Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)=[O:3].[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15].ClC1C=CC(C(C2CC2)(O)CC(OCC)=O)=CC=1>>[O:8]1[C:7]2[CH:12]=[CH:13][C:4]([C:2]([OH:3])([CH3:1])[CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1
Reactant: CC(=O)c1ccc2c(c1)OCCO2
Reactant: CCOC(C)=O
Agent: CCOC(=O)CC(O)(c1ccc(Cl)cc1)C1CC1
Product: CCOC(=O)CC(C)(O)c1ccc2c(c1)OCCO2

Procedure:
The title compound was prepared starting from 2.00 g (11.22 mmol) of 1,4-benzodioxan-6-yl methyl ketone and 4.74 ml (22.45 mmol) of ethyl acetate in analogy to the synthesis of the compound from Example 90A. 2.52 g (84% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]1([CH3:35])[C:2]([NH:7][C:8]2[O:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[C:11]([C:13](=[O:15])[NH2:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl.O1CCOCC1>C(Cl)Cl.CO>[C:1]1([CH3:35])[C:2]([NH:7][C:8]2[O:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[C:11]([C:13]([NH2:14])=[O:15])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1Nc1nc(C(N)=O)c(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)o1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccccc1Nc1nc(C(N)=O)c(-c2ccc(N3CCNCC3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 4-(4-(2-(o-toluidino)-4-carbamoyloxazol-5-yl)phenyl)piperazine-1-carboxylate (0.012 g, 0.025 mmol) in DCM (0.5 ml) was added 0.5M HCl in dioxane (0.25 m, 0.125 mmol) and the resulting solution stirred at room temperature for 2 hours. The mixture was then diluted with MeOH and purified by SPE using a MP-TsOH (500 mg) cartridge to afford 2-(o-toluidino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.0087 g, 0.023 mmol, 92%). 1H NMR (DMSO) δ 2.30 (3H, s), 2.84 (4H, m), 3.15 (4H, m), 6.97-7.01 (3H, m). 7.19-7.23 (2H, m), 7.32 (1H, br. d), 7.41 (1H, br. d), 7.99 (1H, dd), 8.07 (2H, d), 9.26 (1H, s). LCMS (2) Rt: 2.32 min; m/z (ES+) 378.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](F)[N:12]=3)[C:4]=2[CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]1.CN1CCOCC1.O>CN1CCCC1=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:12]=[C:13]([N:18]4[CH2:23][CH2:22][CH2:21][C@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:19]4)[CH:14]=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: Fc1cccc(-n2ncc3cnc(Cl)cc32)n1
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)C1
Temperature: 100 °C
Yield: 83.5 %

Procedure:
A mixture of 6-chloro-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (2.998 mmol; 745.3 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (4.496 mmol; 900.5 mg), and N-Methylmorpholine (8.993 mmol; 919 mg; 0.999 mL) in 1-methyl-2-pyrrolidinone (10 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was poured into water. The precipitate was collect by filtration, then purified on silica eluted with 0 to 40% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]-3-piperidyl]carbamate (1.0738 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([CH3:28])[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)C1=C(C)N(C)C(c2nccs2)=NC1c1ccc(F)cc1Cl
Temperature: 70 °C
Reaction time: 12 h
Yield: 47.9 %

Procedure:
A mixture of ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 5.3 mmol), iodomethane (0.97 g, 6.84 mmol) and potassium carbonate (1.47 g, 10.6 mmol) in acetonitrile (50 mL) was stirred at 70° C. for 12 hours, and cooled to 25° C. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a tawny solid (1.0 g, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:19](=O)[CH3:20])=[CH:4][C:5]2[CH2:11][CH2:10][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:8][CH2:7][C:6]=2[CH:18]=1.[N:22]1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>O>[CH3:20][C:19]1[C:3]2[C:2](=[CH:18][C:6]3[CH2:7][CH2:8][N:9]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:11][C:5]=3[CH:4]=2)[O:1][N:22]=1
Reactant: CC(=O)c1cc2c(cc1O)CCN(C(=O)C(F)(F)F)CC2
Reactant: c1ccncc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cc1noc2cc3c(cc12)CCN(C(=O)C(F)(F)F)CC3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-[8-hydroxy-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]ethanone (7.4 mmol) in pyridine (15 ml) hydroxylamine hydrochloride (8.9 mmol) was added at room temperature and the reaction mixture was stirred for 4 h. Solvent was removed under reduced pressure, the residue was partitioned between 10% aqueous Na2CO3 and EtOAc. The organic layer was collected and the aqueous phase extracted twice with EtOAc. The combined organic layers were concentrated and the resulting material was dissolved in THF (5 ml) and Ph3P (15 mmol) was added. The reaction mixture was stirred at 50° C. for 10 min while DEAD (15 mmol, 40% in toluene) was slowly added. The reaction mixture was stirred at 50° C. for 15 min then cooled to room temperature and water (0.4 ml) was added. Solvent was removed under reduced pressure and the residue was submitted to column chromatography to provide 3-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-isoxazolo[4,5-h][3]benzazepine (NMR 1H, CDCl3): δ 7.4-7.3 (m, 2H), 3.85-3.65 (m, 4H), 3.15-3.05 (m, 4H), 2.55 (s, 3H). MS (m/z): 299 [MH]+). Treatment with K2CO3 (4 eq) in MeOH:H2O (1:1) gave the title compound (1.3 mmol) as pale yellow oil, which was used without further characterisation.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH:4]([CH3:6])[CH3:5])[CH3:3].C[Li].Cl[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12].O>O1CCCC1.C(OCC)C>[C:11](=[O:12])([O:13][CH2:14][CH:15]=[CH2:16])[O:7][C:2]([CH3:3])([CH:4]([CH3:6])[CH3:5])[CH3:1]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)C(C)(C)O
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC(=O)OC(C)(C)C(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 10.22 grams (0.10 mole) of 2,3-dimethylbutan-2-ol in 75 milliliters of anhydrous tetrahydrofuran at 0° C was added one equivalent of methyllithium in diethyl ether, followed by 12.1 grams (0.10 mole) of allyl chloroformate in 25 milliliters of anhydrous tetrahydrofuran. During both additions the temperature was maintained at 0° C. After the last addition was complete the reaction mixture was stirred for about 18 hours and allowed to warm to ambient temperature. The reaction mixture was poured into water, and then extracted with ether. The ether solution was washed four times with water and dried over magnesium sulfate. Removal of solvent under reduced pressure yielded 16.45 grams (88.4% crude yield) of a light yellow oil. Distillation under vacuum provided three fractions.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10](Br)[CH3:11])=[CH:5][CH:4]=1.C1COCC1.C([Li])CCC.Cl[P:34]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>O>[CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[C:10]([P:34]([CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]2)[CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[CH3:11])=[CH:5][CH:4]=1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: CC(Br)=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1)P(C1CCCCC1)C1CCCCC1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
Into a reactor were introduced 1.44 g (4.00 mmol) of the 1,1-bis(4-dimethylaminophenyl)-2-bromopropene obtained in Example 4 (2) and 14 mL of THF under a nitrogen atmosphere. The contents were cooled to −60° C. Thereto was gradually added dropwise 2.8 mL (4.4 mmol; 1.6 M hexane solution) of butyllithium. The resultant mixture was stirred at that temperature for 1 hour. Thereafter, 0.97 mL (4.4 mmol) of chlorodicyclohexylphosphine was added thereto, and this mixture was stirred for 30 minutes, subsequently heated to room temperature, and then further stirred for 17 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol and hexane to obtain 0.44 g (23%) of the target compound as white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[C:8]2\[CH2:9][N:10]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:12][CH:13]\2O)[CH:2]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[C:46]([O-:49])(=[S:48])[CH3:47].[K+]>ClCCl.C(OCC)(=O)C>[C:46]([S:48][CH:13]1[CH2:12][CH2:11][N:10]([C:15]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]/[C:8]/1=[CH:7]\[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:49])[CH3:47]
Reactant: CC([O-])=S
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cccnc1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
To a solution of (E)-3-[(pyridin-3-yl)methylidene]-1-(triphenylmethyl)piperidin-4-ol (5.40 g) in dichloromethane (85 ml) were added successively methanesulfonyl chloride (1.93 ml) and triethylamine (3.49 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated in vacuo, and the residue was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in dimethyl sulfoxide (75 ml) was added potassium thioacetate (7.10 g) at room temperature, and the resulting mixture was stirred at 40° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (2.68 g, yield: 42%) as a pale brown amorphous solid.
Reaction SMILES: C(NC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(OC(C)(C)C)=O)[C@H]1CC(C)(C)CC(O)=O)CCC.COCCC1CC2C(=CC=CC=2)NC1.C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C(=CC=CC=2)CC(COCC=C)C1)=O)CCC.[CH2:90]([NH:94][C:95](=[O:131])[C@H:96]([CH3:130])[CH2:97][C@H:98]([OH:129])[C@@H:99]([NH:121]C(OC(C)(C)C)=O)[CH2:100][C:101]([CH3:120])([CH3:119])[CH2:102][C:103]([N:105]1[C:114]2[C:109](=[CH:110][CH:111]=[CH:112][CH:113]=2)[CH2:108][CH:107]([CH2:115][CH2:116][O:117][CH3:118])[CH2:106]1)=[O:104])[CH2:91][CH2:92][CH3:93].C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)CC(C)(C)CC(N1C2C=CC=CC=2OC(C=NOC)C1)=O)CCC>>[CH2:90]([NH:94][C:95](=[O:131])[C@H:96]([CH3:130])[CH2:97][C@H:98]([OH:129])[C@@H:99]([NH2:121])[CH2:100][C:101]([CH3:119])([CH3:120])[CH2:102][C:103]([N:105]1[C:114]2[C:109](=[CH:110][CH:111]=[CH:112][CH:113]=2)[CH2:108][CH:107]([CH2:115][CH2:116][O:117][CH3:118])[CH2:106]1)=[O:104])[CH2:91][CH2:92][CH3:93]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(CCOC)Cc2ccccc21)NC(=O)OC(C)(C)C
Agent: C=CCOCC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC)C1
Agent: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CC(=O)O
Agent: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)(C)CC(=O)N1CC(C=NOC)Oc2ccccc21)NC(=O)OC(C)(C)C
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(CCOC)Cc2ccccc21

Procedure:
Starting from 230 mg of 3-[N-tert-butoxycarbonyl-4(S)-(3-carboxy-2,2-dimethylpropyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-methyl-propionic acid (N-butyl)amide and 287 mg of 3(R,S)-methoxyethyl-1,2,3,4-tetrahydroquinoline via (4O,5N-isopropylidene)-5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[3(R,S)-methoxyethyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonyl]-octanoic acid (N-butyl)amide (analogously to Example 1a); Rf (A)=0.17; Rt (VI)=35.8 min) and 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[3(R,S)-methoxyethyl-1,2,3,4-tetrahydroquinolin-1-ylcarbonyl]-octanoic acid (N-butyl)amide (Rf (V)=0.81; Rt (VI)=31.0 min) in a manner analogous to that described in Example 1) as a diastereomer mixture: Rf (V)=0.44; Rt (VI)=23.6 min; FAB-MS: (M+H)+ =490.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:14][CH2:15][CH2:16][C@@H:17]2[CH2:19][C@@H:18]2[CH:20]2[CH2:25][CH2:24][N:23]([C:26]#[N:27])[CH2:22][CH2:21]2)=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:7]=1.[OH:28][NH:29][C:30](=N)[CH:31]([CH3:33])[CH3:32].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[N:4][C:3]=1[O:14][CH2:15][CH2:16][C@@H:17]1[CH2:19][C@@H:18]1[CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[O:28][N:29]=[C:30]([CH:31]([CH3:33])[CH3:32])[N:27]=2)[CH2:22][CH2:21]1
Reactant: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C#N)CC1
Reactant: CC(C)C(=N)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCNC2=O)cnc1OCC[C@@H]1C[C@@H]1C1CCN(c2nc(C(C)C)no2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture of 4-[(1R,2S)-2-(2-{[3-methyl-5-(2-oxoimidazolidin-1-yl)pyridine-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carbonitrile (13 mg, 0.035 mmol), N-hydroxy-2-methylpropanimidamide (5 mg., 0.05 mmol) and zinc chloride (0.1 mL., 0.05 mmol) in 1 mL of DMF was stirred 2 hrs at 80° C., then PTSA (7 mg, 0.037 mmol) was added and stirred for additional 2 hrs at 85° C. The mixture was cooled to room temperature and then quenched by sat'd aq soln of NaHCO3. The mixture was extracted with EtOAc (2×5 mL), and the combined organics were then washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified Gilson HPLC eluting with a gradient of 10-90% acetonitrile in water with 0.05% TFA as buffer. The fractions containing product were collected into a 20 mL scintillation vial and frozen via a dry ice/acetone bath. The frozen material was then lyophilized overnight to give the product as a white fluffy solid. LCMS (ESI) m/z 455 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1ccccn1
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: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Temperature: 85 °C
Yield: 74.6 %

Procedure:
A mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.500 g, 1.04 mmol), 2-bromopyridine (0.164 g, 1.04 mmol), sodium carbonate (0.439 g, 4.14 mmol), tetrakis(triphenylphosphine)palladium(0) (0.120 g, 0.103 mmol) in ethylene glycol dimethyl ether (20 mL) and water (10 mL) was heated at about 85° C. for about 12 hours. The reaction mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between water (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by using preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 35 cm; 5-100% acetonitrile—0.1M ammonium acetate over 20 min, 100% acetonitrile hold 10 minutes, 21 mL/min) to give tert-butyl 4-(pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.202 g, 0.776 mmol) as a white solid; RP-HPLC (Table 1, Method b) Rt 2.78 min; m/z: (M+H)+ 261.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:11]=[C:3]1[N:4]([CH2:13][CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2]1
Reactant: O=C1COc2ccccc2N1
Reactant: O=Cc1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2C(=O)COc3ccccc32)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 91.2 %

Procedure:
A mixture of 2H-1,4-benzoxazin-3-(4H)-one (1.6 g, 10.7 mmol), 4-(2-bromoethoxy)benzaldehyde (2.95 g, 12.8 mmol) and potassium carbonate (5.93 g, 42.97 mmol) in dry dimethyl formamide (30 mL) was stirred at 80° C. for 10 h. Water (100 mL) was added and extracted with ethyl acetate (2×75 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na2SO4), filtered and the solvent was evaporated. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (2:8) to afford the title compound (2.9 g, 91%) as a colorless solid. mp: 75-78° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16]C(=O)C)[CH:5]=[CH:6][C:7]=1[S:8]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9].Cl>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[S:8]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2CCCC2)c(C)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)ccc1S(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g of N-[3-methyl-4-(pyrrolidine-1-sulphonyl)-phenyl]-acetamide (2.13 mmol) are dissolved in 5 ml of ethanol and then 10 ml hydrochloric acid (6 N) are added thereto at ambient temperature. The mixture is stirred overnight at ambient temperature and then extracted three times with dichloromethane. The combined organic phases are washed successively with 5% sodium hydrogen carbonate solution and water. The aqueous phase is re-extracted with dichloromethane and combined with the dichloromethane phase already present, dried over sodium sulphate and evaporated down. A yellow oil is obtained which slowly crystallises out.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[O:15]=[C:11]([CH3:10])[CH2:12][C:13]([NH:2][C@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:9])=[O:14]
Reactant: C=C1CC(=O)O1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H](C)NC(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
20.00 g (0.13 mol) of ethyl (2S)-2-aminopropanoate hydrochloride were added to a solution of 10.95 g (0.13 mol) of diketene in 500 ml toluene at 0° C. Then, 21.90 g (0.26 mol) NaHCO3 was added and the reaction mixture was stirred overnight at room temperature. Since no more starting material was detected by thin-layer chromatography, the reaction mixture was filtered, evaporated and the residue purified by column chromatography. This gave 19.36 g (0.096 mol, 74% yield) of a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[C:8]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][C:10]([OH:19])=[C:11]([C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[O:13])(=[O:5])[CH3:4].[CH3:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([Mg]Cl)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Cl-].[NH4+]>O1CCCC1>[C:3]([O:6][C:7]1[C:8]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][C:10]([OH:19])=[C:11]([CH:12]([OH:13])[CH:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[C:14]=1[C:15]([CH3:16])([CH3:18])[CH3:17])(=[O:5])[CH3:4]
Reactant: CCCCCC(CCCCC)[Mg]Cl
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(O)c(C=O)c1C(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(CCCCC)C(O)c1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a nitrogen atmosphere, 270 mL of tetrahydrofuran was added to 13.0 g (0.33 mol) of 60% sodium hydride under cooling with ice; to the mixture, 94.5 g (0.32 mol) of 5-acetoxy-4,6-di-tert-butyl-2-hydroxybenzaldehyde in 200 mL of tetrahydrofuran was added dropwise and the mixture was stirred for 1 hour at room temperature. Thereafter, the Grignard reagent prepared in Example 6 was added dropwise to the mixture, which was subjected to reaction for 1 hour at room temperature. Under cooling with ice, 1000 mL of a saturated aqueous solution of ammonium chloride was added and the mixture was extracted twice with 1000 mL of ethyl acetate. The organic layer was washed with 1000 mL of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering off the magnesium sulfate, the filtrate was concentrated and the concentrate was dissolved in 1000 mL of hexane under heating. Thereafter, the solution was slowly cooled down to 0° C. for crystallization and the crystal was separated and dried to give 85.6 g of 4-acetoxy-3,5-di-tert-butyl-2-(1-hydroxy-2-pentylheptyl)phenol.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[CH:68]=[C:67]([F:69])[CH:66]=[CH:65][C:61]=1[C:62](Cl)=[O:63]>>[F:59][C:60]1[CH:68]=[C:67]([F:69])[CH:66]=[CH:65][C:61]=1[C:62]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:63]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)cc4F)cc3)cc2C1=O

Procedure:
The compound of example 109 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 2,4-difluorobenzoyl chloride. The compound of example 109 was used directly without isolation for the preparation of compound of example 110.