 g of 2-tert.-butoxycarbonylmethyl-4,5-dimethyl-2-oxo-1,3,2-dioxaphospholane which slowly crystallized.
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:5](=[C:7]([C:11]#[N:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[Cl:13]C1SC2C=CC(F)=C(F)C=2N=1>>[Cl:13][C:2]1[S:3][C:4]2[C:5](=[C:7]([C:11]#[N:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: N#Cc1cccc2sc(N)nc12
Reactant: Fc1ccc2sc(Cl)nc2c1F
Product: N#Cc1cccc2sc(Cl)nc12

Procedure:
The title compound was prepared from 2-amino-1,3-benzothiazole-4-carbonitrile as described for 2-chloro-4,5-difluoro-1,3-benzothiazole.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=3)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O>N.CO>[CH2:7]1[C:8]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=3)=[CH:12][C:9]=2[CH2:10][CH2:11][NH:5][CH2:6]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)nc1
Agent: N
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Reaction time: 3 h
Yield: 96.3 %

Procedure:
Dissolve 6-[3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy]nicotinamide (0.306 g, 0.806 mmol) in 7.0 M NH3 in methanol (10 mL). Seal the round bottom and allow to sit without stirring. After three hours, concentrate to give the title compound (0.22 g, 100%): MS ES+ 284.1 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.2 min, 93% purity.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:17])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:26][C:27]1[C:32]([C:2]2[CH:3]=[C:4]([C:8]3([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]([NH2:17])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1cccnc1F
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)ccn1
Product: COc1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)c3ccccc32)ccn1
Yield: 23 %

Procedure:
The title compound was synthesized from 1-(3-bromophenyl)-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine (Example 118) as described in Example 67 Scheme #10, D in 23% yield using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.20-8.26 (m, 1 H), 7.97-8.09 (m, 2 H), 7.75-7.92 (m, 2 H), 7.37-7.58 (m, 7 H), 6.78-7.10 (m, 3 H), 6.67 (s, 1 H), 3.79 (s, 3 H); MS (ESI) m/z 411 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH3:9][C@@H:10]1[CH2:15][N:14]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:13][CH2:12][N:11]1[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([F:27])([F:26])[F:28])=[N:23][N:24]=2)[N:21]=1
Reactant: C[C@@H]1CNCCN1c1ccc2nnc(C(F)(F)F)n2n1
Reactant: O=Cc1cccnc1
Product: C[C@@H]1CN(Cc2cccnc2)CCN1c1ccc2nnc(C(F)(F)F)n2n1

Procedure:
A mixture of pyridine-3-carboxaldehyde and 6-[(2R)-2-methylpiperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[(2R)-2-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in quantitative yield.