Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][NH:6][C:10](=[O:11])[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1
Reactant: NCCCC(F)(F)F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCC(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 94.6 %

Procedure:
To a solution of 0.35 g (2.75 mmol) of 4,4,4-trifluoro-butylamine (CAS 819-46-5) in 20 ml of dichloromethane, cooled to −15° C., is added dropwise 1.00 g (4.96 mmol) of 4-nitrophenyl chloroformate (CAS 7693-46-1) dissolved in 15 ml of dichloromethane, while maintaining the temperature at −15° C. 0.48 ml (2.75 mmol) of diisopropylethylamine in 10 ml of dichloromethane still at −15° C. is then added. Stirring is continued at −15° C. for 45 minutes, and the temperature of the mixture is then allowed to return to 0° C. over 30 minutes. 20 ml of saturated aqueous sodium hydrogen carbonate solution are then added. The organic phase is separated out by settling and dried over sodium sulfate, and the solvent is partially evaporated off under reduced pressure to a volume of about 8 ml. This solution is chromatographed on a column of 40 g of silica gel, eluting with a mixture of 20% cyclohexane in dichloromethane, to give 0.76 g of 4-nitrophenyl 4,4,4-trifluorobutylcarbamate in the form of a white solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:32])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH:30]=[O:31])[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1.Cl>O1CCCC1.O>[CH3:3][O:4][C:5](=[O:32])[CH2:6][C@H:7]1[C:11]2[CH:12]=[CH:13][C:14]([O:16][C@H:17]3[C:25]4[C:20](=[C:21]([CH2:30][OH:31])[C:22]([C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4C=O)ccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CO)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaBH4 (18 mg) is added to a solution of {(S)-6-[(R)-4-formyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.20 g) in tetrahydrofuran (4 mL) and water (1 mL) at room temperature. The mixture is stirred at room temperature for 30 min. 1 N aqueous HCl solution is added and the mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated to give the title compound. The crude product is submitted to the next reaction step without further purification. LC (method 2): tR=1.19 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>COCCOC.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.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)[C:3]=1[O:12][CH3:13])[CH:7]=[O:8]
Reactant: OB(O)c1cccs1
Reactant: COc1cc(C=O)cc(Br)c1OC
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: [Na+]
Solvent: COCCOC
Product: COc1cc(C=O)cc(-c2cccs2)c1OC
Yield: 91 %

Procedure:
Ex-1D: A solution of 5-bromo-3,4-dimethoxybenzaldehyde (10.23 g, 41.7 mmol) in 359 mL of ethylene glycol dimethyl ether was purged with nitrogen gas for 30 min. The solution was treated with tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol), thiophene-2-boronic acid (8.01 g, 62.6 mmol), and a solution of 2 N sodium carbonate 72 mL, 3.45 mmol). The reaction was refluxed for 16 h. The reaction mixture was concentrated, diluted with an aqueous solution of saturated sodium bicarbonate (75 mL), and extracted with dichloromethane (2×100 mL). The organic layer was dried over sodium sulfate and concentrated to a brown solid. The crude material was purified by silica gel chromatography (1:1 ethyl acetate/hexanes) to give 9.42 g (90%) of the desired 3,4-dimethoxy-5-(thien-2-yl)benzaldehyde product. 1H-NMR (300 MHz, CDCl3) δ 9.94 (s, 1H), 7.79 (d, 1H), 7.57 (dd, 1H), 7.41 (d, 1H), 7.36 (d, 1H), 7.13 (dd, 1H), 3.97 (s, 3H), 3.93 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)\[C:12]2[N:16]([CH3:17])[C:15](=[O:18])[O:14][N:13]=2)[CH:5]=[CH:4][CH:3]=1.CO[C:27](OC)([N:29](C)C)[CH3:28].Cl.N[OH:36]>C(O)(C)C>[OH:36][N:29]=[C:27]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](\[C:12]2[N:16]([CH3:17])[C:15](=[O:18])[O:14][N:13]=2)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1)[CH3:28]
Reactant: Cn1c(/C(=N\OCc2cccc(N)n2)c2ccccc2)noc1=O
Reactant: COC(C)(OC)N(C)C
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Product: CC(=NO)Nc1cccc(CO/N=C(/c2ccccc2)c2noc(=O)n2C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75 %

Procedure:
To a solution of 3-[(Z)-{[(6-aminopyridin-2-yl)methoxy]imino}(phenyl)methyl]-4-methyl-1,2,4-oxadiazol-5(4H)-one (600 mg, 1.84 mol, 1 eq) in isopropanol (8 mL) was added N,N-dimethylacetamide dimethyl acetal. The mixture was refluxed for 4 h30. Hydroxylamine hydrochloride (154 mg, 2.21 mmol, 1.2 eq) was added at room temperature and the mixture was stirred at room temperature for 2 days. The solvent was then evaporated and water was added. The resulting precipitate was filtered and dried under vacuum to afford N′-hydroxy-N-{6-[({[(Z)-(4-methyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}ethanimidamide (660 mg, 75% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(NCc3ccc(Cl)cc3)cc2)C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a mixture of (RS)-2-(4-amino-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, CAS 1002726-96-6), 4-chlorobenzaldehyde (33.3 mg) and AcOH (123 μl) in THF (2 ml) was added sodium triacetoxyborohydride (68.5 mg). The reaction mixture was then capped and the mixture was shaken at 60° C. for 3 h. The crude reaction mixture was then concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 65% EtOAc in hexanes) to afford (RS)-2-[4-(4-chloro-benzylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (68 mg, 78%) as a colourless oil. MS (ISP): 405.4 ([{37Cl}M+H]+), 403.4 ([{35Cl}M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][CH2:17][O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:19][O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Yield: 100 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.52 mmol), 1-chloro-2-methoxyethane (0.056 mL, 0.62 mmol) and cesium carbonate (252 mg, 0.73 mmol) in DMF (1 mL) were heated in microwave reactor at 160° C. for 30 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (ISCO, hexanes/ethyl acetate 0-100% over 15 min) to isolate Compound B162a (130 mg, 100% yield). HPLC: RT=1.0 min (LCMS Method M). MS (ES): m/z=253.0 [M+H]+. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.04 (s, 1H), 7.83 (d, J=18.4 Hz, 1H), 4.37 (t, J=5.2 Hz, 1H), 3.78 (t, J=5.2 Hz, 1H), 3.38-3.31 (m, 2H), 2.98 (s, 3H), 2.90 (s, 3H), 1.34 (s, 6H), 1.26 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH2:23][CH2:24][CH2:25][OH:26])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([O:26][CH2:25][CH2:24][CH2:23][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)[NH:12][C:11]1=[O:16])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(CCCO)(c1ccccc1)C(=O)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1ccc2c(c1)C(CCCOS(C)(=O)=O)(c1ccccc1)C(=O)N2
Temperature: 0 °C
Yield: 65.3 %

Procedure:
A mixture of compound 5-(3,5-dimethylisoxazol-4-yl)-3-(3-hydroxypropyl)-3-phenylindolin-2-one (0.72 g, 2.0 mmol), DIPEA (1.05 mL, 6.0 mmol), MsCl (250 mg, 2.2 mmol) in CH2Cl2 (20 mL) was stirred at 0° C. then gradually raised to RT overnight. The contents were diluted with CH2Cl2, washed with water (2×10 mL), and concentrated. The crude was purified with flash chromatography to afford compound 3-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)propyl methanesulfonate (575 mg, 65.3%). 1H NMR (400 MHz, DMSO-d6): δH 10.73 (s, 1H), 7.24-7.38 (m, 7H), 7.02 (d, J=8.0 Hz, 1H), 4.13-4.16 (m, 2H), 3.12 (s, 3H), 2.37 (s, 3H), 2.30-2.34 (m, 2H), 2.20 (s, 3H), 1.30-1.48 (m, 2H). To a stirred solution of 3-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)propyl methanesulfonate (440 mg, 1.0 mmol) in dry THF (10 mL) was successively added triethylamine (280 μl, 2.0 mmol) and morpholine (174 mg, 2.0 mmol) at room temperature. The reaction mixture was heated at 80° C. for 15 h and then water (10 mL) was added. The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and filtered. After concentration of the filtrate in vacuo, the residue was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH: 95/5) to afford compound (385 mg, 89.3%) as a white solid. 1H NMR (400 MHz, CDCl3): δH 7.88 (s, 1H), 7.28-7.39 (m, 5H), 7.14-7.16 (m, 1H), 7.08 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.76 (m, 4H), 2.45-2.55 (m, 5H), 2.37-2.39 (m, 4H), 2.22-2.29 (m, 5H), 1.54-1.55 (m, 2H). MS (ESI) m/e [M+1]+ 432.0.
Reaction SMILES: [O:1]([C:8]([NH:10][C:11](=[S:24])[C:12](=[CH:18]N(CC)CC)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][S:26]([C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32](=[O:35])[CH2:33]Br)(=[O:28])=[O:27].C(O)(C)C>O>[F:25][S:26]([C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([C:33]1[S:24][C:11]([NH:10][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=1)=[O:35])(=[O:28])=[O:27]
Reactant: CCOC(=O)C(=CN(CC)CC)C(=S)NC(=O)Oc1ccccc1
Reactant: O=C(CBr)c1cccc(S(=O)(=O)F)c1
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1cc(C(=O)c2cccc(S(=O)(=O)F)c2)sc1NC(=O)Oc1ccccc1
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 130 g of ethyl 2-[[(phenoxycarbonyl)-amino]thioxomethyl]-3-(diethylamino)propenoate (0.37 mole), 104 g of m-fluorosulfonylphenacyl bromide (0.37 mole), and 350 ml of isopropanol was heated to reflux and held one hour. During this time, the reactants dissolved and the product precipitated. The mixture was cooled to 20°-25°, filtered, washed with isopropanol and then water to yield 133 g of white solid, ethyl 5-[3-(fluorosulfonyl)benzoyl]-2-[(phenoxycarbonyl)-amino]-3-thiophenecarboxylate, (75% yield), melting point 161°-163°. Ir: 2.88, 5.72, 5.98, 6.18, 7.12, 8.10, 8.40μ; NMR (CDCl3) δ10.75 (s,1,N-H); 8.4 (m,1); 8.2 (m,2); 7.8 (m,1); 7.7 (s,1, thiophene-proton); 4.4 (q,2); 1.4 (t,3).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[N:19]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:12][CH:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[N:19]4)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nccnc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6nccnc6c5O4)CC3)c2c1
Temperature: 80 °C

Procedure:
To a solution of (2R)-2,3-dihydro[1,4]dioxino[2,3-f]quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.462 g, 1.241 mmole) in methyl sulfoxide (25 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.073 g, 4.962 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.382 g (74%) of the (S)-enantiomer of the title compound as a tan solid. Rf=0.37 (silica, methanol:ethyl acetate 1:9); mp>200° C. dec.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][C:13](C)([O-])C.[Li+].C([Mg]Br)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: CC[Mg]Br
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc(Cl)ncc1[N+](=O)[O-]

Procedure:
In Scheme A, reaction of 2,4-dichloro-5-nitropyrimidine (1) with lithium t-butoxide, cuprous iodide and ethylmagnesium bromide in THF at -78° C. gives 2-chloro-4-ethyl-5-nitropyrimidine (2). Displacement of the 2-chloro group in 2, is accomplished by treatment with 2-ethyl-4-methylimidazole or imidazole in acetonitrile at room temperature. Reduction of the nitro moiety in 3 to produce 4 is accomplished as illustrated. Reduction of 2,6-dichloro-4-ethyl-5-nitropyrimidine (5) is accomplished as illustrated to produce the compound 4 where R is hydrogen. ##STR6##
Reaction SMILES: [CH2:1]([S:11]([OH:14])(=[O:13])=[O:12])[CH2:2][S:3][S:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[OH-].[Ca+2:16].[OH-].CC(C)=O>O>[CH2:1]([S:11]([O-:14])(=[O:13])=[O:12])[CH2:2][S:3][S:4][CH2:5][CH2:6][S:7]([O-:10])(=[O:8])=[O:9].[Ca+2:16]
Reactant: O=S(=O)(O)CCSSCCS(=O)(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)([O-])CCSSCCS(=O)(=O)[O-]
Yield: 85 %

Procedure:
A solution of 2,2′-dithiobis ethane sulfonic acid (2.5 g, containing 9% water, 8.1 mmol) in water (1.0 mL) was titrated with calcium hydroxide (98+% purity, Acros Organics) aqueous solution until the pH of the reaction solution was adjusted to 7.0. Overall, 0.60 g (8.1 mmol) calcium hydroxide was used. Acetone (200 mL) was added to the reaction solution to precipitate the product. The resulting white solid was isolated by filtration and dried under high vacuum to give 2.20 g of product (85% yield). The purity of the product was 97.4% from HPLC analysis.
Reaction SMILES: CNS(CC1C=CC(NC2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34](N5CCOCC5)=[C:33]([C:43]([F:46])([F:45])[F:44])[CH:32]=4)=[O:29])=[CH:23][CH:22]=3)[N:17]=[CH:16][N:15]=2)=CC=1)(=O)=O.[CH2:47]([Cl:49])Cl.[CH3:50]C(C)=O>>[Cl:49][C:47]1[N:15]=[CH:16][N:17]=[C:18]([O:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([CH3:50])=[C:33]([C:43]([F:45])([F:44])[F:46])[CH:32]=3)=[O:29])=[CH:25][CH:26]=2)[CH:19]=1
Reactant: CNS(=O)(=O)Cc1ccc(Nc2cc(Oc3ccc(NC(=O)Nc4ccc(N5CCOCC5)c(C(F)(F)F)c4)cc3)ncn2)cc1
Reactant: ClCCl
Reactant: CC(C)=O
Product: Cc1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1C(F)(F)F

Procedure:
The title compound is synthesized in analogy to the preparation of compound of Example 48 starting from compound of Stage 56.1: M+H=423.1/M+18=440.1; Rf (CH2Cl2/acetone=9:1): 0.42; 1H-NMR (400 MHz, DMSO-d6): 8.93/8.80 (s/s, 2H, urea), 7.91 (d, 2 Hz, 1H, pyrimidinyl), 7.51 (d, 9.5 Hz, 2H, phenyl), 7.47 (d, 8.0 Hz, 1H, phenyl-CF3), 7.29 (d, 8 Hz, 1H, phenyl-CF3), 7.27 (s, 1H, phenyl-CF3), 7.13 (d, 9.5 Hz, 2H, phenyl), 4.08 (m, 1H, pyrimidinyl), 2.63 (s/broad, 3H, CH3); m.p.=183.0-184.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:27][C:28]([CH3:31])([O-])[CH3:29].[K+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][C:28]([CH3:31])([CH3:29])[CH3:27])=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 30 °C
Reaction time: 0.67 h
Yield: 59.9 %

Procedure:
To a stirred solution of 9 (12.8 g, 61.2 mmol) in dry THF (200 mL) under argon was added oxalyl chloride (12.0 mL, 137.5 mmol) followed by DMF (0.1 mL), which caused a vigorous evolution of gas. After 40 min, the reaction mixture was evaporated to dryness. The resulting solid was re-dissolved in THF (150 mL), cooled to ˜30° C., and stirred under argon. A solution of potassium t-butoxide (1.0 M in THF, 140 mL, 140 mmol) was then added dropwise over 45 min, and stirring was continued for an additional 45 min. The reaction was quenched with 600 mL of water, neutralized with few drops of a 10% aqueous solution of H3PO4 and extracted with ethyl acetate (3×400 mL). The organic extracts were washed with saturated aqueous NaHCO3, water, and then dried over magnesium sulfate, filtered, concentrated and crystallized with ethanol/hexane to afford compound 10 (9.62 g, 85% yield). Rf=0.35 (1:5 Ethyl acetate/Hexane); 1H NMR (CDCl3), 11.63 (s, 1H), 8.66 (dd, 1H, J=0.5, 1.3Hz), 8.20 (dd, 1H, J=0.5, 9.0 Hz), 7.48 (dd, 1H, J=0.5, 9.1 Hz), 7.28 (dd, 1H, J=0.9, 11.1 Hz), 1.63 (s, 9H); 13C NMR 160.39, 142.12, 138.11, 132.10, 126.78, 120.22, 119.83, 111.98, 109.82, 82.91, 28.26; MS m/z 285.43 (M+Na)+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C=O)C>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:10][CH3:17])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)c1ccccc1
Yield: 98.7 %

Procedure:
To a 500 mL three-opening flask were added 2,2-diphenylacetic acid (20 g, 94 mmol) and 200 mL dichloromethane. After stirring, 1 mL DMF was added. To the mixture was slowly added oxalyl chloride (13.16 g, 104 mmol) dropwisely in an ice bath. The reaction was conducted at 25° C. After the completion of reaction, the mixture was evaporated under reduced pressure to remove oxalyl chloride. To the reaction flask were slowly added dichloromethane (100 mL) and anhydrous methanol (3.61 g, 113 mmol) dropwisely under cooling in an ice bath respectively. The reaction was conducted at 25° C. After the completion of reaction, the reaction solution was washed with a saturated aqueous NaCl solution. The organic phase was dried over sodium sulfate, and filtered by suction. The filtrate was evaporated to dryness to produce methyl 2,2-diphenylacetate (21 g) in a yield of 98.7%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH:15][C:16](OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[N:29]=[C:28](Cl)[C:27](C=O)=[C:26]([Cl:33])[N:25]=1.N1C(=O)CC(=O)NC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:28]3=[N:29][C:24]([Cl:23])=[N:25][C:26]([Cl:33])=[C:27]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C1CC(=O)NC(=O)N1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)nc(Cl)nc32)CC1

Procedure:
4-(4,6-Dichloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester was prepared using Method C described for the preparation of Intermediate 19, by the reaction of 4-(tert-butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 15) with 2,4,6-trichloro-pyrimidine-5-carbaldehyde (which can be prepared from barbituric acid using the procedure of J. Dehnert DE 3603797).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([F:28])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:28][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(N3CCNCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(N2CCNCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 29.7 %

Procedure:
A mixture of 2-(3-fluoro-5-piperazin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.18 g, 0.43 mmol), lithium hydroxide hydrate (0.18 g, 4.3 mmol), water (2 mL) in methanol (5 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-fluoro-5-piperazin-1-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (49 mg, 30%) as a white solid: LC/MS m/e calcd for C22H26FN3O2 (M+H)+: 384.5, observed: 384.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Cl)[N:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H][H]>O.CN(C)C=O>[CH2:14]([O:21][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1)[C:5]([OH:7])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: [H][H]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(OCc2ccccc2)nc(OCc2ccccc2)c1

Procedure:
In an argon atmosphere, 2,6-dichloroisonicotinic acid (57.6 g) was gradually added to 55% sodium hydride (52.5 g) and dimethylformamide (1 L) while being cooled and stirred. Subsequently, benzyl alcohol (93 mL) was gradually added dropwise to the reaction product at the same temperature. After hydrogen was no longer generated, the reaction product was stirred for 4 hours at 80° C., and water (1 L) was then added thereto. The mixture was separated by a mixed solvent (1 L) of ethyl acetate and n-hexane (1:1). The acidity of the aqueous layer was lowered with acetic acid (75.5 mL), and water (1.7 L) was further added thereto. The precipitate was filtered and dried to obtain Compound 2a.