Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([NH:9][C@@H:10]([CH2:32][CH2:33][S:34][CH3:35])[C:11]([NH:13][C@@:14]1([C:29]([OH:31])=[O:30])[CH2:19][C@@H:18]([S:20][C:21]2[NH:25][CH:24]=[N:23][N:22]=2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:26]([OH:28])=[O:27])=[O:12])=O)(C)(C)C.COC(C)(C)C>O1CCOCC1>[ClH:1].[NH2:9][C@@H:10]([CH2:32][CH2:33][S:34][CH3:35])[C:11]([NH:13][C@@:14]1([C:29]([OH:31])=[O:30])[CH2:19][C@@H:18]([S:20][C:21]2[NH:25][CH:24]=[N:23][N:22]=2)[C@@H:17]2[C@H:15]1[C@H:16]2[C:26]([OH:28])=[O:27])=[O:12]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@]1(C(=O)O)C[C@@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: Cl
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CSCC[C@H](N)C(=O)N[C@@]1(C(=O)O)C[C@@H](Sc2nnc[nH]2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 4M hydrogen chloride in 1,4-dioxane (19.35 mL, 77.38 mmol) dropwise to a solution of (1R,2S,4R,5R,6R)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methylsulfanyl-butanoyl]amino]-4-(4H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (2.66 g, 5.16 mmol) in 1,4-dioxane (26.6 mL) at room temperature in a water bath, and maintain stirring overnight at room temperature. Add methyl-t-butyl ether (200 mL) and stir the mixture for 2 hours. Filter the solid and dry in vacuo overnight. Redissolve the material in water and freeze-dry overnight. Triturate the solid in acetone (10 volumes) at reflux, filter and dry in vacuo under nitrogen for 48 hours to give the title compound (2.33 g, 5.16 mmol) as a white solid. MS (m/z): 416 (M+1).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([Si:24]([C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:43][C:40]1[CH:39]=[CH:38][C:37]([Si:24]([C:31]2[CH:32]=[CH:33][C:34]([C:13]3[CH:12]=[CH:11][CH2:10][C:8]45[CH:9]=[CH:1][CH:2]=[CH:3][C:4]4=[CH:5][O:6][C:7]=35)=[CH:35][CH:36]=2)([C:21]2[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:42][CH:41]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Brc1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc([Si](c2ccccc2)(c2ccccc2)c2ccc(C3=C4OC=C5C=CC=CC54CC=C3)cc2)cc1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of dibenzo[b,d]furan-4-ylboronic acid (2.60 g, 12.26 mmol), with bis(4-bromophenyl)diphenylsilane (12.12 g, 24.53 mmol), Pd(PPh3)4 (0.283 g, 0.245 mmol) and K2CO3 (5.08 g, 36.8 mmol) in toluene (200 mL) and water (50 mL) was refluxed under nitrogen overnight. After cooling to room temperature, the organic phase was isolated. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:DCM (9:1, v/v) as eluent to yield (4-bromophenyl)(4-(dibenzo[b,c]furan-4-yl)phenyl)diphenylsilane (3.14 g, 44%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:19]O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:17][N:19]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)on1
Yield: 73.5 %

Procedure:
A solution of crude ethyl 4-(3-chlorophenyl)-2,4-dioxobutanoate (max 294 g, 1.16 mol) and hydroxylamine hydrochloride (120.4 g, 1.73 mol) in ethanol (4 L) was heated at 80° C. for 4 h. After cooling (over night) to ca 5-10° C., the mixture was filtered, washed with cold ethanol and dried in vacuo to afford the title compound (214.5 g, 74%). 1H NMR: 7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H). MS (M++1)=252.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[O:18]1[CH2:22][CH2:21][NH:20]C1=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C)CCN>O1CCOCC1.[Cu](I)I>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:20][CH2:21][CH2:22][OH:18])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1NCCO1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: I[Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: OCCNc1cc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (150 mg), 2-oxazolidinone (103 mg), potassium phosphate tribasic (250 mg), copper iodide (7 mg), 4 μL of N,N-dimethylethylenediamine in 2 mL of 1,4-dioxane was heated to 100° C. for 15 hr. The reaction mixture was evaporated and the residue was diluted with ethyl acetate (50 mL), washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified on reverse phase HPLC to give 2-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-ylamino)ethanol as a by-product.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[C:5]([O:12][CH3:13])=[CH:4][N:3]=1.[CH3:14][O-:15].[Na+].CO>C(#N)C>[CH3:14][O:15][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[C:5]([O:12][CH3:13])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: COc1cnc(Cl)n2nc(N)nc12
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COc1cnc(OC)n2nc(N)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
5-Chloro-8-methoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (4; 100 mg, 0.50 mmol) was suspended in acetonitrile (5 mL) at room temperature and treated with 25% sodium methoxide in methanol (200 mg, 2 eq). The resulting slurry was stirred at room temperature for 1.5 hours and then filtered. The solids were washed with water and dried to afford the title compound as a chalk-colored solid (87 mg, 88%) that was identical in HPLC retention to authentic 5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (5): mp 185-186° C.; 1H NMR (DMSO-d6) δ 7.48 (s, 1H), 6.38 (br s, 2H), 4.04 (s, 3H), 3.88 (s, 3H); EIMS m/z 195.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:17](=O)([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Br:24])[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Cl[SiH](Cl)Cl>>[C:13]([C:9]1[CH:8]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Br:24])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[O:11][CH3:12])([CH3:14])([CH3:15])[CH3:16]
Reactant: COc1c(C(C)(C)C)cc(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2Br)cc1C(C)(C)C
Agent: Cl[SiH](Cl)Cl
Product: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2Br)cc1C(C)(C)C

Procedure:
For example, referring to the reaction sequence shown below, 2-bromophenol (4) is reacted with trifluoromethanesulfonic anhydride to form 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), which is then reacted with bis(3,5-di-t-butyl-4-methoxyphenyl)phosphine oxide in the presence of a palladium complex catalyst to obtain bis(3,5-di-t-butyl-4-methoxyphenyl)(2-bromophenyl)phosphine oxide (6). Next, the compound (6) is reduced with trichlorosilane in the presence of N,N′-dimethylaniline to obtain bis(3,5-di-t-butyl-4-methoxyphenyl)(2-bromophenyl)phosphine (7). The compound (7) is reacted with diethyl chlorophosphonite in the presence of n-butyllithium to obtain diethyl 2-[bis(3,5-di-t-butyl-4-methoxyphenyl)phosphino]phenylphosphonite (8). Then, the compound (8) is reduced with lithium aluminum hydride in the presence of trimethylsilyl chloride to form 2-[bis(3,5-di-t-butyl-4-methoxyphenyl)phosphino]phenylphosphine (9). Thereafter, in the presence of n-butyllithium, the compound (9) is reacted with dimesylate of (2R,5R)-2,5-hexanediol, which is producible, for example, according to the method described in the literature (Tetrahedron: Asymmetry, 1991, 2, 569), whereby the aimed (S,S)-Me-UCAP-DTBM (3) can be produced in a high efficiency.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:10]=[N:11][C:12]([C:15](=[O:35])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C@:24]3([CH:32]([F:34])[F:33])[C@@H:30]4[C@@H:28]([CH2:29]4)[O:27][C:26]([NH2:31])=[N:25]3)[CH:18]=2)=[N:13][CH:14]=1)C)(C)(C)C.[ClH:37].O>O1CCOCC1>[ClH:37].[ClH:37].[NH2:31][C:26]1[O:27][C@H:28]2[C@@H:30]([C@:24]([C:19]3[CH:18]=[C:17]([NH:16][C:15]([C:12]4[N:13]=[CH:14][C:9]([NH:7][CH3:6])=[CH:10][N:11]=4)=[O:35])[CH:22]=[CH:21][C:20]=3[F:23])([CH:32]([F:34])[F:33])[N:25]=1)[CH2:29]2
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(C(=O)Nc2ccc(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CNc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)nc1
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of tert-butyl(2-((3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)carbamoyl)pyrimidin-5-yl)(methyl)carbamate (0.06 g, 0.11 mmol) in 1,4-dioxane (2 mL) was treated with HCl (4.0M in 1,4-dioxane; 1 mL). The resulting suspension was treated with water (0.1 mL) resulting in a pale-yellow biphasic solution. The solution was stirred for 2 h, concentrated, and lyophilized from 1,4-dioxane to give N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(methylamino)pyrimidine-2-carboxamide dihydrochloride (0.05 g, 0.105 mmol, 93% yield) as a pale-yellow solid.
Reaction SMILES: [NH4+].[OH-].[CH3:3][CH:4]1[CH2:6][C:5]1([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[C:7]([NH2:9])=[O:8]>O1CCCC1.[Zn]>[CH3:3][CH:4]1[CH2:6][C:5]1([C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)[C:7]([NH2:9])=[O:8]
Reactant: CC1CC1(C(N)=O)c1ccc([N+](=O)[O-])cc1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1CC1(C(N)=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 289.3 %

Procedure:
To a suspension of 3.56 g (54.49 mmol) of zinc powder in 15 mL of concentrated aqueous 33% NH4OH solution are added 1.2 g (5.45 mmol) of the product prepared in step 9.1 dissolved in 15 mL of tetrahydrofuran. The mixture is stirred for 1 hour at room temperature, the zinc is then separated out by filtration and the mixture is extracted with ether. The organic phases are combined, dried over Na2SO4, filtered and concentrated under vacuum. The oily residue is purified by chromatography on a column of silica, eluting with a cyclohexane/ethyl acetate gradient (70/30 to 60/40). 3 g of the expected product are obtained in the form of a yellow oil. Quantitative yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[N:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:27]([C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:17]=[CH:18][CH:19]=[CH:20]3)=[O:28])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: NCc1ccc(NCc2ccccc2)cc1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(NCc2ccccc2)cc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
The resulting (4-aminomethyl-phenyl)-benzylamine (162 mg, 0.763 mmol), quinoline-6-carboxylic acid (132 mg, 0.736 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (506 mg, 1.14 mmol) and triethylamine (319 μl, 2.29 mmol) were dissolved in N,N-dimethylformamide (4.0 mL), and the solution was stirred for 2 hours at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (224 mg, 0.610 mmol, 80%) was obtained as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:8](=[O:16])[NH:7][C:6]1=[O:17].Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[C:25]1([CH2:29][CH2:28][NH:27][CH2:26]1)[CH2:24][CH2:23]2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>O.CN1C(=O)CCC1>[ClH:1].[Cl:19][C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[C:25]1([CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[CH:10]=[C:9]([C:11]4[S:12][CH:13]=[CH:14][CH:15]=4)[C:8](=[O:16])[NH:7][C:6]3=[O:17])[CH2:26]1)[CH2:24][CH2:23]2
Reactant: Clc1ccc2c(c1)CCC21CCNC1
Reactant: O=c1[nH]c(=O)n(CCCCl)cc1-c1cccs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c(=O)n(CCCN2CCC3(CCc4cc(Cl)ccc43)C2)cc1-c1cccs1
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A mixture of 1-(3-chloropropyl)-5-(thiophen-2-yl)pyrimidine-2,4(1H,3H)-dione (Prep24, 50 mg, 0.18 mmol), 5-chloro-2,3-dihydrospiro[indene-1,3′-pyrrolidine]hydrochloride salt (Prep10, 66 mg, 0.27 mmol), potassium carbonate (112 mg, 0.81 mmol), sodium iodide (112 mg, 0.75 mmol) and NMP (1 ml) was stirred at 70° C. overnight. Then it was cooled down to room temperature and diluted with water and extracted with ethyl acetate. The EA phase was evaporated and the crude purified by preparative TLC (TLC analysis performed by eluting with EA/MeOH 10:1) to give the free base of the title compound (70 mg). The compound was purified by preparative HPLC and treated with a 1N solution of HCl-ether to give the title compound (9 mg, y=10%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(O[N:38]1N=N[C:40]2[CH:41]=[CH:42]C=C[C:39]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CCC>CN(C=O)C.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCCCN
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)c1cccc(N2CCc3nc(N)ncc3C2)c1
Temperature: 50 °C
Reaction time: 16.5 h
Yield: 86 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (41 mg, 0.15 mmol), N,N-diisopropylethylamine (0.105 mL, 0.60 mmol), and HBTU (63 mg, 0.165 mmol) in 1.5 mL DMF was briefly warmed to approx. 50° C. to dissolve solids, then continued stirring at room temperature. After 10 minutes n-butylamine (0.022 mL, 0.225 mmol) was added and the reaction continued at room temperature for 16.5 hours. The reaction was added drop wise to a stirring mixture of 30 mL water containing 5 mL brine at room temperature, and the resulting precipitate filtered and rinsed with water. The damp solid was dissolved in 20% MeOH in CHCl3 and evaporated to a dry solid. The solid was triturated with an EtOAc/hexane mixture to give the title compound as a light beige solid (42 mg, 86%). 1H NMR (acetone-d6) δ: 8.13 (s, 1H), 7.62 (br. s., 1H), 7.53-7.55 (m, 1H), 7.26-7.30 (m, 2H), 7.13-7.20 (m, 1H), 5.74 (br. s., 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 3.38 (td, J=7.1, 5.7 Hz, 2H), 2.81 (t, J=6.0 Hz, 2H), 1.52-1.63 (m, 2H), 1.32-1.45 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4]([CH3:14])[N:3]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH3:14][C:4]1[N:3]=[C:2]([N:11]2[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)[C:7]2[O:8][CH:9]([CH3:13])[C:10](=[O:12])[N:11]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])[C:6]=2[N:5]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)C(C)O2
Product: CCOC(=O)C(C)N1C(=O)C(C)Oc2c(N3CCOCC3)nc(C)nc21
Yield: 42 %

Procedure:
Starting from 4-chloro-2,6-dimethyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one (Khim. Geterotsikl. Soed. 1972, 1285) and ethyl 2-bromopropionate, Example 32 is followed. After refluxing for 12 hours and evaporating, the residue [the most part of which is 4-chloro-2,6-dimethyl-(1-ethoxycarbonyl-1-ethyl)-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one] is reacted with morpholine and worked up as described in Example 1, except that the evaporation residue is triturated with ether, filtered, the filtrate is evaporated and the residue is recrystallized from n-hexane to give the product in a yield of 42%, m.p.: 80°-82° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[SH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(O)c1ccc(S)nc1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccc(C(=O)O)cn2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 6-mercaptonicotinic acid using the procedure described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.49 (s, 3H) 7.30 (s, 1H) 7.50 (t, J=7.58 Hz, 1H) 7.72-7.82 (m, 1H) 7.99 (t, J=9.09 Hz, 2H) 8.11 (dd, J=8.34, 1.77 Hz, 1H) 8.17 (s, 1H) 8.88 (d, J=1.52 Hz, 1H); ESI-MS: m/z calc'd for C19H14N4O3S 378.08. found 379.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([CH2:17][CH2:18][OH:19])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][CH2:6]1)=[O:4].CS(C)=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([CH2:17][CH:18]=[O:19])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)C(=O)N1CCC(CCO)(c2ccccc2)OC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)N1CCC(CC=O)(c2ccccc2)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a 0° C. solution of the above 2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethanol, dimethyl sulfoxide (10 mL, 141 mmol) and diisopropylethylamine (10.5 mL, 60 mmol) in 60 mL CH2Cl2 was added SO3.pyr (9.0 g, 57 mmol) in one portion. The reaction mixture was stirred at 0° C. for 2 h, quenched with saturated aqueous NaHCO3, extracted with CHCl3, dried (Na2SO4) and chromatographed (2:1 Hex:EtOAc) to provide [3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (2.84 g, 98%) as an oil. 1H NMR (400 MHz, CDCl3): δ 9.64 (t, 1H, J=2.7 Hz), 7.45-7.41 (m, 4H), 7.33 (m, 1H), 5.49 (dd, 1H, J=11.1, 1.9 Hz), 4.74 (d, 1H, J=11.5 Hz), 4.27 (m, 1H), 3.08 (m, 1H), 2.72 (ABqd, 2H, J=15.3, 2.8 Hz), 2.43 (ddd, 1H, J=14.2, 4.1, 3.0 Hz), 2.11 (ddd, 1H, J=14.2; 11.4, 4.3 Hz), 1.28 (s, 9H). ESI-MS 312 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[N:6][CH:7]=1.[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(=O)([O-])[O-].[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH3:15])=[N:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: Brc1ccc(I)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccccc1-c1ccc(Br)cn1
Yield: 84 %

Procedure:
To an argon-purged and evacuated slurry of 910 mg (3.21 mmol) of 5-bromo-2-iodopyridine and 436 mg (3.21 mmol, 1.0 eq.) of 2-o-tolylboronic acid in 8 mL of toluene and 3.2 mL of 2 M aqueous sodium carbonate, was added 36 mg (0.032 mmol, 0.01 eq) of tetrakis(triphenylphosphine) palladium. The reaction mixture was purged and evacuated with argon twice more and then set to reflux under argon for 15 h. The reaction was cooled and partitioned between water and EtOAc. The layers were separated, and the aqueous layer extracted once more with EtOAc. The organic extracts were combined, dried over magnesium sulfate, filtered, concentrated and dried in vacuo to give the crude product as an orange oil. Purification by silica gel chromatography (7:3 CH2Cl2/hexanes) provided the title compound as a yellow oil, 666 mg, 84% yield.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([NH:36][C:37](OC2C=CC=CC=2)=[O:38])[C:23](=[CH:34][CH:35]=1)[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:15]([NH:18][C:37]([NH:36][C:22]2[CH:21]=[C:20]([Cl:19])[CH:35]=[CH:34][C:23]=2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:38])(=[O:16])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cc(S(N)(=O)=O)ccc1O
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)ccc1O
Yield: 93.1 %

Procedure:
320 mg (1.17 mmol) of 3-t-butoxycarbonyl-4-hydroxybenzenesulfonamide and 447 mg (1.17 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 17 to obtain 611 mg (yield 93%) of benzyl 2-{[(3-t-butoxycarbonyl-4-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, CDCl3): 1.62 (9H, s), 5.35 (2H, s), 7.01–7.05 (2H, m), 7.37–7.41 (5H, m), 7.96 (1H, d), 8.10 (1H, dd), 8.46–8.48 (2H, m), 10.99 (1H, s), 11.66 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9]Br.[C:11]([O-:14])(=[O:13])[CH3:12].[K+].CN(C=O)C>O>[C:11]([O:14][CH2:9][C:3]1[C:4]([Br:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:13])[CH3:12]
Reactant: BrCc1c(Br)cccc1Br
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.7 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 1,3-dibromo-2-(bromomethyl)benzene (3.28 g, 10.0 mmol), potassium acetate (3.93 g, 40.0 mmol) and DMF (100 mL). The solution was stirred at room temperature for 14 h. After that time, the reaction mixture was diluted with water (900 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford an 88% yield (2.70 g) of 2,6-dibromobenzyl acetate 104g as an off-white solid: mp 62-65° C.; 1H NMR (300 MHz, CDCl3) d 7.57 (d, 2H, J=8.0 Hz), 7.07 (t, 1H, J=7.9 Hz), 5.42 (s, 2H), 2.11 (s, 3H); MS (ESI+)