Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([CH:44]([CH3:46])[CH3:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7].ClC1C=C(C=CC=1)C(OO)=[O:53]>C(Cl)Cl>[C:34]([C:33]1[CH:38]=[CH:39][C:30]([C:17]2[C:18]([CH3:29])([CH3:28])[C@H:19]3[C@:14]([CH3:40])([CH2:15][CH:16]=2)[C@@H:13]2[C@:22]([CH3:27])([C@@:23]4([CH3:26])[C@H:10]([CH2:11][CH2:12]2)[C@H:9]2[C@H:41]([CH:44]([CH3:46])[CH3:45])[CH2:42][CH2:43][C@:8]2([C:6]([NH:5][CH2:4][CH2:3][N+:2]([O-:53])([CH3:1])[CH3:47])=[O:7])[CH2:25][CH2:24]4)[CH2:21][CH2:20]3)=[CH:31][CH:32]=1)([OH:36])=[O:35]
Reactant: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)NCCN(C)C)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@]2(C(=O)NCC[N+](C)(C)[O-])CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 3 h
Yield: 49.9 %

Procedure:
To a mixture of methyl 4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.031 mmol) in DCM (2 mL) was added 3-chlorobenzoperoxoic acid (13.90 mg, 0.062 mmol) at −78° C. The reaction mixture was stirred for 3 hours. LCMS indicated the formation of desired product and consumption of the starting material. The reaction mixture was quenched with distilled water, extracted with DCM (3×2 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as an yellow oil (10 mg, 49%). LCMS: m/e 661.49 (M+H)+, 2.79 min (method 1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2([O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](I)[CH3:22].Cl>O.CN(C)C=O>[CH2:21]([N:13]1[CH2:12][C:11]2([CH2:17][CH2:18][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[O:15][C:14]1=[O:16])[CH3:22]
Reactant: CCI
Reactant: O=C1NCC2(CCN(Cc3ccccc3)CC2)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CC2(CCN(Cc3ccccc3)CC2)OC1=O

Procedure:
A mixture of 16.5 g 8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, 6.6 g, 50% suspension of sodium hydride in mineral oil, 15 g ethyl iodide and 70 ml N,N-dimethylformamide is heated at 90° for one hour. The mixture is poured into 150 ml water and the resulting mixture acidified with 10 N hydrochloric acid. The mixture is extracted with two 100 ml portions of hexane. The aqueous layer is basified with sodium hydroxide and extracted with three 75 ml portions of dichloromethane. Removal of solvent in vacuum affords a residue which when crystallized from heptane gives 3-ethyl-8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 105°-106°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])[CH2:9][C:10]1[N:14]2[CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21](Cl)=[CH:20][C:19]=3[C:13]2=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[H][H]>[Pd].CO>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])[CH2:9][C:10]1[N:14]2[CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:13]2=[N:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)Cc1nnc2n1CCOc1ccc(Cl)cc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)ccc1F)Cc1nnc2n1CCOc1ccccc1-2

Procedure:
A mixture of 20 mg (0.0407 mmol) of tert-butyl[(1R)-2-(10-chloro-5,6-dihydro[1,2,4]triazolo[4,3-d][1,4]benzoxazepin-3-yl)-1-(2,5-difluorobenzyl)ethyl]carbamate, 0.007 mL (5.1 mg, 0.05 mmol) of triethylamine, 9.3 mg of 10% palladium on carbon, and 0.5 mL of methanol was shaken with hydrogen (45 psig) for 3 h. The catalyst was removed by filtration, and the filtrate was concentrated to yield the title compound. LC-MS 457 (M+1).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH3:21])=[C:10]([CH2:12][O:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([OH:20])[CH2:15]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].C(O)(=O)C>CO>[C:1]1([C:7]2[O:8][C:9]([CH3:21])=[C:10]([CH2:12][O:13][C@H:14]3[CH2:19][CH2:18][CH2:17][C@@H:16]([OH:20])[CH2:15]3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1CO[C@@H]1CCC[C@H](O)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)nc1CO[C@H]1CCC[C@@H](O)C1
Reaction time: 3 h
Yield: 87.5 %

Procedure:
0.96 g of the (1R,3S)-acetyl compound from Example 20 was dissolved in approx. 5–10 ml of MeOH, admixed with 0.1 ml of NaOMe (30%) and stirred at 20–23° C. After 3 h, the mixture was neutralized with acetic acid and concentrated under reduced pressure, taken up with ethyl acetate, washed with saturated NaHCO3, dried (MgSO4) and concentrated under reduced pressure. After filtration through silica gel (10:1–0:1 n-heptane/ethyl acetate), 0.84 g of the desired (1R,3S)-3-[2-phenyl-5-methyloxazol-4-ylmethoxy]cyclohexan-1-ol having 95% ee (HPLC on Chiralpak AD 250×4.6; 1 ml/min, 25:1:0.5 heptane/EtOH/CH3CN+0.1% TFA) was obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH:10]=2)O1.C([O-])([O-])=O.[K+].[K+].[NH2:23][C:24]1[CH:25]=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:27]=[C:28](Br)[CH:29]=1>CN(C=O)C.CCOC(C)=O>[CH3:15][N:12]1[CH2:13][CH2:14][C:9]([C:28]2[CH:27]=[C:26]([C:31]([F:32])([F:34])[F:33])[CH:25]=[C:24]([NH2:23])[CH:29]=2)=[CH:10][CH2:11]1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CC=C(c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 80 °C

Procedure:
To a mixture of 4,4,5,5-tetramethyl-2-(1-methyl(4-1,2,5,6-tetrahydropyridyl))-1,3,2-dioxaborolane (1.0 g, 4.4 mmol), PdCl2pddf (0.16 g, 0.2 mmol) and K2CO3 (1.8 g, 13.2 mmol) and 3-amino-5-bromobenzotrifluoride (0.8 g, 3.3 mmol) in DMF (25 mL) was heated at 80° C. for 16 h. The resulting mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, and concentrated. The residue was purified by SiO2 chromatography to give the title intermediate. MS (ES+): 257 (M+H)+. Calc'd C13H15F3N2—256.3.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])=[C:11]([Cl:13])[CH:12]=1)C.[OH-].[Na+]>C1COCC1.O>[Cl:13][C:11]1[CH:12]=[C:7]([CH2:6][CH2:5][C:4]([OH:19])=[O:3])[CH:8]=[N:9][C:10]=1[C:14]([C:17]#[N:18])([CH3:16])[CH3:15]
Reactant: CCOC(=O)CCc1cnc(C(C)(C)C#N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ncc(CCC(=O)O)cc1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-[5-chloro-6-(cyano-dimethyl-methyl)-pyridin-3-yl]-propionic acid ethyl ester (0.68 g, 2.43 mmol) from step 4 above, in 1:1 THF/H2O (4 mL) was added 2 N NaOH (2.43 mL). The resulting solution was stirred at 60° C. for 1 hour. Solvents were removed and residue was partitioned between ethyl acetate and 10% citric acid and extracted. The organic phase was washed with brine (50 mL), dried over Na2SO4 and evaporated. The residue solidified to a white solid and was used without further purification. (0.39 g, 64%) as a white solid. ESIMS (MH−): 251.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH3:23]N(C)C=O.CI>O>[CH3:23][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CCC(=O)N(C)c1cccc(-c2ccc3nncn3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 3.58 g of N-[3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]propanamide, 0.71 g of sodium hydride (50% in oil) and 200 ml of dimethylformamide was stirred under argon, for 1 hour. A 0.92 ml portion of methyl iodide was added and the mixture was stirred overnight. A 0.355 g portion of sodium hydride (50% in oil) and 0.46 ml of methyl iodide were added and stirring was continued overnight. The mixture was poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was crystallized from ethyl acetate-hexane, giving 1.60 g of the desired product as light orange crystals, mp 146°-150° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][CH3:10])[N:4]=[CH:3]1.[C:11]([O:19]CC)(=O)[CH2:12][C:13]([O:15]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>>[OH:19][C:11]1[C:12]2[C:13](=[O:15])[N:9]([CH3:10])[CH:5]=[N:4][C:3]=2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=1
Reactant: CNc1cc(=O)n(C)cn1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CN1CCCC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1cnc2c(c(O)cc(=O)n2C)c1=O
Reaction time: 0.5 h

Procedure:
3-Methyl-6-(methylamino)pyrimidin-4(3H)-one (compound 1B; 400 mg, 2.88 mmol, 1 eq), diethyl malonate (873 μl, 5.76 mmol, 2 eq) and phenyl ether (915 μl, 5.76 mmol, 2 eq) were dissolved in 1-methyl-2-pyrrolidinone (2 ml, 20 mmol). The mixture was placed in a microwave reactor at 240° C. for 30 minutes to yield 5-hydroxy-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (compound 1C). The product was confirmed by LC-MS and isolated by HPLC to give 125 mg (21%) of compound 1C. [M+H] calc'd for C9H9N3O3, 208. found, 208.
Reaction SMILES: [CH2:1]([C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:11][O:12][CH3:13])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>>[CH2:14]([C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:9][O:10][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH2:11][O:12][CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COCC(CO)(Cc1ccccc1)Cc1ccccc1
Reactant: C[Si](C)(C)Cl
Product: COCC(CO[Si](C)(C)C)(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the procedure as described in Example 1,2,2-dibenzyl-1-methoxy-3-[(trimethylsilyl)oxy]propane was prepared from intermediate 2,2-dibenzyl-3-methoxy-1-propanol and reagent trimethylsilyl chloride.
Reaction SMILES: CSC.B.[F:5][C:6]1([F:25])[C:11](=O)[NH:10][CH2:9][C:8]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[O:7]1>C1COCC1>[F:25][C:6]1([F:5])[CH2:11][NH:10][CH2:9][C:8]2([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:16][CH2:17]2)[O:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C(F)(F)O2
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Temperature: 55 °C

Procedure:
Borane methyl sulfide complex (2M in THF, 2.69 mL) was added dropwise to a solution of tert-butyl 2,2-difluoro-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 37, step b) (0.55 g) in THF (15 mL). The reaction mixture was heated at 55° C. under nitrogen for 25 minutes and then cooled to room temperature. The mixture was quenched by careful dropwise addition of methanol (5 mL). N1,N2-dimethylethane-1,2-diamine (0.633 g) was then added and the mixture heated at 70° C. for 40 minutes. The solvents were removed under reduced pressure and the residue was purified by flash silica chromatography using 4% methanol in dichloromethane with 1% triethylamine as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.32 g. Used directly.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4]([OH:11])[N:3]=1.NC1N=C(N)C(N)=[C:15]([OH:21])N=1>C(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH:9][CH:15]=[O:21])=[C:4]([OH:11])[N:3]=1
Reactant: Nc1nc(N)c(N=O)c(O)n1
Reactant: Nc1nc(N)c(N)c(O)n1
Solvent: O=CO
Product: Nc1nc(N)c(NC=O)c(O)n1

Procedure:
The invention relates to an improved process for the catalytic hydrogenation of 2,4-diamino-6-hydroxy-5-nitrosopyrimidine (DAHNP) and the reaction of the resulting 2,4,5-triamino-6-hydroxy-pyrimidine (TAHP) with formic acid to yield 2,4-diamino-5-formylamino-6-hydroxy-pyrimidine (DAFHP).
Reaction SMILES: [F:1][C:2]1[C:12]([SH:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1C(=O)N(Cl)C(=O)C1.[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([CH:27]=[CH:28][N:29]2[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([C:27]([S:13][C:12]3[C:2]([F:1])=[C:3]([CH:9]=[CH:10][CH:11]=3)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:28][N:29]2[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cccc(S)c1F
Reactant: Fc1c(Cl)ccc2ccn(-c3cccnc3)c12
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)c1cccc(Sc2cn(-c3cccnc3)c3c(F)c(Cl)ccc23)c1F
Reaction time: 1 h
Yield: 13.9 %

Procedure:
To a stirred solution of Intermediate A (243 mg, 1.21 mmol) in 1,2-dichloroethane (8 mL) under inert atmosphere was added NCS (163 mg, 1.21 mmol) at RT and stirred for 1 h. To this, compound 2 (200 mg, 0.81 mmol) in 1,2-dichloroethane (2 mL) and NaHCO3 (204 mg, 2.45 mmol) were added at RT. After 24 h stirring at RT, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel; 10% EtOAc/Hexanes) to afford compound 3 (50 mg, 9%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.70 (d, J=5.0 Hz, 1H), 8.30 (s, 1H), 8.18-8.15 (m, 1H), 7.66-7.762 (m, 2H), 7.36-7.34 (m, 2H), 7.17-7.13 (m, 2H), 4.34 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O.OP([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1ccnc(Cl)c1[N+](=O)[O-]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccnc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 40 h
Yield: 67.4 %

Procedure:
A mixture of 2-chloro-4-methyl-3-nitropyridine (28; 1.08 g, 6.24 mmol), 2,4-dichlorophenyl boronic acid (1.26 g, 6.62 mmol), (Ph3P)4Pd(0) (0.405 g, 0.350 mmol), 40 mL of DMF, and 20 mL of a 2 M aqueous K2HPO4 solution was stirred at 70° C. for 40 h. The mixture was partitioned between 200 mL of diethyl ether and 200 mL of water. The organic layer was sequentially washed with 200 mL of water and 200 mL of a saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated to a yellow oil mixed with white solid. Column chromatography (0→20% EtOAc/hexanes) afforded slightly impure 2-(2,4-dichloro-phenyl)4-methyl-3-nitro-pyridine (29; 1.19 g; 68%) as a yellow oil that was used without further purification.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:9][N:10]([CH3:32])[CH:11]1[C:25]2=[CH:26][CH:22]([O:23][C:24]2=[O:27])[CH:21]2[CH:17]([O:18][C:19](=[O:29])[CH:20]2[CH3:28])[CH2:16][C:15]2([CH3:30])[CH:13]([O:14]2)[CH:12]1[OH:31].N1C=CN=C1.O>CN(C=O)C>[O:31]([CH:12]1[CH:11]([N:10]([CH3:9])[CH3:32])[C:25]2=[CH:26][CH:22]([O:23][C:24]2=[O:27])[CH:21]2[CH:17]([O:18][C:19](=[O:29])[CH:20]2[CH3:28])[CH2:16][C:15]2([CH3:30])[CH:13]1[O:14]2)[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CC1C(=O)OC2CC3(C)OC3C(O)C(N(C)C)C3=CC(OC3=O)C21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC1C(=O)OC2CC3(C)OC3C(O[Si](C)(C)C(C)(C)C)C(N(C)C)C3=CC(OC3=O)C21
Reaction time: 20 h
Yield: 55.4 %

Procedure:
Terbutyldimethylsilyl chloride (80 μmol, 12 mg) is added to a solution of the compound of Example 5 (80 μmol; 27 mg) and imidazole (160 μmol; 11 mg) in DMF (0.5 ml). The solution obtained is stirred for 20 hours then the reaction mass is poured into water. The aqueous phase is extracted twice with ethyl acetate, the organic phase is washed with water then with a solution of sodium chloride. The organic phase is dried over magnesium sulphate, filtered then evaporated. The residue is eluted on silica with a mixture of isopropyl acetate and dichloromethane (20/80). 20 mg of product is obtained in the form of a white powder.
Reaction SMILES: [Cl-].[CH3:2][C:3]1([CH3:16])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH2:11][CH2:12][NH2+:13][CH2:14][CH:15]=2)[O:4]1.C(N(C(C)C)C(C)C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([N:13]1[CH2:12][CH:11]=[C:10]([B:5]2[O:4][C:3]([CH3:16])([CH3:2])[C:7]([CH3:8])([CH3:9])[O:6]2)[CH2:15][CH2:14]1)(=[O:29])=[O:28]
Reactant: CC1(C)OB(C2=CC[NH2+]CC2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a cooled (0° C.) solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride (8 g) and N-ethyldiisopropylamine (12 mL) in dichloromethane (100 mL) is added dropwise methanesulfonyl chloride (3 mL). The mixture is stirred for 12 hours at room temperature. The mixture is partitioned between dichloromethane and 0.1 M hydrochloric acid. The organic phase is separated, washed with brine and dried (MgSO4). The solvent is evaporated and the residue is crystallized from diethylether to give the title compound. Yield: 7.4 g; LC (method 15): tR=0.98 min; Mass spectrum (ESI+): m/z=288 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8](=[S:11])[NH:9][NH2:10])=O)C.[NH3:12]>C(O)C>[C:4]([CH2:6][NH:7][C:8](=[S:11])[NH:9][NH2:10])(=[O:3])[NH2:12]
Reactant: CCOC(=O)CNC(=S)NN
Reactant: N
Solvent: CCO
Product: NNC(=S)NCC(N)=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
4-Ethoxycarbonylmethyl-thiosemicarbazide (8.33 g) (GANTE and LANTSCH, Chem. Ber., 97, 989 (1964)) are suspended in a saturated solution (250 cc) of ammonia in ethanol, and the reaction mixture is stirred at 25° C. for 22 hours. The insoluble matter is filtered off and washed with alcohol (2×25 cc) and ether (2×50 cc); after drying, 4-carbamylmethyl-thiosemicarbazide (6.2 g), m.p.=188° C., is obtained.
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:21]3)[N:17]=[C:16]([NH2:33])[N:15]=2)=[CH:9][CH:8]=1)C>O1CCCC1.O.[K]>[NH2:33][C:16]1[N:15]=[C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:41])([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:4]([OH:42])=[O:3])=[CH:8][CH:9]=2)[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:21]2)[N:17]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCN(Cc4ccccc4)CC3)nc(N)n2)cc1)Oc1ccccc1
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1ccc(Oc2cc(N3CCN(Cc4ccccc4)CC3)nc(N)n2)cc1)(Oc1ccccc1)C(=O)O
Reaction time: 20 h

Procedure:
3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionic acid ethyl ester was dissolved in tetrahydrofuran (THF)/alcohol solvent in the presence of an excess of aqueous potassium hydrate, the reaction is allowed to proceed for about 20 h. After most of the solve was removed in vacuo, the aqueous solution was acidified to pH 6, the white product was precipitated, then filtered through celite, rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-methyl-2-phenoxy-propionic acid (11 g, 95%) was collected.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=1)(=[O:4])=[O:3].[OH-].[K+]>C(O)C.O>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)Cc1ccc(CNS(C)(=O)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)NCc1ccc(CC(=O)O)cc1

Procedure:
A solution of ethyl 4-[[(methylsulphonyl)amino]methyl]benzeneacetate (3.1 g) and 1M KOH (22 ml) in ethanol (50 ml) was stirred at room temperature for 3 h and evaporated in vacuo to leave an off-white solid. This solid was dissolved in water (50 ml) and washed with EA (2×50 ml). The organic extract was discarded and the aqueous layer was acidified (pH1) with 5M hydrochloric acid (about 10 ml) to precipitate the title compound (2.54 g) as a white solid m.p. 167°-169°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]>C(O)CO>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)c(Cl)c1
Solvent: OCCO
Product: CCOC(=O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21

Procedure:
A mixture of N-[3-[(3,4-dichlorobenzoyl)amino]-2-pyridinyl] glycine ethyl ester (33 g, 0.09 mole) and 167 ml of ethylene glycol was heated at reflux for 11/2 hr. The material crystallized upon cooling. A small portion of the solid was collected by filtration, washed with water, and dried under high vacuum. The solid was recrystallized from ethanol withh refrigeration, collected by filtration, washed with ethanol-water mixture, and dried under high vacuum at 70° C. over 2 days to give 2.0 g, mp 141°-42° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[N:11]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Br)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a solution of 0.413 g (1.03 mmol) of the product of Example 198 in 10 mL of DMF was added 0.062 g (1.55 mmol) of 60% sodium hydride. Stirring was continued for 15 min at 25° C. and 0.125 mL (1.442 mmol) of benzyl bromide was then added and the mixture was stird for 18 h at 55° C. The reaction was cooled to room temperature and the reaction mixture was poured into 200 mL water and 50 mL 1N HCl. The aqueous layer was then extracted with dichlromethane (100 mL) and ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica eluting with 10%-20% ethyl acetate/hexane to provide 0.390 g (77%) of the desired product. Electrospray Mass Spec 490.0 (M+H)