Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)c(N)n1
Reactant: OB(O)c1cccc(Cl)c1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2cccc(Cl)c2Cl)c(N)n1
Temperature: 80 °C
Yield: 35.4 %

Procedure:
To a suspension of 3-bromopyridine-2,6-diamine (0.376 g, 2.00 mmol) in 1,4-dioxane (12 ml) and water (6 ml) was added 2,3-dichlorophenyl boronic acid (0.573 g, 3.00 mmol), potassium carbonate (0.552 g, 4.00 mmol) and palladium tetrakis(triphenylphosphine) (0.115 g, 0.01 mmol). The reaction was purged with nitrogen and heated at 80° C. for 18 hours. Further palladium tetrakis(triphenylphosphine) (0.115 g, 0.01 mmol) and 2,3-dichlorophenyl boronic acid (0.573 g, 3.00 mmol) were added and the reaction heated at 80° C. for a further 18 hours before concentrating in vacuo. The residue was taken up in ethyl acetate (20 ml) and washed with a saturated aqueous solution of K2CO3 before drying over MgSO4 and concentrating in vacuo. The residue was purified by silica gel column chromatography, eluting with 99:1 dichloromethane:methanol, then recrystallised from toluene to afford the title compound (0.180 g, 35% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[CH2:30][CH:31]=O>>[C:22]1([CH3:21])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[C:30]1[CH:31]=[N:1][C:2]2[C:3]([C:12]=1[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(C)c(CC=O)c(C)c1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Product: Cc1cc(C)c(-c2cnc3c(C(F)(F)F)cccc3c2-c2cccc(O)c2)c(C)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (2,4,6-Trimethyl-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 405.9; HRMS: calcd for C25H20F3NO+H+, 408.15697; found (ESI, [M+H]+), 408.1573.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[CH:5]=[CH:6][C:7]2[CH:23]=[CH:22][C:11]3=[N:12][CH:13]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[CH:15]=[C:10]3[C:9](=[O:24])[C:8]=2[CH:25]=1)[CH3:3].[H-].[Na+].[CH3:28]I.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:28][O:1][C@@H:2]([C:4]1[CH:5]=[CH:6][C:7]2[CH:23]=[CH:22][C:11]3=[N:12][CH:13]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[CH:15]=[C:10]3[C:9](=[O:24])[C:8]=2[CH:25]=1)[CH3:3]
Reactant: CI
Reactant: C[C@@H](O)c1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@H](C)c1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-[(1R)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (7 mg, 0.02 mmol) was dissolved in 1 mL of tetrahydrofuran. Sodium hydride (10 mg of 60% dispersion in oil) was added and the reaction was stirred at room temperature for 2 hours. Methyl iodide (26 μL, 0.42 mmol) was added and the reaction was stirred an additional 3 hours. The reaction was then poured into a mixture of ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via reverse phase HPLC (10-100% acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 9.05 (d, 1H); 8.73 (s, 1H); 8.21 (d, 1H); 7.94 (s, 1H); 7.85 (s, 1H); 7.73 (dd, 1H); 7.65 (d, 1H); 7.51 (d, 1H); 7.34 (d, 1H); 4.47 (q, 1H); 4.01 (s, 3H); 3.27 (s, 3H); 1.46 (d, 3H). LRMS (APCI) calc'd for (C21H20N3O2) [M+H]+, 346.2; found 346.2.
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=1.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCCCCC.C1(C)C=CC=CC=1.C(O)(=O)C>[Br:19][C:15]1[N:14]=[C:13]([C:21]2([CH:22]=[CH:23][CH:24]=[CH:25][CH2:26]2)[CH2:20][OH:27])[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OCC1(c2cccc(Br)n2)C=CC=CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
n-Butylmagnesium chloride (3.49 mmol) in 2.05M tetrahydrofuran solution (1.70 mL) was added to ice-cooled n-butyllithium (7.03 mmol) in 1.45M hexane solution (4.85 mL) (“Hexanes”, Product of Wako Pure and Chemical Industries, Ltd. The solvent was used in the same way in the working examples hereinafter described). The mixture was stirred at 0° C. for 15 minutes, and then cooled to −10° C. to give a suspension. 2,6-Dibromopyridine (2.37 g, 10.0 mmol) in toluene (25 mL) was added to the suspension below −5° C. over a period of 10 minutes or more. The mixture was stirred at −10° C. for 2 hours, and then benzaldehyde (1.35 ml, 13.3 mmol) was added. After stirring at 0° C. for one hour, 1M acetic acid solution (15 mL) was added. The organic phase was separated, and the aqueous phase was extracted twice with ethyl acetate (10 mL). The organic extracts were combined, washed with an aqueous saturated solution (10 mL) of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent. The resultant residue was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (15:1, v/v) to give the title compound (2.56 g) in 97% yield as a pale yellowish viscous oil.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7][C:6]=2[C:5]([NH2:13])=[C:4]([N+:14]([O-])=O)[CH:3]=1>C1COCC1.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([NH2:13])=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2
Reactant: CN1CCc2c(N)c([N+](=O)[O-])cc(Br)c2C1
Agent: [Ni]
Solvent: C1CCOC1
Product: CN1CCc2c(N)c(N)cc(Br)c2C1
Yield: 90.1 %

Procedure:
A solution of the product from Example 10 (0.78 g, 2.73 mmol) in 100 mL of THF was treated with Raney nickel (1.0 g) and hydrogenated for 1.5 hours at room temperature. The reaction mixture was filtered and concentrated to give the title compound as a tan solid (0.63 g, 90%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C@@H:7]1([NH2:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH2:5]([O:4][C:2](=[O:3])[NH:17][C@@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: N[C@H]1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixture of (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K2CO3 (18.8 g, 136 mmol) in CH3CN (100 mL). The resulting mixture is stirred at room temperature overnight. Water (100 mL) is added and the mixture is extracted with ether (2×100 mL). The combined extract is washed with 1 N HCl (2×10 mL), water, dried (Na2SO4), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[NH:9][C:10](=[O:17])[CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)=O>C(O)(=O)C.[H][H].[Pd]>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:4]=1[C:5]1[N:7]=[C:8]2[NH:9][C:10](=[O:17])[CH2:11][CH:12]=[C:13]2[N:14]=1
Reactant: [H][H]
Reactant: COc1cc(SC)ccc1C(=O)Nc1[nH]c(=O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(SC)ccc1C1=NC2=CCC(=O)NC2=N1

Procedure:
An amount of 6.2 gm of 2-[(2-methoxy-4-methylmercapto-benzoyl)-amino]-3-nitro-1H-pyridin-6-one is dissolved in 370 ml of glacial acetic acid and hydrogenated with hydrogen in the presence of 6 gm of 10% palladium charcoal at ambient temperature under 5 bars of pressure (duration of reaction: two hours). The catalyst is filtered off, and the filtrate is refluxed for about 1.5 hours with stirring. Then, about 250 ml of the solvent is evaporated off, and the remaining solution is poured onto ice water and neutralized with ammonia. The precipitate obtained is recrystallized from methanol. Another fraction can be obtained by evaporating the mother liquors of crystallization and triturating the residue with ether:
Reaction SMILES: [OH:1][CH:2]([CH:21]1[CH2:23][O:22]1)[CH2:3][S:4][CH2:5][CH2:6][C:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:9])[CH3:8].[OH-:24].[K+]>CS(C)=O.O.C(OCC)(=O)C>[CH3:9][C:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH2:6][CH2:5][S:4][CH2:3][CH:2]([OH:1])[CH:21]([OH:24])[CH2:23][OH:22])[CH3:8]
Reactant: CC(C)(CCSCC(O)C1CO1)NC(=O)OCc1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CCSCC(O)C(O)CO)NC(=O)OCc1ccccc1
Temperature: 90 °C
Yield: 14.9 %

Procedure:
To a solution of benzyl 4-(2-hydroxy-2-(oxiran-2-yl)ethylthio)-2-methylbutan-2-ylcarbamate (3.33 g, 9.81 mmol) in dimethylsulfoxide (50 ml) and H2O (10 ml) was added 5.0 M KOH (600 μl, 3.0 mmol). The solution was heated to 90° C. for 5 hour, cooled to room temperature, diluted with 400 ml ethyl acetate, washed with 1×200 ml 5% NaHSO4, 5×200 ml saturated NaCl, dried on MgSO4, and concentrated in vacuo. The residue was purified by preparatory HPLC (H2O/acetonitrile) to give the title compound as a clear oil (159.3 mg, 0.446 mmol, 45%) as a mixture of diastereomers. 1H NMR (400 MHz, CDCl3) δ 1.28 (s, 6H), 1.9-2.1 (m, 2H), 2.50 (m, 2H), 2.6-2.7 (m, 2H), 3.6-3.8 (m, 4H), 3.85 (br s, 3H), 4.93 (s, 1H), 5.04 (s, 2H), 7.3-7.4 (m, 5H); LRMS (ESI/APCI) m/z 358 [M+H]+, 380 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][N:10]2[C:29](=[O:30])[N:13]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[CH:16]=[CH:17][C:12]3=[N:11]2)[CH:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:31]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][CH2:9][N:10]3[C:29](=[O:30])[N:13]4[CH:14]=[C:15]([C:18]5[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:22][CH:23]=5)[CH:16]=[CH:17][C:12]4=[N:11]3)[CH:3]=2)[CH2:33][CH2:32]1
Reactant: O=c1n(CCc2cc(Br)ccn2)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1n(CCc2cc(C3CC3)ccn2)nc2ccc(-c3ccc(OC(F)(F)F)cc3)cn12
Temperature: 100 °C
Yield: 81.1 %

Procedure:
A mixture of 2-(2-(4-bromopyridin-2-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (synthesized according to Example 1, 40 mg, 0.084 mmol), cyclopropyl boronic acid (22 mg, 0.25 mmol), dppf(Pd)Cl2 (9.0 mg, 0.013 mmol), potassium carbonate (46 mg, 0.33 mmol) in degassed dioxane (1 mL) was heated at 100° C. for 3 hours. The reaction was concentrated and the residue was purified by reverse phase HPLC to provide compound 57 as a white powder (30 mg, 81% yield). C23H19F3N4O2, m/z (ESI)=441.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:25])=[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:6]([CH3:11])=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=[O:29]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:6]([CH3:11])[C:7](=[O:29])[C:8]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COC(=O)CCCCCCCCCc1c(C)cc(OC)c(OC)c1O
Product: COC(=O)CCCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O

Procedure:
A dimethylformamide solution of methyl 10-(3,4-dimethoxy-2-hydroxy-6-methylphenyl)decanoate (129 mg) is oxidized in the same manner as Example 20. This procedure yields 2,3-dimethoxy-5-methyl-6-(9-methoxycarbonylnonyl)-1,4-benzoquinone (91 mg) as orange-yellow needles melting at 37° C.-38° C.
Reaction SMILES: [F:1][C:2]1([CH2:8][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][OH:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:11][CH2:10][C@@H:9]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[CH2:8][C:2]1([F:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1(F)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1(F)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-tert-butyl 1-(1-fluorocyclohexyl)-3-hydroxypropan-2-ylcarbamate (275 mg, 1.0 mmol, 1.0 equiv) was dissolved in CH2Cl2 and the mixture was cooled to 0° C. To this solution was added methanesulfonyl chloride (230 mg, 2.0 mmol, 2.0 equiv) and triethylamine (304 mg, 3.0 mmol, 3.0 equiv). The mixture was stirred at 0° C. for 0.5 h. After this time LC/MS showed consumption of the starting material. The mixture was transferred to a separatory funnel and 1.0 M aq HCl added. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The crude (S)-2-(tert-butoxycarbonylamino)-3-(1-fluorocyclohexyl)propyl methanesulfonate was used directly in the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:6]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1.[H-].[Na+].Cl[C:27]1[N:32]=[CH:31][C:30]([Br:33])=[CH:29][N:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:33][C:30]1[CH:29]=[N:28][C:27]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[C:6]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[N:32][CH:31]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(C)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 34.4 %

Procedure:
Ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (135 mg) was dissolved in THF (15 ml) and sodium hydride (80 mg) was added followed by stirring for 15 min at 50° C. Then 2-chloro-5-bromo-pyrimidine (162 mg) was added and stirring was continued for 8 h at 70 C. The reaction mixture was poured onto ice water, acidified with solid citric acid and extracted with ethylacetate. The combined organic extracts were dried over magnesium sulfate and the solvent was evaporated. The crude material was purified by plate chromatography with ethyl acetate/hexane=½ to give ethanesulfonic acid {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (68 mg) as a white powder. LC-MS: tR: 4.64, [M+H]+: 496.19.
Reaction SMILES: COS(O)(=O)=O.B(OC)(OC)OC.C(=O)(OC)OC.C(OC)(=O)C.C[C:26]([O:28][CH2:29][C:30]1[CH2:39][S:38][C@@H:33]2[C@H:34]([NH2:37])[C:35](=[O:36])[N:32]2[C:31]=1[C:40]([OH:42])=[O:41])=O>>[NH2:37][CH:34]1[C:35](=[O:36])[N:32]2[C:31]([C:40]([OH:42])=[O:41])=[C:30]([CH2:29][O:28][CH3:26])[CH2:39][S:38][C@H:33]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: COS(=O)(=O)O
Solvent: COC(C)=O
Solvent: COC(=O)OC
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
11.9 g of a methanolic solution of methoxysulfonic acid (prepared as described in Preparation 2) and 3.11 g of trimethyl borate were added to a mixture of 25 ml of dimethyl carbonate and 5 ml of methyl acetate. The mixture was cooled to 20° C., and 2.74 g of 7-ACA were added thereto, followed by stirring at 20° C. for 1 hour. After completion of the reaction, the reaction mixture was treated following the procedures described in Example 2. 2.06 g (yield 84%) of the title compound in a highly pure form were produced.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:18][NH2:19].O>CCO>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 18 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (1 g, 7.3 mmol) in EtOH (10 mL) was added Na2CO3 (1.3 g, 12.3 mmol) and MeNH2 at 18° C. The mixture was stirred for 16 hours at 18° C. after which TLC analysis showed the reaction was complete. The reaction mixture was then concentrated to get the crude material which was treated with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to get yield the crude product which was purified by crystallized with ethanol to give the desired product (780 mg, 55.7%) as a yellow solid. LCMS (m/z): 188.1 [M+H]+.
Reaction SMILES: Br.[NH2:2][C:3]1[N:11]=[CH:10][C:9]([Br:12])=[CH:8][C:4]=1[C:5]([OH:7])=O.CCN(CC)CC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>C(Cl)Cl>[NH2:2][C:3]1[N:11]=[CH:10][C:9]([Br:12])=[CH:8][C:4]=1[C:5]([NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[O:7]
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CN(C)CCN
Agent: Br
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(C)CCNC(=O)c1cc(Br)cnc1N
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a suspension of 2-amino-5-bromo-nicotinic acid hydrobromide (4.00 g, 13.4 mmol) in CH2Cl2 (150 mL) was added Et3N (2.79 mL, 20.1 mmol), EDC (2.70 g, 14.1 mmol), and HOBt (1.91 g, 14.1 mmol) at 0° C., and the mixture was stirred for 10 min. N,N-dimethylethylenediamine was then added, and the mixture was allowed to stir overnight at room temperature. The organic solution was washed with 2 N NaOH (2×20 mL), H2O (2×20 mL) and brine, dried over Na2SO4 and filtered. The solvent was concentrated to give the title compound (2.70 g, 70%) as a yellow solid: MS (ESI) m/e 287 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[N:36]=2)[N:33]=1>CN(C)C=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([N:34]=[C:35]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)OC(=O)c1nc2ccc(Cl)nn2n1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
653 mg of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 10 ml of N,N-dimethylformamide; 88 mg of a 60% dispersion of sodium hydride in mineral oil was added, followed by stirring at room temperature under reduced pressure for 1.5 hours. To the reaction mixture, 483 mg of isopropyl (6-chloro[1,2,4]triazolo[1,5-b]pyridazin-2-yl)carboxylate was added under ice cooling conditions, followed by stirring at constant temperature for 3.5 hours. Ice water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (10:1). The desired fraction was collected and concentrated; the crystal precipitated was washed with ethyl ether, collected by filtration and dried to yield 462 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29][N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH2:26]3)[CH:9]=2)[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](n3cc(-c4cccc(OCc5ccccc5)c4)c4c(N)ncnc43)C2)cc1
Reactant: C1COCCN1
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CN2CCOCC2)C1

Procedure:
A solution of 50 mg (0.09 mmol) of trans-toluene-4-sulfonic acid 3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl ester in 1 ml of morpholine (Fluka, Buchs, Switzerland) is stirred at RT for 72 h. The solvent is evaporated to dryness and the residue is purified by flash-chromatography (ethylacetate:methanol:NH4OHaqu.=95:5:1) to provide trans-5-(3-benzyloxy-phenyl)-7-(3-morpholin-4-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine. Analytical HPLC: tR=9.29 min (Grad 1); ES-MS: m/eo=470.0.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C:8](=[S:11])([O-:10])[CH3:9].[K+]>CN(C=O)C>[C:8](=[O:10])([S:11][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)[CH3:9]
Reactant: CC([O-])=S
Reactant: ClC1CCOCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCOCC1

Procedure:
A mixrue of 4-chlorotetrahydro-2H-pyran (1 g, 8.29 mmol) and potassium ethanethioate (0.947 g, 8.29 mmol) in DMF (15 mL) was stirred at 80° C. for 24 h. The reaction mixture was cooled down and partitioned between hexane and cold 1N Na OH. The organic layer was washed with brine, dried (MgSO4), removed the solvent to afford S-tetrahydro-2H-pyran-4-yl ethanethioate as a pale brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.68 (2 H, m), 1.90 (2 H, m), 2.32 (3 H, s), 3.55 (2 H, m), 3.68 (1 H, m), 3.91 (2 H, dt, J=11.83, 3.90 Hz). Into a solution of S-tetrahydro-2H-pyran-4-yl ethanethioate in DCm (3 mL) and water (3 mL) at −10° C., chlorine gas was bubbled for ˜5 min slowly until persistent greenish color was maintained. The mixture was stirred for 0.5 h at r.t. and blown with air for 5 min and diluted with ether (5 mL). The mixture was added to concentrated ammonium hydroxide (5mL, 128 mmol) at 0° C. over 10 min. The mixture was stirred for 1 h and evaporated to dryness. The residue was taken up with EtOAc and filtered through 2″ silica gel pad and eluted with EtOAc/hexane (80% to 100%) to afford tetrahydro-2H-pyran-4-sulfonamide as a brown solid (113 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.88 (2 H, m), 2.08 (2 H, ddd, J=12.72, 3.65, 1.76 Hz), 3.15 (1 H, tt, J=12.06, 3.81 Hz), 3.40 (2 H, td, J=11.96, 2.27 Hz), 4.11 (2 H, dd, J=11.33, 4.28 Hz), 4.48 (2 H, br. s.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC(C)C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
127 mg (0.23 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)benzoate (racemate) (Example 25.1C) were hydrolysed with TFA according to General Method 2. Yield: 79 mg (71% of theory)