Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[C:29]([Cl:30])=[CH:28][CH:27]=[C:26]([NH:31][C:32]3[C:35](=[O:36])[C:34](=[O:37])[C:33]=3[NH:38][C@@H:39]([C@H:42]3[CH2:46][CH2:45][C@@H:44]([CH3:47])[O:43]3)[CH2:40][CH3:41])[C:25]=2[OH:48])(=[O:23])=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:30][C:29]1[CH:28]=[CH:27][C:26]([NH:31][C:32]2[C:35](=[O:36])[C:34](=[O:37])[C:33]=2[NH:38][C@@H:39]([C@H:42]2[CH2:46][CH2:45][C@@H:44]([CH3:47])[O:43]2)[CH2:40][CH3:41])=[C:25]([OH:48])[C:24]=1[S:21]([N:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)(=[O:22])=[O:23]
Reactant: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2O)c(=O)c1=O)[C@H]1CC[C@@H](C)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N3CCNCC3)c2O)c(=O)c1=O)[C@H]1CC[C@@H](C)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.4 ml of TFA are added dropwise to an ice-cooled solution of 54 mg of 4-(6-chloro-2-hydroxy-3-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydrofuran-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzene sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (Ex. 17) in 1 ml of dry DCM under an inert atmosphere of nitrogen. After stirring at rt for 4 hours, a reaction mixture obtained is diluted with 25 ml DCM and 25 ml NaHCO3(aq) are added. An organic portion is separated and washed with 3×NaHCO3(aq), dried over MgSO4 and solvent is evaporated. The title compound is obtained. MH+ 513.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH2:12][C:13]2[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=2)=[N:6][CH:5]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)[C:7]([O:11][CH2:12][C:13]2[N:14]([CH3:18])[CH:15]=[CH:16][N:17]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(OCc2nccn2C)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(OCc2nccn2C)c(-c2ccc(Cl)cc2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
5-Bromo-6-(1-methyl-1H-imidazol-2-ylmethoxy)-nicotinic acid methyl ester (0.35 g, 1.1 mmol) was dissolved in toluene (6 mL). To this solution was added (4-chloro-phenyl)-boronic acid (0.17 g, 1.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloro-methane complex (43 mg), and 2 N sodium carbonate solution (2 mL). The whole mixture was heated with stirring at 90° C. for 18 h, cooled to room temperature and eluted with ethyl acetate over 10 g ChemElut (Varian). The solvent was evaporated and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 0.29 g of the title compound as an off-white solid, MS (ISP) 358.1 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+]>>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1
Reactant: Nc1cccc(I)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CNc1cccc(I)c1
Yield: 150.5 %

Procedure:
3-Iodoaniline (40.0 g), methyl chloroacetate (37.12 g) and sodium bicarbonate (30.75 g) were treated according to the method of Intermediate 5 to give an oil (ca. 80 g), a sample of which (1.2 g) was purified by FCC eluting with System A (7:3) to give the title compound (0.8 g) as a solid, m.p. 83°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][NH:32][C:31]4=[O:35])=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: NCCN1CCNC1=O
Product: Cn1c(=O)c(C(=O)NCCN2CCNC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 97.5 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.028 mmol) described in example 92 and 1-(2-aminoethyl)-2-imidazolidinone (47 mg, 0.364 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-N-[2-(2-oxo-1-imidazolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide (12 mg, 98% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.33 (br s, 1 H), 8.54 (s, 1 H), 7.37 (s, 1 H), 7.16-7.13 (m, 2 H), 7.03-6.99 (m, 2 H), 4.38 (s, 1 H), 4.12 (s, 2 H), 3.62 (m, 2 H), 3.56-3.53 (m, 5 H), 3.45-3.39 (m, 4 H); HRMS m/z calcd for C22H23N5O4F: 440.1734 Found: 440.1732.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:11]2[CH:16]=[C:15]([Cl:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:11]3[CH:16]=[C:15]([Cl:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2cc(Cl)sc2n1
Product: Cc1nccn1-c1nc(NCc2ccc3c(c2)OCCO3)c2cc(Cl)sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,6-dichloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-chloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[O:3]1.C(=O)([O-])[O-].[K+].[K+].F[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[O:5]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccccc2Oc2ccc([N+](=O)[O-])cc2)OC1(C)C
Reaction time: 18 h

Procedure:
To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.00 g, 9.09 mmol) in DMF was added Potassium carbonate (2.51 g, 18.2 mmol) and 1-fluoro-4-nitrobenzene (0.964 ml, 9.09 mmol). The reaction was flushed with nitrogen, sealed, and heated to 120 deg.C. After 18 h, water was added and the mixture extracted twice with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purify by silica gel chromatography, eluting with 0-15% EtOAc/hexanes to give 4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane as a white solid. MS m/z=342 [M+1]+. Calc'd for C18H20BNO5: 341.17.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[NH2:8][C:9]1[C:18]2[C:13](=[C:14](F)[C:15]([N:19]3[C:27]4[CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][C:23](=[O:30])[C:22]=4[C:21]([CH3:31])=[CH:20]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1>CN(C=O)C>[NH2:8][C:9]1[C:18]2[C:13](=[C:14]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:15]([N:19]3[C:27]4[CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][C:23](=[O:30])[C:22]=4[C:21]([CH3:31])=[CH:20]3)=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: Cc1cn(-c2ccc3c(N)ncnc3c2F)c2c1C(=O)CC(C)(C)C2
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1c(-n2cc(C)c3c2CC(C)(C)CC3=O)ccc2c(N)ncnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
In a small microwave vial with a stir bar, 2-methoxyethanol (19.3 mg, 0.253 mmol) is dissolved in DMF (1 mL). To this solution is added sodium hydride (60% suspension in mineral oil, 10.13 mg, 0.2532 mmol) and the mixture is stirred at room temperature for 5 minutes and 1-(4-Amino-8-fluoro-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (42.8 mg, 0.126 mmol) is added. The reaction is sealed and placed in the microwave reactor where it is heated to 150° C. for 30 minutes. The reaction is cooled, quenched by adding 5 mL sat. NH4Cl (aq) and extracted with CH2Cl2 (3×1 mL). The combined organics are purified by silica gel chromatography by two gradient runs on the same column, the first 0% to 100% ethyl acetate in hexanes and the second 0% to 50% methanol in ethyl acetate. This gives the desired 1-[4-Amino-8-(2-methoxy-ethoxy)-quinazolin-7-yl]-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one as a tan powder (40 mg, 80% yield) (LC/MS m/z=395 [M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[O:19][CH2:20][CH2:21][F:22])[CH:3]=1.CN.[C:25]([BH3-])#[N:26].[Na+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(=O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:26][CH3:25])[C:12]=2[O:19][CH2:20][CH2:21][F:22])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCCF
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1OCCF
Yield: 43 %

Procedure:
4-Chloro-2-[2-(2-fluoroethoxy)-3-formylphenoxy]benzonitrile (0.35 g, 1.1 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 16 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.12 g, 1.0 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration and dried to give 4-chloro-2-[2-(2-fluoroethoxy)-3-(methylaminomethyl)phenoxy]benzonitrile fumarate (194 mg, 40%) as a beige solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:22]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:35])=[C:31]([NH2:34])[CH:32]=2)[C:27]([CH3:37])([CH3:36])[CH2:26]1)(=[O:24])[CH3:23]>>[C:22]([N:25]1[C:33]2=[CH:32][C:31]3[NH:34][C:3]([C:2]([F:7])([F:6])[F:1])=[N:35][C:30]=3[CH:29]=[C:28]2[C:27]([CH3:37])([CH3:36])[CH2:26]1)(=[O:24])[CH3:23]
Reactant: CC(=O)N1CC(C)(C)c2cc(N)c(N)cc21
Reactant: O=C(O)C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC(=O)N1CC(C)(C)c2cc3nc(C(F)(F)F)[nH]c3cc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
A mixture of 60 g. polyphosphoric acid, 1.6 ml. trifluoroacetic acid, 18 g. phosphorus pentoxide and 4.0 g. (18 mmole) 1-acetyl-5,6-diamino-3,3-dimethylindoline (Example 2b) is stirred for 7 hours at 150°-160° C. The reaction mixture is allowed to cool to 90° C., poured on to ice, left to stand overnight and filtered to give 1.7 g. (31%) of the title compound; m.p. 290°-291° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][C:8](=[O:10])[CH2:7][C:6](=[O:11])[CH2:5]1)[CH2:2][CH3:3].[Br:12]Br>CC(O)=O>[Br:12][CH:7]1[C:6](=[O:11])[CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][C:8]1=[O:10]
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCC1CC(=O)C(Br)C(=O)C1

Procedure:
To a stirred solution of 5-propylcyclohexane-1,3-dione (1.54 g, 10 mmol) in AcOH (20 mL) at r.t. was added bromine (1.6 g, 0.51 mL, 1 mmol) dropwise. The reaction was carried out according to Method A to give the title compound in quantitative yield as a light brown solid, which was used without further purification. LCMS (ES+) 232.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:37])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:16][C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)=[N:10][S:9]2(=[O:36])=[O:35])[CH:5]=[CH:6][CH:7]=1.[N:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C@@H:17]([NH:16][C:11]1[O:12][C:13]([CH3:14])([CH3:15])[C:8]([CH3:37])([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:42]3[CH:43]=[N:38][CH:39]=[N:40][CH:41]=3)[CH:3]=2)[S:9](=[O:36])(=[O:35])[N:10]=1)[CH2:18][CH2:19][OH:20]
Reactant: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2F)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(N[C@@H](CCO)c2ccccc2F)=NS(=O)(=O)C1(C)c1cccc(-c2cncnc2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 34.5 %

Procedure:
Under inert gas, 45 mg of [5-(3-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-2-yl]-[(S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propyl]amine, 11 mg of pyrimidine-5-boronic acid and 96 mg of cesium carbonate were dissolved in a mixture of 1 ml of dioxane and 0.4 ml of water. After purging with argon for 10 minutes, 6 mg of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium were added and the reaction mixture was stirred at 80° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with water. The organic phase was dried using a diatomaceous earth cartridge (Varian Chem Elut®) and concentrated by rotary evaporation. To detach the protecting group, the residue was dissolved in 1.5 ml of methanol, 0.18 ml of concentrated hydrochloric acid was added and the mixture was stirred at room temperature for 2.5 hours. After the removal of the solvent under reduced pressure, the crude product was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was basified with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated by rotary evaporation, and the residue was taken up again in a mixture of acetonitrile and water and lyophilized. This gave the product (12.6 mg) with a molecular weight of 498.6 g/mol (C25H27N4O4S); MS (ESI): m/e=499 (M+H+).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([C:14]1([CH2:20][OH:21])[CH2:18][O:17][C:16](=[O:19])[NH:15]1)[CH3:13].Cl>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:12]([C:14]1([CH2:20][O:21][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH2:18][O:17][C:16](=[O:19])[NH:15]1)[CH3:13]
Reactant: CCC1(CO)COC(=O)N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC(=O)N1
Temperature: 0 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
Tosyl chloride (142.2 g, Aldrich) was added to an ice-chilled solution of the product from step (a) (102.7 g) dissolved in pyridine (175 ml. Aldrich). The reaction mixture was stirred at ice bath temperature for six hours, then allowed to come to room temperature. The heterogeneous mixture was added to 1500 ml of a solution of brine and 1N HCl. stirred until solids appeared, filtered and washed with diethyl ether to give 194.6 g of a beige solid as the title product. 1H NMR consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][C@@H:15](C)[CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].[NH2:33][C@@H](C)CO>>[NH2:33][C:16]([CH2:15][NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Br:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)=[O:17]
Reactant: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: C[C@H](N)CO
Product: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 2 of the synthesis of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamide by substituting glycineamide HCl for (S)-(+)-2-amino-1-propanol. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.95 (m, 1H), 7.80 (s, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.58 (m, 2H), 4.01 (s, 2H), 2.20 (s, 3H). ESHRMS m/z 507.0474 (M+H calculated for C21H18BrF2N4O4 requires 507.0474).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1([CH2:19][CH3:20])[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7][CH2:6][O:5]1)=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][CH3:18].[SnH](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH2:19]([C:4]1([CH2:3][CH3:2])[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[CH2:7][CH2:6][O:5]1)=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][CH3:18])[CH3:20]
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCCl)OCC3
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC)OCC3
Temperature: 110 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a stirred solution of compound 4 (103 mg, 0.35 mmol), AlBN (11 mg, 0.07 mmol, 0.2 eq), and toluene (3 mL) at room temperature under argon, HSnBu3 (380 μL, 1.41 mmol, 4.0 eq) was added in a dropwise manner. The resulting mixture was stirred overnight at 110° C. and concentrated. The residue was diluted with hexane and extracted three times with acetonitrile. The acetonitrile layers were combined, concentrated, and purified by column chromatography using 3:97:EtOAc:Hexane to give an off-white solid (56 mg, 62%): mp 133–134° C. 1HNMR (CDCl3, δ TMS): 0.88 (t, 6H), 1.37 (t, 3H), 1.87 (q, 4H), 2.78 (t, 2H), 2.86 (q, 2H), 4.02 (t, 2H), 7.01–7.38 (m, 3H, Ar—H), 7.46 (br, 1H, NH). MS−: m/z 256 ([M−H]−). Anal. (C17H23NO): C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13](=[O:15])[CH3:14])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.[CH2:21](O)[CH2:22][OH:23]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3([CH3:14])[O:23][CH2:22][CH2:21][O:15]3)[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1
Reactant: OCCO
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=Cc2cc(Br)ccc2N(CC2(C)OCCO2)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of methyl 7-bromo-1-(2-oxopropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.29 g), ethylene glycol (2.3 g) and p-toluenesulfonic acid monohydrate (36 mg) in toluene (10 ml) was heated to reflux for 3 days while removing water. After cooled to room temperature, an aqueous solution of sodium hydrogen carbonate was added to alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4) to give methyl 7-bromo-1-[(2-methyl-1,3-dioxolan-2-yl)methyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (992 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[OH:15].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]2[O:15][CH:12]2[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine (18.9 g) in dichloromethane (400 ml) was added in turn sodium hydrogen carbonate (11.3 g) and m-chloroperoxybenzoic acid (23.4 g) with care at 0° C., and which was stirred for 2 hours. Insoluble material was removed by filtration, mother liquor was washed saturated sodium chloride in water (100 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was dissolved in n-hexane (300 ml) and insoluble material was removed by filtration. Mother liquor was concentrated in vacuo, the remainings were dissolved in ethyl acetate (300 ml) and washed in turn with saturated sodium hydrogen carbonate in water (100 ml×5) and saturated sodium chloride in water (100 ml×2), which was dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (350 ml) eluting in turn with 10%, 20% and 30% ethyl acetate in n-hexane. Fractions, containing desired product, were collected and concentrated in vacuo to give 1-tert-butoxycarbonyl-3,4-epoxypiperidine (13.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].O.C(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C=O
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cccc(F)c1
Yield: 48.1 %

Procedure:
To a cooled (ice bath) solution of 11.2 g (0.1 mole) of 3-fluorophenol (98%, Aldrich) in 75 ml of toluene was added 9.1 ml (14.8 g, 0.105 mol) of chlorosulfonyl isocyanate, and the solution heated at reflux overnight. The solution was cooled and cautiously treated dropwise with water until carbon dioxide evolution ceased. An oil separated and ethyl acetate was added to dissolve this oil. The layers were separated and the organic layer was washed with water, dried (sodium sulfate) and concentrated to give an oil which gradually crystallized. The solid was purified by column chromatography on 400 g of silica gel eluted with methylene chloride. The appropriate fractions were combined and concentrated to yield 9.2 g (48%) of the title compound which was recrystallized from benzene to give a white solid, mp 53°-55° C.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[O:7][CH3:8].[NH2:9][C:10]1[C:15]2[CH:16]=[C:17](Br)[S:18][C:14]=2[C:13]([C:20]([NH2:22])=[O:21])=[CH:12][N:11]=1>>[NH2:9][C:10]1[C:15]2[CH:16]=[C:17]([C:2]3[CH:6]=[CH:5][S:4][C:3]=3[O:7][CH3:8])[S:18][C:14]=2[C:13]([C:20]([NH2:22])=[O:21])=[CH:12][N:11]=1
Reactant: COc1sccc1Br
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Product: COc1sccc1-c1cc2c(N)ncc(C(N)=O)c2s1

Procedure:
92 was prepared from 3-bromo-2-methoxythiophene 91 (Zhang, Y.; Hornfeldt, A.-B.; Gronowitz, S.; Stalhandske, C. Acta Chemica Scand. 1994, 48, 843-849) and 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide in a similar manner to that described for Example 14. 1H NMR (400 MHz, d6-DMSO) δ: 4.10 (s, 3H), 7.13 (d, J6.0 Hz, 1H), 7.28 (d, J6.0 Hz, 1H), 7.69-7.78 (br s, 1H), 8.19 (s, 1H), 8.20-8.30 (br s, 1H), 8.40 (s, 1H), 8.60-8.80 (br s, 2H). MS (EI) m/z (M+H+) 306, (2M+H+) 611.