Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:4][C:5]2[C:6]([N:17]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15][OH:16])[O:8]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[NH:4][C:5]2[C:6]([N:17]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15][O:16][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[O:8]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCc2ccc3[nH]c(C(F)(F)F)nc3c2O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Yield: 86.9 %

Procedure:
A solution of (2-trifluoromethyl-3,6,7,8-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl)-methanol (400 mg, 1.47 mmol) and p-toluenesulfonyl chloride (344 mg, 1.76 mmol) in anhydrous pyridine (50 mL) was stirred for 12 hours and then the solvent was removed in vacuo to give a residue. The residue was dissolved in ethyl acetate (100 mL) and washed with water (3×30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent removed in vacuo to a residue. The residue was purified by chromatography (20% CH2Cl2-hexanes) to give 545 mg (87%) of the title compound as a solid: mp 160° C.; 1H NMR (400 MHz, CDCl3): [tautamer a]:δ1.95 (m, 1H), 2.05 (m, 1H), 2.44 (s, 3H), 2.90 (m, 2H), 4.30 (m, 2H), 4.40 (m, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.3 Hz, 2H), 10.35 (bs, 1H). [tautamer b]: δ1.95 (m, 1H), 2.05 (m, 1H), 2.44 (s, 3H), 2.90 (m, 2H), 4.25 (m, 2H), 4.40 (m, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.84 (d, J=8.3 Hz, 2H), 9.95 (bs, 1H); IR: 3400, 3080, 2970, 1600, 1550, 1500, 1080 cm−1; MS 427 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:5]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][C@@H:31]2[CH2:33][C@H:28]1[CH2:29][NH:30]2)=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(CC)CC>CC#N>[C:20]([O:24][C:25]([N:27]1[CH2:32][C@@H:31]2[CH2:33][C@H:28]1[CH2:29][N:30]2[CH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:5]=1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: BrCCc1ccc(Oc2nc3ccccc3s2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2CCc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.1 %

Procedure:
To a stirred solution of 2-[4-(2-bromo-ethyl)-phenoxy]-benzothiazole (1.5 g, 4.5 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (980 mg, 4.9 mmol) in CH3CN (20 mL) at rt was added Et3N (900 μL, 6.3 mmol). The resulting suspension was stirred at rt for 24 h and then partitioned between CH2Cl2 (200 mL) and satd. aq. NaHCO3 (80 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (EtOAc) afforded the title compound as a white foam (1.1 g, 56%). MS (ESI): mass calcd. for C25H29N3O3S, 451.19; m/z found, 452.2 [M+H]+. 1H NMR (500 MHz, CDCl3, mixture of rotamers): 7.73 (d, J=8.4 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.38 (m, 1H), 7.30-7.24 (m, 5H), 4.38 (br m, 0.5H), 4.24 (br m, 0.5H), 3.53 (br m, 2H), 3.16 (t, J=10.4 Hz, 1H), 3.03 (d, J=8.4 Hz, 0.5H), 2.98 (d, J=9.8 Hz, 0.5H), 2.86-2.74 (br m, 4H), 2.69 (br d, J=9.8 Hz, 0.5H), 2.52 (br d, J=9.4 Hz, 0.5H), 1.84 (br d, J=9.2 Hz, 1H), 1.73 (br d, J=10.0 Hz, 0.5H), 1.69 (br d, J=9.2 Hz, 0.5H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[N:25]1([C:30]2[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[CH2:38]O)=[CH:32][CH:31]=2)[CH:29]=[CH:28][N:27]=[CH:26]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:38]/[CH:37]=[CH:36]/[C:33]1[CH:32]=[CH:31][C:30]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:35][CH:34]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OC/C=C/c1ccc(-n2ccnc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(-n3ccnc3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 200 mg (1 mM) of (E)-3-{4-(1-imidazolyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced was filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 494 mg (96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24](N(OC)C)=[O:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:37]1.C[Mg]Br.O>O1CCCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24](=[O:25])[CH3:37])=[CH:14][CH:13]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(=O)N(C)OC)cc12
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(C)=O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl(4-butoxy-2-isobutyl-6{[methoxy(methyl)amino]carbonyl}-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.49 g, 1 mmol) in tetrahydrofuran (10 ml) was added 1N methylmagnesium bromide tetrahydrofuran solution (5 ml) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(6-acetyl-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.37 g, 84.1%) as crystals.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH3:2].[OH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20]([OH:22])=O>B(F)(F)F.CCOCC>[CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[C:5]([C:20](=[O:22])[C:19]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:17]([OH:16])[CH:18]=2)[C:4]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH3:2]
Reactant: CCc1c(O)cc(O)cc1CC(=O)OC
Reactant: COc1ccc(C(=O)O)cc1O
Agent: FB(F)F
Solvent: CCOCC
Product: CCc1c(O)cc(O)c(C(=O)c2ccc(OC)c(O)c2)c1CC(=O)OC
Temperature: 80 °C
Reaction time: 5 h
Yield: 62.9 %

Procedure:
Methyl 2-ethyl-3,5-dihydroxyphenylacetate (2.0 g, 9.7 mmol) obtained in Example 7, Step 2 was suspended in boron trifluoride diethyl etherate (40 mL), and 3-hydroxy-4-methoxybenzoic acid (1.7 g, 11 mmol) was added thereto, followed by stirring at 80° C. for 5 hours. After cooling to room temperature, the reaction mixture was added dropwise to ice-cold water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-9/1) to obtain methyl 2-ethyl-3,5-dihydroxy-6-(3-hydroxy-4-methoxybenzoyl)phenylacetate (2.2 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[N+:6]([O-:8])[CH:7]=1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[C:10]1([CH2:9][S:16][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N+:6]=2[O-:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [O-][n+]1cccc(Cl)c1
Reactant: SCc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Cl)ccc1SCc1ccccc1

Procedure:
As described in U.S. Pat. No. 4,394,155, Example 1, 2-(phenylmethylthio)-5-chloropyridine N-oxide is prepared from 5-chloropyridine N-oxide and benzylmercaptan. To a well stirred solution of 2.5 g (9.01 mol) of the thio compound in 25 mL chloroform is added 4 g (0.02 mol) of MCPBA in 50 mL chloroform.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].[C:17]1([S:23]([NH2:26])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[C:17]1([S:23]([NH:26][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
N,N'-carbonyldiimidazole (14.45 g) was added to a solution of 10.00 g of 4-acetylamino-3-nitrobenzoic acid in 300 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, 14.03 g of benzenesulfonamide and 13.58 g of diazabicycloundecene were added thereto, and the mixture was stirred at 100° C. for 72 hours. The reaction mixture was separated with the addition of chloroform and water. The organic layer was then concentrated, and the resulting residue was purified through silica-gel column chromatography (eluent: a mixture of ethyl acetate and methanol at a ratio of 4:1) to give 12.67 g of N-benzenesulfonyl-4-acetylamino-3-nitrobenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH:12]=[C:13]([CH3:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:18][NH2:19]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][C:13]([CH3:15])([CH3:14])[NH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: COc1ccc(C(=O)C=C(C)C)cc1OC
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NNC(C)(C)C2)cc1OC
Temperature: 80 °C
Yield: 100 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar, Vigreux column and nitrogen inlet was charged with 1-(3,4-dimethoxy-phenyl)-3-methyl-but-2-en-1-one (1.4 g, 10 mmol), EtOH (40 mL) and hydrazine monohydrate (0.58 mL, 12 mmol). The mixture was heated at 80° C. for 2 h. LC-MS and TLC analysis showed consumption of SM. The solvent was evaporated under reduced pressure and trace hydrazine and EtOH was removed under high vacuum for 30 min. The material was used as in the next step. Amount obtained: 2.3 g, 10 mmol, 100% yield. LC-MS (ESI) m/e 235 (M+H). Step 3
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.[C:44]([C:48]1[O:49][C:50]([CH3:68])=[C:51]([CH2:53][CH2:54][O:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]([CH:66]=[O:67])=[CH:58][CH:57]=2)[N:52]=1)([CH3:47])([CH3:46])[CH3:45]>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:66]([C:59]1[C:60]2[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:56]([O:55][CH2:54][CH2:53][C:51]2[N:52]=[C:48]([C:44]([CH3:47])([CH3:46])[CH3:45])[O:49][C:50]=2[CH3:68])=[CH:57][CH:58]=1)[OH:67])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Cc1oc(C(C)(C)C)nc1CCOc1ccc(C=O)c2ccccc12
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(C(C)(C)C)oc2C)c2ccccc12

Procedure:
0.234 g of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (0.889 mmol) was dissolved under an argon atmosphere in 3 ml of abs. CH2Cl2 and treated with 0.149 ml of triethylamine (1.2 eq.). After cooling to −78°, nBu2BOTf was added slowly (0.980 ml of 1M solution in CH2Cl2) and enolborinate formation allowed to proceed for 15 Min. at −78° and for 50 Min. at 0°. After recooling, a solution of 0.300 g of the above prepared 4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-naphthalene-1-carbaldehyde (0.889 mmol) in 5 ml of abs. CH2Cl2 was slowly added via dropping funnel and the mixture kept for 30 Min. at −78° and for additional 30 Min. at 0°. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=1/1) left finally 0.268 g of the title compound as white foam.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=1)=O.Br.Br.Br.[CH2:14]([C:16]1[C:17]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([C:33]4[NH:34][C:35]5[CH2:40][CH2:39][NH:38][CH2:37][C:36]=5[N:41]=4)=[N:29][NH:30]3)=[CH:26][CH:25]=2)=[CH:18][C:19]([F:23])=[C:20]([OH:22])[CH:21]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:21]=[C:20]([OH:22])[C:19]([F:23])=[CH:18][C:17]=1[C:24]1[CH:32]=[C:31]2[C:27]([C:28]([C:33]3[NH:34][C:35]4[CH2:40][CH2:39][N:38]([CH2:1][C:3]5[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[CH:4]=5)[CH2:37][C:36]=4[N:41]=3)=[N:29][NH:30]2)=[CH:26][CH:25]=1)[CH3:15]
Reactant: N#Cc1cc(C=O)ccn1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccnc(C#N)c3)C4)n[nH]c2c1
Yield: 24.6 %

Procedure:
The title compound was prepared from 4-formyl-pyridine-2-carbonitrile (26 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 18. The crude material was purified by HPLC Method B to afford 16 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH:8]2[CH:6]([O:7]2)[C:5](=[O:9])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:13]O>O>[CH3:13][O:7][C:6]1[C:5](=[O:9])[CH2:4][CH2:3][C:2]([CH3:10])([CH3:1])[CH:8]=1
Reactant: CC1(C)CCC(=O)C2OC21
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC1=CC(C)(C)CCC1=O
Reaction time: 20 h
Yield: 45.9 %

Procedure:
A solution of 5,5-dimethyl-7-oxabicyclo[4.1.0]heptan-2-one (19.4 g, 138.4 mmol) in methanol (95 mL) was added to a solution of 85% potassium hydroxide (9.1 g, 138.4 mmol) in methanol (285 mL) at room temperature. The mixture was kept at this temperature for 20 hours and was then heated to reflux for 30 minutes. After cooling, the solution was diluted with water (750 mL) and extracted with diethyl ether (350 mL×4). The organic extracts were collected, washed with brine, dried on Na2SO4 and evaporated to dryness. The crude material was taken up with hexane (380 mL), maintained under vigorous stirring for 30 minutes and filtered to remove the solid material. The filtrate was evaporated under vacuum to obtain the pure title compound (9.8 g, 45.9% yield) as a pale yellow oil.
Reaction SMILES: [C:1]([CH:5]1[N:9]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[CH:17]=2)=[C:6]1[OH:33])([CH3:4])([CH3:3])[CH3:2].C(C1[N:42](CC2C=CC(F)=C(C)C=2)[C:41](=O)C(C2NC3C=CC(NS(C)(=O)=O)=CC=3S(=O)(=O)C=2)=C1O)(C)(C)C>>[C:1]([CH:5]1[N:9]([CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[C:17]=2[C:41]#[N:42])=[C:6]1[OH:33])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(CN2C(=O)C(C3=CS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)C2C(C)(C)C)ccc1F
Reactant: CC(C)CCN1C(=O)C(C2=CS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C1C(C)(C)C
Product: CC(C)CCN1C(=O)C(C2=C(C#N)S(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)C1C(C)(C)C

Procedure:
N-{3-[5-tert-Butyl-4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-2-cyano-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide was prepared from N-{3-[5-tert-butyl-4-hydroxy-1-(3-methyl-butyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-7-yl}-methanesulfonamide (15c, R3=Me2CH(CH2)2) to afford 28 mg (27%) of I-26: LCMS RT 2.48 min, M−H.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.Cl.[CH3:16][N:17]([CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1)[C:18]([C:20]1[N:25]=[C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=1)=[O:19].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:16][N:17]([CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1)[C:18]([C:20]1[N:25]=[C:24]([CH:26]2[CH2:27][CH2:28][N:29]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:30][CH2:31]2)[CH:23]=[CH:22][CH:21]=1)=[O:19]
Reactant: CN(C(=O)c1cccc(C2CCNCC2)n1)C1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2cccc(C(=O)N(C)C3CCCc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (81 mg, 0.39 mmol), 1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide hydrochloride salt (150 mg, 0.39 mmol), and diisopropylethylamine (0.41 mL, 0.39 mmol) in DMF (10 mL) was added dropwise BOP (191 mg, 0.39 mmol) at RT. After stirring overnight at RT, the reaction mixture was poured on water (10 mL) and extracted with ethylacetate (20 mL). The aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with aq. sat. sodium bicarbonate solution (30 mL), 1M HCl solution (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate) to give 1′-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-carboxylic acid methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide (150 mg, 71%). M.p 62-65° C. 1H-NMR (400 MHz, CDCl3): δ=1.67-2.02 (m, 6H), 2.18-2.22 (m, 1H), 2.30 (s, 3H), 2.71 (s, 3H), 2.72-2.75 (m, 2H), 3.17-3.27 (m, 2H), 3.97-4.05 (m, 2H), 4.58-4.78 (m, 2H), 4.96 (s, 2H), 5.05-5.15 (m, 1H), 6.33 (s, 1H), 7.10-7.24 (m, 4H), 7.28-7.32 (m, 1H), 7.57-7.58 (m, 1H), 7.76-7.78 (m, 1H).
Reaction SMILES: C([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH2:28])=[N:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[C:13](=[O:29])[CH:12]1[CH2:30][O:31][CH3:32])=O)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:64][C:65]1[CH:66]=[CH:67][C:68]2[N:72]=[C:71](C(O)=O)[NH:70][C:69]=2[CH:76]=1>CN(C=O)C>[NH2:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:71]4[NH:70][C:69]5[CH:76]=[C:65]([Cl:64])[CH:66]=[CH:67][C:68]=5[N:72]=4)=[O:8])[C@@H:12]([CH2:30][O:31][CH3:32])[C:13]3=[O:29])=[CH:19][CH:20]=2)[N:25]=[CH:24][N:23]=1
Reactant: O=C(O)c1nc2ccc(Cl)cc2[nH]1
Reactant: COCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)c1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(4-amino-quinazoline-7-ylmethyl)-2-methoxymethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester, EXAMPLE 75, (20 mg, 0.066 mmol) in 1.5 mL of DMF is added TBTU (923.4 mg, 0.073 mmol), diisopropylethylamine (0.013 ml, 0.073 mmol) and 6-chloro-1H-benzoimidazole-2-carboxylic acid (prepared from literature in Eur.J.med.Chem. 1993, 28, 71) (14.3 mg, 0.073 mmol). The resulting mixture is left to stir at room temperature overnight. The crude mixture is directly purified by reverse phase HPLC (10-70% ACN/H2O). The product (30.1 mg, 55%) is isolated as a white powder. C23H22ClN7O3 MS m/z: 480, 481. Anal. cald. for C23H22ClN7O3. 2C2HF3O2: C, 45.81; H, 3.42; N, 13.85. Found C, 45.19; H, 3.59; N, 13.76.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].[CH2:28]([S:31](Cl)(=[O:33])=[O:32])[CH2:29][CH3:30]>>[CH2:28]([S:31]([O:26][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=1[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:27])[NH:6]2)(=[O:33])=[O:32])[CH2:29][CH3:30]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Product: CCCS(=O)(=O)Oc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(C)=O)=C(C)N2

Procedure:
The title compound is prepared in analogy to example 10 from 50 mg (0.13 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one and 17 μl (0.15 mmol) of propanesulfonyl chloride. 46 mg (71% of theory) of the product are obtained as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:30][C@H:31]1[CH2:36][NH:35][CH2:34][C@@H:33]([CH3:37])[NH:32]1>CS(C)=O>[CH3:30][C@H:31]1[NH:32][C@@H:33]([CH3:37])[CH2:34][N:35]([C:2]2[N:3]([CH2:24][CH:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C:4]3[C:9]([N:10]=2)=[C:8]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:7]=[C:6]([C:17]2[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=2)[N:5]=3)[CH2:36]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CCOC2)C[C@H](C)N1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
A mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.24 mmol), cis-2,6-dimethylpiperazine (82 mg, 0.72 mmol), and dimethyl sulfoxide (800 μl) was stirred at 150° C. for 1.5 hours. The reaction mixture was cooled and then partitioned with ethyl acetate and water and the organic layer was washed twice with saturated brine and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (chloroform:methanol=9:1) to give the title compound (64 mg, 57%) as a light brown solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:12]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:24][C:23]2[CH:25]=[CH:26][C:20]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCCCCCCCc1ccc(N)cc1
Product: CCCCCCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 66.7 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (0.75 g) and 4-octylaniline (1.0 g) as starting materials, [(4-dimethylaminophenyl)methyl](4-octylphenyl)amine (1.1 g) was obtained.