Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[N:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:15]=[N:14][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[N:18][CH:17]=1
Reactant: NC(N)=S
Reactant: COc1cnc(Oc2cc(C)c(C(=O)CBr)c(C)c2)nc1
Solvent: CCO
Product: COc1cnc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)nc1
Yield: 83.2 %

Procedure:
A mixture of 2-bromo-1-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (8-3, 0.51 g, 1.5 mmol) and thiourea (0.13 g, 1.6 mmol) in 95% EtOH (10.0 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (8-4, 0.41 g) as yellow solids in 86% yield: 1H NMR (500 MHz, DMSO-d) 9.00 (s, 2 H), 8.41 (s, 2 H), 6.99 (s, 2 H), 6.88 (s, 1 H), 3.87 (s, 3 H), 2.17 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[N:11]2[C:12](=[O:20])[C:13](=[O:19])[NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:9]([C:10]=32)[CH2:8][CH2:7]1)=[O:4].[N+:21]([O-])([O:23]C(C)C)=[O:22]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]([CH2:5][CH:6]1[N:11]2[C:12](=[O:20])[C:13](=[O:19])[NH:14][C:15]3[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=[C:9]([C:10]=32)[CH2:8][CH2:7]1)=[O:4]
Reactant: CC(C)O[N+](=O)[O-]
Reactant: COC(=O)CC1CCc2cccc3[nH]c(=O)c(=O)n1c23
Agent: O=S(=O)(O)O
Product: COC(=O)CC1CCc2cc([N+](=O)[O-])cc3[nH]c(=O)c(=O)n1c23
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 43.1 %

Procedure:
To a solution of 5-methoxycarbonylmethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (66 mg, 0.24 mmol) in concentrated sulfuric acid (1.5 mL) was added isopropyl nitrate (30 μL, 0.3 mmol) at 0° C. The mixture was stirred for 45 min at 0° C., poured into ice-water, and extracted with ethyl acetate (100 mL×2). The extracts were washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 0.1% acetic acid/ethyl acetate to give 33 mg of the title compound (43%): mp 254°~256° C.; 1H NMR (270 MHz, DMSO-d6) δ12.23 (bs, 1H), 7.91 (d, 1H, J=2.6 Hz), 7.85 (d, 1H, J=2.6 Hz), 5.05~5.21 (m, 1H), 3.64 (s, 3H), 2.85~3.10 (m, 2H), 2.56~2.72 (m, 2H), 2.17 (dm, 1H, J=13.5 Hz), 1.80~2.00 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[C:30]([CH:35]3[CH2:37][CH2:36]3)=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]1([C:30]2[C:29]([C:25]3[CH:24]=[C:23]([C:21]4[CH2:20][C:19](=[O:38])[NH:18][C:9]5[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=5[N:7]=4)[CH:28]=[CH:27][CH:26]=3)=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2C2CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3C3CC3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M200) (223 mg, 0.413 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (107 mg, 61%).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]([NH2:22])=[O:21])=[CH:19][C:14]=2[CH2:13][O:12]1)[Si](C(C)(C)C)(C)C.OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1>>[OH:1][CH2:9][CH2:10][CH:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]([NH2:22])=[O:21])=[CH:19][C:14]=2[CH2:13][O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1OCc2cc(C(N)=O)ccc21
Agent: NC(=O)c1ccc2c(c1)CCO[C@H]2CCO
Product: NC(=O)c1ccc2c(c1)COC2CCO

Procedure:
Prepared from 1-[2-(tert-butyldimethylsilanoxy)-ethyl]-1,3-dihydro-2-benzofuran-5-carboxamide, as described for the preparation of (1S)-1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[CH:34]([C:37]([C:39]1[CH:52]=[CH:51][C:42]2[O:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[O:46][C:41]=2[CH:40]=1)=[O:38])([CH3:36])[CH3:35]>O1CCCC1>[F:50][C:44]1([F:49])[O:43][C:42]2[CH:51]=[CH:52][C:39]([C:37]([C:34]([Br:1])([CH3:36])[CH3:35])=[O:38])=[CH:40][C:41]=2[O:46][C:45]1([F:48])[F:47]
Reactant: CC(C)C(=O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)c1ccc2c(c1)OC(F)(F)C(F)(F)O2
Yield: 171 %

Procedure:
1.89 g of phenyltrimethylammonium tribromide was added to a mixture comprising 1.40 g of 2,2,3,3-tetrafluoro-1,4-benzodioxan-6-yl isopropyl ketone and 19.7 ml of tetrahydrofuran, followed by a reaction for two hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.78 g of oily α-bromoisopropyl 2,2,3,3-tetrafluoro-1,4-benzodioxan-6-yl ketone.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH2:18][CH:17]([C:19]([O:21]C)=[O:20])[CH2:16]3)[CH:9]=2)[N:3]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16]3)[CH:9]=2)[N:3]=1
Reactant: COC(=O)C1CN(c2cc(-n3nc(C)nc3C)nc(C)n2)C1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(N2CC(C(=O)O)C2)cc(-n2nc(C)nc2C)n1
Reaction time: 1 h

Procedure:
Compound 107-1 (429 mg, 1.42 mmol) was dissolved in THF (10 mL) and treated with potassium trimethylsilanolate (273 mg, 2.13 mmol). After stirring for 1 h, the mixture was concentrated in vacuo to provide 107-2 that was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6](=[N:7]N)[C:5](=[N:9][OH:10])[C:4]([CH3:12])([CH3:11])[O:3]1.Cl.N[OH:16]>O>[CH3:1][C:2]1([CH3:13])[C:6](=[N:7][OH:16])[C:5](=[N:9][OH:10])[C:4]([CH3:12])([CH3:11])[O:3]1
Reactant: NO
Reactant: CC1(C)OC(C)(C)C(=NO)C1=NN
Agent: Cl
Solvent: O
Product: CC1(C)OC(C)(C)C(=NO)C1=NO
Yield: 86 %

Procedure:
10.0 g (54 mmol) of commercially available 2,2,5,5-tetramethyl-3,4-(2H, 5H)-furandione hydrazone oxime are heated under reflux for 2 hours with 75 g (1.1 mmol) of hydroxylamine hydrochloride in 800 ml of water. The precipitated product is filtered off with suction and washed with water. 8 g (86%) of 2,2,5,5-tetramethyl-3,4(2H, 5H)-furandione dioxime are obtained as a mixture of 2 isomers, m.p. 252° C.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[C:25]1([C:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[C:25]1([C:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Yield: 26.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.5 g), triethylamine (3.4 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (3.9 g) in toluene (150 cc). The mixture is heated for 9 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (10 cc), 2-[2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (2.5 g) is obtained, m.p. 106° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=O)[N:8]2[C@@H:3]1[CH2:4]C[C:6](Cl)=[C:7]2C(O)=O.C[Si]([I:19])(C)C.C[Si](N[Si](C)(C)C)(C)C.C1N2CCN(CC2)C1>C(#N)C>[CH2:3]1[N:8]2[CH2:9][CH2:2][N:1]([CH2:6][CH2:7]2)[CH2:4]1.[IH:19]
Reactant: C[Si](C)(C)I
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CC[C@H]12
Agent: C1CN2CCN1CC2
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 2-carboxylic acid (8c), as produced in Example 13a, was converted to the carbacephem (9a) through reaction with trimethylsilyl iodide (TMSI). Specifically, the carboxylic acid (8c) (0.726 g, 2 mM), was combined with 5 ml acetonitrile (ACN), HMDS (1.06 ml, 5 mM), and TMSI (0.72 ml, 5 mM), and the mixture was stirred for 4 hours at room temperature. DABCO (0.56 g, 5 mM) in 5 ml ACN was added and the solution stirred overnight at room temperature, yielding a DABCO-HI precipitate. Both reactions appeared normal and the DABCO reaction (elimination) gave an HPLC ratio of product to starting material of 39.1/12.0 for a conversion of about 77%. 5 ml of 1N HCl was added and the mixture stirred for 30 min. at room temperature. The pH was at 3.55. The DABCO-HI precipitate dissolved and the desired carbacephem product (9a) appeared as a precipitate. The product was filtered and washed successively with 10 ml of ACN/H2O (2/1), 5 ml of H2O, and 5 ml of ACN. Vacuum drying at 50° C. yielded 0.275 g of a nearly white solid. Yield was about 63.5%. NMR was excellent in DMSO (d-6) with trifluoroacetic acid (TFA) to dissolve. NMR (DMSO d-6, TFA): δ1.95 (m, 2), 2.67 (m, 2), 3.94 (m, 1), 4.83 (d, 1), 8.87 (bs, 5).
Reaction SMILES: C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.C([Li])CCC.CCCCCC.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28].[Cl-].[NH4+]>O1CCCC1>[F:15]/[C:9](=[CH:34]\[C:33]1[CH:36]=[CH:37][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=1)/[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)/C(F)=C/c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
A solution of ethyl diethylphosphono-2-fluoroacetate (4.90 g, 20.2 mmol) in tetrahydrofuran (40 mL) was stirred under a nitrogen atmosphere at 0° C. and 1.6 M n-butyllithium/hexane solution (13.1 mL, 21.0 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min, and a solution of 4-nitrobenzaldehyde (3.05 g, 20.2 mmol) in tetrahydrofuran (40 mL) was added dropwise. The mixture was stirred at room temperature for 16 hr, and ice-cooled aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3%-40% ethyl acetate/hexane) to give the title compound (3.46 g, yield 72%) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cc1ccc(CO)c(C)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(C)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,4-dimethylphenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C18H16N4O, 305. Found, 305.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12].[H-].[Na+].I[CH3:16]>CN(C=O)C>[Br:1][C:2]1[N:6]([CH3:16])[CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12]
Reactant: CI
Reactant: CCOC(=O)c1c[nH]c(Br)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c(Br)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of ethyl 4-methyl-3-pyrrolecarboxylate (1.57 g, 10 mmol) in anhyd THF (30 mL) cooled to −78° C. was added NBS (1.9 g, 10 mmol). After stirring 1 h at −30° C., the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography, eluting with EtOAc-Hex (0:100 to 30:70), to yield ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (2.0, 86%) as a white solid. 1H-NMR (CDCl3): δ 8.54 (1H, brs), 7.38 (1H, d), 4.27 (2H, q), 2.24 (3H, s), 1.33 (3H, t). To a solution of ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (2.0 g, 8.6 mmol) in anhyd DMF (30 mL) at 0° C. was added portionwise NaH (60% in mineral oil, 705 mg, 17.6 mmol) under nitrogen. After 1 h at ambient temperature, the reaction mixture was charged with iodomethane (1.5 mL, 24 mmol) and then stirred at ambient temperature overnight. The reaction mixture was quenched by cautious addition of water and then extracted with DCM. The combined extracts were washed with water, dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography, eluting with EtOAc-Hex (0:100 to 20:80), to provide the title compound (1.64 g, 78%) as a white solid. 1H-NMR (CDCl3): δ 7.33 (1H, s), 4.25 (2H, q), 3.58 (3H, s), 2.24 (3H, s), 1.33 (3H, t).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:19]=1.[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1OB(O)O>O.CO.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:19]=1
Reactant: Cc1ccccc1
Reactant: N#Cc1ccc(Cc2nc3cc(Br)ccc3s2)cc1
Agent: Cl[Pd]Cl
Agent: Cc1ccccc1OB(O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1ccccc1-c1ccc2sc(Cc3ccc(C#N)cc3)nc2c1

Procedure:
Under a nitrogen atmosphere 1.3 g (3.95 mmol) of 4-[(5-bromobenzothiazol-2-yl)-methyl]-benzonitrile and 1.3 g (1.1 mmol) of bis(triphenylphosphine)-palladium(II)-chloride are stirred into 40 ml toluene for 15 minutes at 40° C. Then 1.3 g (12.3 mmol) of sodium carbonate in 5.6 ml water and 0.84 g (6.1 mmol) of o-tolylboric acid in 5 ml methanol are added. The reaction mixture is refluxed for 10 hours. After cooling the reaction solution is diluted with ethyl acetate and extracted with water. The combined organic extracts are washed with sodium chloride solution and dried. The residue is chromatographed on silica gel and eluted with ethyl acetate/petroleum ether 5:95, 10:95 and 15:85. The desired fractions are combined and concentrated by evaporation.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>C(O)C.O>[O:9]=[C:8]([CH3:10])[CH:7]([C:6]([O:12][CH2:13][CH3:14])=[O:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CCCCCN1C(=O)c2ccccc2C1=O)C(C)=O
Reaction time: 8 h

Procedure:
A solution of sodium ethoxide in ethanol, prepared by dissolving 23.69 g (1.03 moles) of sodium in 800 ml of absolute alcohol, was treated slowly with ethyl acetoacetate. To this solution was added, in one portion, 308 g (1.04 moles) of N-(5-bromopentyl)phthalimide and the resulting mixture was refluxed for two hours and stirred overnight at 25°. The ethanol was stripped, 1500 ml of water was added to the residue, and the resulting mixture was extracted with 3×400 ml of ether. The ether layers were combined, dried over anhydrous sodium sulfate, filtered and stripped to give 350 g of light brown oil. This material was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(Cl)c(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,4,5-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (51.0 mg) with purity >90%. MS (pos) m/z 429.0. 431.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1>>[CH:16]1([N:13]2[CH2:12][CH2:11][CH:10]([O:9][C:2]3[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=3)[CH2:15][CH2:14]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCN(C2CCCC2)CC1
Reactant: Clc1ncc(Br)cn1
Product: Brc1cnc(OC2CCN(C3CCCC3)CC2)nc1

Procedure:
According to the same reaction process as in Example 1-1) but using 2-chloro-5-bromopyrimidine and 4-hydroxy-1-cyclopentylpiperidine, the entitled compound was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]([NH2:13])=[CH:11][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.9 %

Procedure:
Chloroacetyl chloride (0.68 mL, 8.58 mmol) was added dropwise to a stirred solution of 4-fluoro-N2-phenylbenzene-1,2-diamine (1.24 g, 6.13 mmol) and pyridine (2.0 mL, 24.5 mmol) in DCM (8 mL) at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 20 min, the mixture was slowly warmed to RT and stirring at RT was continued for 2 h. The mixture was partitioned between DCM and aqueous HCl (1M, 50 mL) cooled at 0° C. and the aqueous phase was further extracted with DCM (×3). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in cyclohexane) to afford the title compound as a white crystalline solid (750 mg, 44%). LCMS (Method C): RT 3.42 min [M+H]+ 279.2.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]([CH3:18])([CH3:17])[CH2:11][C:12]([O:14]CC)=[O:13])=O.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]=[C:7]2[NH:9][C:10]([CH3:17])([CH3:18])[CH2:11][C:12](=[O:13])[O:14]2)[CH2:27][CH2:26]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCOC(=O)CC(C)(C)NC(=O)NCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)OC(=NCCCCN2CCN(c3ncccn3)CC2)N1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 3-[(4-bromobutyl)aminocarbonylamino]-3-methylbutanoate (3.21 g), 1-(2-pyrimidinyl)piperazine (1.64 g), potassium carbonate (1.38 g) and dimethylformamide (50 ml) is heated at 100° C. for 3 hours, left overnight at room temperature, filtered, and evaporated to dryness. The residue is chromatographed on silica gel using a mixture of ethyl acetate-ethanol (90:10) as the eluent to yield 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butylimino]-tetrahydro-4,4-dimethyl-6H-1,3-oxazine-6-one, m.p. 124°-6° C. when crystallized from aqueous methanol (Rf 0.3) and 1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]tetrahydro-6,6-dimethylpyrimidine-2,4-dione, as an oil (Rf 0.2).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][C@H:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:21]([O:23][CH3:24])=[O:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.O1CCOCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH2:19][C@H:20]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:21]([O:23][CH3:24])=[O:22])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
0.4 g of palladium on carbon at 10% is added to a solution of 4 g (9.2 mmol) of methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-morpholin-4-ylpropanoate (prepared as described in example 7.3) in 200 ml of methanol and 20 ml of dioxane degassed beforehand with nitrogen. The reaction mixture is stirred for one hour at ambient temperature under atmospheric hydrogen pressure. After filtration through celite and concentration of the filtrate under vacuum, the residue obtained is purified by chromatography on silica gel, elution being carried out with a 60/40 ethyl acetate/heptane mixture. 2.6 g (81%) of methyl(S)-3-(4-hydroxybenzenesulfonylamino)-2-morpholin-4-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:6](=[O:22])[NH:7][C:8](=[O:21])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:10]=1)#[N:4].[Cl:23][C:24]([Cl:28])([Cl:27])[S:25]Cl>O.ClCCl>[C:3]([C:5]1[C:6](=[O:22])[N:7]([S:25][C:24]([Cl:28])([Cl:27])[Cl:23])[C:8](=[O:21])[N:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[CH:10]=1)#[N:4]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: N#Cc1cn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#Cc1cn(-c2ccc(C(F)(F)F)cc2)c(=O)n(SC(Cl)(Cl)Cl)c1=O
Reaction time: 2 h

Procedure:
To 290 mg of NaOH in 15 ml of water, cooled in an ice bath, is added 1.0 g (3.56 mol) of 5-cyano-1-(4-trifluoromethylphenyl)uracil. Then 15 ml of dichloromethane is added, followed by 0.725 ml of trichloromethanesulfenyl chloride in 1.5 ml of dichloromethane. The mixture is stirred for approximately 2 hr at 5°. Then dichloromethane and ice cold water are added and the layers separated. The organic phase is washed with ice cold water, dried over MgSO4 and evaporated. The product is taken up with ether, filtered and washed again with ether to yield 5-cyano-3-trichloromethanesulfenyl-1-(4-trifluoromethylphenyl)uracil, m.p. 167°-168.5°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1[N:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[C:10]([C:18]([NH:52][CH2:51][C:48]3[CH:49]=[N:50][C:45]([CH3:44])=[CH:46][CH:47]=3)=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Reactant: Cc1ccc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (40 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (53 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (21 mg, 0.14 mmol), and CH2Cl2 (3 mL) were added (6-methylpyridin-3-yl)methanamine (25 mg, 0.21 mmol), and N,N-diisopropylethylamine (48 μL, 0.28 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water[10 mM Et2NH]) to afford a white solid.