Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([O:32][CH2:33][C:34]([O:36]C)=[O:35])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of methyl ({6-[2-(1-benzyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (271 mg, 0.555 mmol), prepared in the previous step, and 1N NaOH (1.11 mL, 1.11 mmol) in 35 mL of THF plus 20 mL of H2O was stirred at room temperature for 15 h (overnight). The reaction was acidified by the addition of 1.2 mL of 1N HCl and then concentrated under reduced pressure to remove the THF. The white solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (236 mg, 90%) as a white solid, mp 238-242° C. Elemental Analysis for C30H22N2O4+0.32 mole of H2O. Calc'd: C, 75.03; H, 4.75; N, 5.83. Found: C, 74.67; H, 5.34; N, 5.19.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]([OH:14])=O)=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:29][C:12]([C:7]2[C:8]3[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=3[CH:4]=[CH:5][CH:6]=2)=[O:14])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: O=C(O)c1cccc2c1CCCC2=O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3=O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (430 mg, 2.26 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (464 mg, 2.26 mmol), HATU (1 g, 2.70 mmol) in anhydrous DMF (20 mL) is added DIPEA (446 μL, 2.70 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (65) as white solid (828 mg, 97%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[OH-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>O1CCOCC1>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
L-Asparagine (10.0 g, 75.7 mmol) was placed in a 500 mL round bottom flask equipped with a magnetic stir bar and an addition funnel. 1N Sodium hydroxide (170 mL, 166.5 mmol) was added along with 50 mL dioxane. p-Toluenesulfonyl chloride (15.88 g, 83.27 mmol) dissolved in dioxane (50 mL) was added to the reaction mixture with vigorous stirring. The reaction mixture was then stirred for 2 h at room temperature, cooled to 0° C., and acidified to pH 2-3 with hydrochloric acid (conc.). The desired product 14-2 formed as a white crystalline solid (20.3 g, 94%) that was collected by filtration.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][NH:6]C(OC(C)(C)C)=O.S(O)(C)(=O)=O>CCOC(C)=O>[NH2:1][C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: NCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 222 %

Procedure:
Boc-Orn(Boc)-Amp (1.35 g, 3 mmol) was dissolved in EtOAc (200 ml) and to the slightly cloudy solution was added MsOH (0.43 ml, 6.6 mmol) drop wise. The reaction mixture became a clear solution which was stirred at room temperature for approximately 20 hrs. Solvent was removed and the residue was triturated in hexanes. Off-white solid product was formed which was filtered under vacuum and washed with hexanes. The solid was dried in vacuum oven for 20 hrs to obtain 0.88 g of Orn-Amp-2MsOH (l-ornithine-d-amphetamine dimesylate).
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]C)=[O:11])[C:6]=1[C:14]([F:17])([F:16])[F:15])[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+]>CO.O>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[C:14]([F:17])([F:16])[F:15])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1noc(CC(C)C)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Cc1onc(C(=O)O)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A mixture of methyl 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carboxylate (0.816 g, 3.25 mmol) and lithium hydroxide hydrate (0.136 g, 3.25 mmol) in methanol (18 mL) and water (9.00 mL) was stirred at room temperature overnight. By HPLC and LCMS, the hydrolysis was complete. The reaction mixture was concentrated under reduced pressure, and the residue dissolved in 1N aqueous hydrochloric acid and extracted with ether. The organic layer was collected and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (0.746 g, 3.15 mmol, 97% yield) as an off-white solid. The product had an HPLC ret. time=2.00 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (s, 3H), 0.93 (s, 3H), 1.97-2.09 (m, 1H), and 2.89 (d, J=7.28 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22]C)=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][O:31][CH3:32])[S:8][C:7]=2[CH:33]=1.[Li+].[OH-].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:30][O:31][CH3:32])[S:8][C:7]=2[CH:33]=1
Reactant: COCc1ccccc1-c1sc2cc(OC)ccc2c1Oc1ccc(/C=C/C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COCc1ccccc1-c1sc2cc(OC)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.8 %

Procedure:
To a solution of (E)-methyl 3-(4-((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (86.6 mg, 0.188 mmol) in MeOH (3.0 mL) was added LiOH (2.0N aqueous, 0.564 mL, 1.128 mmol). The resulting mixture was stirred at room temperature for 48 h after which time the reaction was brought to pH 7 by addition of 1N HCl, the neutralized reaction was then concentrated in vacuo to afford (E)-3-(4-((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (45.9 mg, 0.103 mmol, 55% yield). LC/MS (m/z, MH+): 447.0.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=3)=[N:10][O:9][S:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N2C(C3C=CC(Cl)=CC=3Cl)=NOS2=O)C=CC=CC=1.ClC1C=C(Cl)C=CC=1N1C(C2C(Cl)=CC=CC=2Cl)=NOS1=O>>[C:1]1([N:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:10][O:9][S:8]2=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S1ON=C(c2ccc(F)cc2)N1c1ccccc1
Agent: O=S1ON=C(c2c(Cl)cccc2Cl)N1c1ccc(Cl)cc1Cl
Agent: O=S1ON=C(c2ccc(Cl)cc2Cl)N1c1ccccc1
Product: O=S1ON=C(c2ccccc2)N1c1ccccc1

Procedure:
3-phenyl-4-(4-fluorophenyl)-1,2,3,5-oxathiadiazole -2-oxide; 3-phenyl-4-(2,4-dichlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide; 3-(2,4-dichlorophenyl)-4-(2,6-dichlorophenyl)-1,2,3,5-oxathiadiazole-2-oxide.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([CH:25]=[O:26])=[CH:10][N:9]=1.C[Li].[C:29](=O)([O-])O.[Na+]>O1CCCC1.CCOCC>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C@@H:25]([OH:26])[CH3:29])=[CH:10][N:9]=1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Reactant: O=C([O-])O
Agent: [Li]C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CNc2nc(N3CCCC3CO)ncc2[C@H](C)O)cc1Cl

Procedure:
To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-formylpyrimidine (91.0 mg) in tetrahydrofuran (20 ml) is added 1.10 M solution of methyl lithium in ether (1.1 ml) at −78° C., and the mixture is reacted for 10 minutes, and thereto is added aqueous sodium hydrogen carbonate solution. The reaction mixture is extracted with ethyl acetate to give crude (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-(1-hydroxyethyl)pyrimidine, MS (m/z): 393 (MH30).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+].Cl>O1CCCC1>[F:34][CH:32]([F:33])[O:31][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:35])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A solution of [4-difluoromethoxy-2-ethyl-8-fluoro-3-(4-trifluoromethoxybenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.054 g) in tetrahydrofuran (4.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.21 mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified by the addition of 0.1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound as a white solid (0.042 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][CH:11]1[CH2:17][C:16]2[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:15]=2[CH2:14][CH2:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][CH2:24][CH2:25]Br.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:3]([NH:10][CH:11]1[CH2:12][CH2:13][CH2:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][CH:24]([CH3:25])[CH3:23])=[CH:18][C:16]=2[CH2:17]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCBr
Reactant: Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reaction time: 0.5 h

Procedure:
Under nitrogen, to a suspension of sodium hydride (60% in oil, 47 mg) in N,N-dimethylformamide (3 ml) was dropwise added 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (300 mg) in N,N-dimethylformamide (2 ml) at 5° C., and the mixture was stirred at the same temperature for 30 minutes. To this one was added n-propyl bromide (0.10 ml), and the mixture was stirred at the same temperature for 3 hours. The resulting mixture was poured into saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=50:1 to 30:1) to give N-benzyl-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (278 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=1.C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]([C:16]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:18])=[C:13]([CH3:15])[N:14]=1
Reactant: C1COCCN1
Reactant: COc1nccc(I)c1-c1nc(C)c(C(=O)O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Product: COc1nccc(I)c1-c1nc(C)c(C(=O)N2CCOCC2)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
To a stirred solution of 2-(4-iodo-2-methoxypyridin-3-yl)-4-methyl-1H-imidazole-5-carboxylic acid (0.039 g, 0.1085 mmol) in N,N-diemthylformamide (2 mL) was added triethylamine (60 mL, 0.434 mmol), morpholine (14 mL, 0.1627 mmol) and PyBOP (85 mgs, 0.1627 mmol) at room temperature. The reaction was stirred at room temperature for 10 minutes then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on Prep HPLC (ammonium acetate/acetonitrile/water) to give the title material (0.024 g, 52%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 2.32 (s, 3H) 3.54 (s, 8H) 3.76 (s, 3H) 7.55 (d, J=5.31 Hz, 1H) 7.87 (d, J=5.31 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=O)=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].CSC.B>O1CCCC1>[NH2:26][CH2:24][C:23]1[CH:27]=[CH:28][C:20]([CH2:19][N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Cl:1])[C:3]2=[O:29])=[CH:21][CH:22]=1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(C(N)=O)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc(CN)cc1
Temperature: 25 °C
Yield: 31.7 %

Procedure:
The compound of Example 606 (10.0 g, 23.38 mmol) was suspended in tetrahydrofuran (100 mL) and cooled in an ice-bath. Borane dimethyl sulfide (29.9 mL, 2.0 M in tetrahydrofuran, 59.7 mmol) was added. The resulting mixture was heated to reflux overnight and then cooled in an ice-bath. Additional borane dimethyl sulfide (5.85 mL, 2.0 M in tetrahydrofuran, 11.7 mmol) was added. The resulting mixture was heated to reflux overnight and the cooled to room temperature. The flask was fitted with a distillation head and the reaction was partially concentrated. Additional borane dimethyl sulfide (5.85 mL, 2.0 M in tetrahydrofuran, 11.7 mmol) was added. The mixture was heated to reflux overnight and the cooled in an ice-bath. The reaction was quenched by the addition of 1.0 N HCl (75.0 mL) then partially concentrated. The aqueous layer was made alkaline with 2.5 N NaOH and a precipitate developed. The solid was collected by filtration washing with diethyl ether to give a pale purple solid (3.00 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ 7.64 (app q, J=7.9 Hz, 1H), 7.44 (d, J=7.9 Hz, 2H), 7.32 (app dt, J=2.4, 9.9 Hz, 1H), 7.14 (app dt, J=1.9, 8.5 Hz, 1H), 7.13 (d, J=7.9 Hz, 2H), 6.61 (s, 1H), 5.27 (s, 4H), 3.90 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH2:24]([O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>>[CH2:24]([O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:30][CH:29]=1)[CH3:25]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19, Step 5) was reacted with ethyl-4-(bromomethyl)benzoate and potassium carbonate to give the title compound as a colorless viscous oil. MS (m/e, ISP neg. ion)=528.3 [M−H−].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[Cl-:16].CN(C=O)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: [Cl-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoic acid with oxalkyl chloride and DMF in chloroform at room temperature followed by evaporation in vacua.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([OH:8])[CH:4]=1.[C:9](Cl)([Cl:11])=[O:10]>C1C=CC=CC=1>[Cl:11][C:9]([N:6]1[C:5](=[O:8])[CH:4]=[C:3]([CH2:2][Cl:1])[O:7]1)=[O:10]
Reactant: O=C(Cl)Cl
Reactant: Oc1cc(CCl)on1
Solvent: c1ccccc1
Product: O=C(Cl)n1oc(CCl)cc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
A mixture of 673 mg of 5-chloromethyl-3-hydroxyisoxazole, 19 ml of benzene and about 1 ml of liquified phosgene was stirred at room temperature for 5 hours. At the end of this time, the excess phosgene and the solvent were distilled off, giving 900 mg (yield 100% of theory) of the title compound, in the form of a colourless oil having a refractive index, nD24 =1.5391.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[N:5]=1.C(=O)([O-])[O-].[Na+].[Na+].CO.O>C(=O)(O)[O-].[Na+]>[Br:1][C:7]1[C:6]([Cl:11])=[N:5][C:4]([NH2:3])=[N:9][C:8]=1[Cl:10]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1nc(Cl)c(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 42 h
Yield: 83.7 %

Procedure:
Bromine (0.85 mL, 0.0166 mole) was added dropwise over 20 minutes to a stirred suspension of 2-amino-4,6-dichloropyrimidine (CAS#56-05-3, 1.70 g, 0.01037 mole) and sodium carbonate (1.00 g, 0.01244 mole) in 1:1 methanol/water (30 mL) at ambient temperature. Ten minutes after the addition was complete, more sodium carbonate (0.78 g, 0.0093 mole) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 42 hours, then it was diluted with aqueous sodium bicarbonate to provide 5-bromo-4,6-dichloropyrimidin-2-amine as a precipitate that was collected by filtration and rinsed with water. The vacuum-dried solid weighed 2.11 g (83.7% yield). 1H NMR (300 MHz, d6-DMSO) δ ppm 7.67 (s, 1H), 7.70 (s, 1H). MS (DCl—NH3) m/z=241 (M+H)+, m/z=258 (M+NH4)+.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].C([Li])CCC.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[S:17][CH2:18][CH2:19][OH:20]>O1CCCC1.CN1C(=O)N(C)CCC1.CCCCCC.O1CCCC1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[S:17][CH2:18][CH2:19][O:20][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CCl
Reactant: OCCSC1CCCCO1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)COCCSC1CCCCO1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
To a solution of chloroacetic acid (22.7 g) in tetrahydrofuran-DMPU (5:1, 300 ml) was added a solution of butyllithium (0.24 mol) in hexane (150 ml) at -78° C. and the resulting suspension was warmed to room temperature. Separately, a solution of butyllithium (0.24 mol) in hexane (150 ml) was added to a solution of 2-[(tetrahydropyran-2-yl)thio]ethanol (38.9 g) in tetrahydrofuran (200 ml) at -78° C. and this solution was also warmed to room temperature. This solution and the above suspension were pooled and refluxed for 18 hours. After cooling, the reaction mixture was diluted with ice-aqueous sodium chloride solution (water-saturated NaCl solution=3:1, 400 ml) and the unreacted chloroacetic acid was extracted with ether (200 ml×6). The aqueous layer was adjusted to pH 2 with 4N-hydrochloric acid and extracted with ether (200 ml×3). The organic layer was washed successively with aqueous sodium chloride solution (saturated aqueous sodium chloride solution-water=1:1, 200 ml×2) and saturated aqueous sodium chloride solution (100 ml) and dried over anhydrous sodium sulfate. Finally the solvent was distilled off under reduced pressure to give 27.0 g of [2-[(tetrahydropyran-2-yl)thio]ethoxy]acetic acid as a colorless oil.
Reaction SMILES: [C:1](Cl)(=O)[CH3:2].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][NH:11][CH:10]([C:16]([OH:18])=[O:17])[CH2:9]2>>[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][NH:11][CH:10]([C:16]([O:18][CH2:1][CH3:2])=[O:17])[CH2:9]2
Reactant: CC(=O)Cl
Reactant: O=C(O)C1Cc2cc(O)ccc2CN1
Product: CCOC(=O)C1Cc2cc(O)ccc2CN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 140.4 %

Procedure:
Acetyl chloride (30 mL, 33 g, 422 mmol) was added carefully to ice-cold anhydrous EtOH and the resulting solution was stirred at RT for 10 min. 6-Hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3.30 g, 14 mmol) was added and the mixture was stirred at 50° C. for 5 h. The solvent was evaporated and the residue was dried under vacuum to yield ethyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (4.35 g, crude yield>100%) as a yellow solid. MS expected 222.1 found 222.0. 1H NMR (400 MHz, CD3OD): δ 7.06 (d, J=8.4 Hz, 1H), 6.74 (dd, J=8.0, and 2.4 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 4.44-4.29 (m, 5H), 3.35 (dd, J=17.2, and 5.2 Hz, 1H), 3.15 (dd, J=17.2, and 11.6 Hz, 1H), 1.35 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7]([CH3:10])(=[O:9])=[O:8])C>Cl>[CH2:11]([CH:5]([CH2:6][S:7]([CH3:10])(=[O:9])=[O:8])[C:4]([OH:18])=[O:3])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(C)(=O)=O
Agent: Cl
Product: CS(=O)(=O)CC(Cc1ccccc1)C(=O)O

Procedure:
1.74 g of 2-benzyl-3-methylsulphonyl-propionic acid ethyl ester in 35 ml of 4N hydrochloric acid are heated under reflux for 2 hours. The cooled solution is extracted with ethyl acetate, the extracts are dried and concentrated and the residue is purified by medium-pressure chromatography (1 Lobar® column size B, eluant A). 1H-NMR (DMSO-d6): 2.95 ppm(s, 3H); 2.8-3.8 (m, 5H); 7.2 (s, 5H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([N+:29]([O-])=[O:30])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[N:21]=[C:20]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]3[C:14](=[CH:15][C:16]([NH:29][OH:30])=[CH:17][CH:18]=3)[N:13]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc([N+](=O)[O-])cc3n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccc(Sc2nc(Nc3cc(C)n[nH]3)c3ccc(NO)cc3n2)cc1

Procedure:
To a solution of [2-(4-acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (147 mg, 3.38.10−4 mol) in methanol (5 mL) is added Pd/C 10% (40 mg) and the reaction mixture is treated with hydrogen at balloon pressure at 45° C. for 20 hours. The catalyst is filtered through a pad of celite which is then washed with dilute HCl. The combined yellow filtrate is evaporated and the resulting solid residue is crystallized from methanol to afford the desired [2-(4-acetamido-phenylsulfanyl)-7-hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.