Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17](O)(=[O:25])[C@@H:18]([C@H:20]([C:22](O)=[O:23])[OH:21])[OH:19].CO>CCOC(C)=O>[CH2:9]([N:16]1[C:22](=[O:23])[C@H:20]([OH:21])[C@@H:18]([OH:19])[C:17]1=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1[C@H](O)[C@@H](O)C(=O)N1Cc1ccccc1
Temperature: 135 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A mixture of xylene, (1.2 L), benzylamine (120 g, 1.10 mol, 1.0 eq) and L-(+)-tartaric acid (173 g, 1.15 mol, 1.05 eq) were heated at 135° C. for 12 hr (flask jacket temperature). Upon reaction completion, the mixture was cooled to 65° C. and MeOH (120 mL, 1 vol) was added. The resulting mixture was stirred for 1 hr and the resulting suspension was cooled to 20° C. followed by the addition of EtOAc (480 mL). Stirring was continued at 10° C. for 2 hr. The crude product was isolated by filtration and washed with EtOAc (120 mL) and dried on the filter. The crude product was then taken up in MeOH (480 mL) and heated at a gentle reflux for 1 hr, then cooled to 20° C. and granulated for 1 hr. The suspension was filtered and the precipitate washed with MeOH (240 mL) and dried to give the title compound (191 g, 864 mmol, 79%) as a white granular solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.38-7.30 (m, 2H) 7.30-7.22 (m, 3 H) 6.32 (br. s., 1 H) 4.59 (d, J=14.8 Hz, 1 H) 4.53 (d, J=14.8 Hz, 1 H) 4.40 (br. D., J=4.3 Hz, 2 H). m/z (EI+) for C11H11NO4 221.0 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.Cl[CH2:25][CH:26]1[O:31][CH2:30][CH2:29][N:28](CC2C=CC=CC=2)[CH2:27]1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH:26]3[O:31][CH2:30][CH2:29][NH:28][CH2:27]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CNCCO2)cc1

Procedure:
The title compound was prepared by alkylation of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide with 2-chloromethyl-4-benzylmorpholine, according to the procedure described in example S-1, step b, followed by subsequent deprotection using the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 0.05M in MeOH, 70° C.). 1H NMR (DMSO) δ 2.59-2.70 (2H, m), 2.90-3.00 (2H, m), 3.41-3.51 (1H, m), 3.69-3.79 (2H, m), 4.00 (2H, d), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.21-8.30 (2H, m). LCMS (2) 2.38 min; m/z (ES+) 416.
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.O.O.O.O.O.O.[Ni:16](Cl)Cl>>[CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[Ni:16]
Reactant: Cl[Ni]Cl
Agent: O=c1cccccc1O
Solvent: O
Product: [Ni]

Procedure:
Tropolone (244 mg) is treated with nickel chloride hexahydrate (237 mg) in the same manner as that in the case of cobalt complex to give 287 mg of tropolone nickel complex as light green needles.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:24][C:25]#[N:26])[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)[CH:12]=2)[N:5]2[CH:27]=[CH:28][N:29]=[C:4]2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.C([O-])(O)=O.[Na+].C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[C:25]([CH2:24][C:13]1([N:11]2[CH:12]=[C:8]([C:6]3[N:5]4[CH:27]=[CH:28][N:29]=[C:4]4[CH:3]=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)#[N:26]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3nc(Cl)cc4nccn34)cn2)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cc1
Temperature: 75 °C
Yield: 104.2 %

Procedure:
tert-Butyl 3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate (Preparation N; 2.80 g, 6.76 mmol), 4-methoxybenzeneboronic acid (1.54 g, 10.1 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.644 g, 1.35 mmol) and K3PO4 (10.1 mL, 20.3 mmol) were suspended in 1,4-dioxane (30 mL) and purged with Ar (g). Pd2dba3 (0.619 g, 0.676 mmol) was added and the system sealed and heated at 75° C. overnight. The reaction mixture was diluted with EtOAc and saturated aqueous NaHCO3. The bi-phasic mixture was passed through a pad of Celite® to remove solids. The Celite® was washed with DCM and MeOH. The organic layer was separated and then washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford some crude material. This was combined with the DCM and MeOH washed off the Celite® to afford the crude total material. The crude material was suspended in DCM to load onto a column. Many solids did not dissolve and were collected and identified as desired crude material. The crude material was loaded onto a column and purified by flash column chromatography, eluting with 2-4% (9:1 MeOH:NH4OH)/DCM to provide tert-butyl 3-(cyanomethyl)-3-(4-(7-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3.42 g, 7.044 mmol, 104.3% yield). MS (apci) m/z=486.2 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH2:15][C:16]([OH:18])=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl>CN(C=O)C.O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:7]([CH2:15][C:16]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:18])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1CC(=O)O
Reactant: C1COCCN1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(C)(C)C)nn1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
To a solution of 2-(3-tert-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)acetic acid from Example B17 (0.77 g, 3.02 mmol) in DMF (5 mL) were added EDC (0.75 g, 3.93 mmol), HOBt (0.55 g, 3.62 mmol) and morpholine (0.39 g, 4.53 mmol). After stirring the mixture for 4 h at RT, water (50 mL) and 3M HCl (5 mL) were added and the product was extracted with EtOAc (3×30 mL). The combined organic layers were washed with aq. LiCl, dried (Na2SO4), concentrated and purified by chromatography (EtOAc/CH2Cl2) to afford ethyl 3-tert-butyl-1-(2-morpholino-2-oxoethyl)-1H-pyrazole-5-carboxylate (0.67 g, 69% yield) as a solid. 1H NMR (400 MHz, Acetone-d6): δ 6.74 (s, 1H), 5.40 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.73 (brs, 2H), 3.65-3.62 (m, 4H), 3.51 (brs, 2H), 1.32 (t, J=7.2 Hz, 3H), 1.29 (s, 9H); MS (ESI) m/z: 324.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].Cl>C(Cl)Cl>[CH3:36][S:37]([NH:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CCN(CCOc3ccc(N)cc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCCN2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Reaction time: 2 h
Yield: 47.7 %

Procedure:
To the above amine (1.50 g, 3.59 mmol) in CH2Cl2 (30 mL) at 0° C. under nitrogen was added pyridine (0.58 mL, 7.18 mmol) and methanesulfonyl chloride (0.42 mL, 5.38 mmol). After stirring for 2 hours, the mixture was partitioned between 10% aqueous NaHCO3 and 4:1 CH2Cl2 /isopropanol. The organic phase was dried and concentrated to afford a residue which was treated with ethanolic HCl to give 0.85 g (48%) of the title compound as a hydrochloride: mp: 170°-175° C.; 1H NMR (DMSO-d6): δ10.12 (s, 1H), 9.45 (s, 1H), 7.45 (d, J=8.56 Hz, 2H), 7.25 (d, J=8.59 Hz, 2H), 7.16 (d, J=8.96 Hz, 2H), 6.97 (d, J=8.97 Hz, 2H), 4.37 (m, 2H), 3.60-3.25 (m, 10H), 3.05 (s, 3H), 2.87 (s, 3H), IR (KBr): 3010, 2580, 2460, 1640, 1610 cm-1 ; MS (m/z) 497 (MH+, 10 %) 198 (35), 79 (100).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14].[OH-].[Na+]>>[I:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[NH:4][C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][C:13]2=[O:14]
Reactant: Nc1ccccc1I
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: O=c1cc(C(F)(F)F)[nH]c2c(I)cccc12
Temperature: 180 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
A mixture of 2-iodoaniline (25.0 g), ethyl 4,4,4-trifluoro-3-oxobutanoate (20.8 g), and PPA (78.0 g) was stirred at 180° C. for 1 hour. After cooling, the reaction solution was neutralized with an aqueous sodium hydroxide solution, and the deposit was filtered and washed with water. The filtrate was rendered acidic with hydrochloric acid, and the deposit was filtered and washed with water. The filtration residues were dried under reduced pressure to obtain compound (3a) (16.2 g, 42%) as a white solid.
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH:26]([O:29][C:30]1[N:35]=[C:34]([C:36]([OH:38])=O)[CH:33]=[N:32][C:31]=1[N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)([CH3:28])[CH3:27].[CH3:45][O:46][C:47](=[O:54])[C:48]([NH2:53])([CH2:51][CH3:52])[CH2:49][CH3:50]>>[CH3:45][O:46][C:47](=[O:54])[C:48]([CH2:51][CH3:52])([NH:53][C:36]([C:34]1[CH:33]=[N:32][C:31]([N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[C:30]([O:29][CH:26]([CH3:27])[CH3:28])[N:35]=1)=[O:38])[CH2:49][CH3:50]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: CC(C)Oc1nc(C(=O)O)cnc1N1CCCCC1
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCC(CC)(NC(=O)c1cnc(N2CCCCC2)c(OC(C)C)n1)C(=O)OC

Procedure:
In analogy to the procedure described for the synthesis of 6-Propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-Isopropoxy-5-piperidin-1-yl-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 393.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>C(#N)C>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][O:1][C:2]1[CH:18]=[CH:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[N:9]=[C:4]2[CH:3]=1
Reactant: O=c1cc(N2CCOCC2)nc2cc(O)ccn12
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc(N2CCOCC2)nc2cc(OCc3ccccc3Cl)ccn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
8-Hydroxy-2-morpholinyl-4H-pyrido[1,2-a]pyrimidin-4-one (59 mg, 0.24 mmol) was dissolved in acetonitrile (10 ml) and then treated with anhydrous potassium carbonate (197 mg, 1.4 mmol) followed by 2-chlorobenzylbromide (46 mg, 0.29 mmol) and the mixture was stirred at 80° C. overnight. Upon cooling the mixture was adsorbed directly onto silica, then eluted through a silica column using ethyl acetate. The purified product was obtained as a tan solid (34 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]([C:17]1[C:18](=[O:34])[C:19]2[C:24]([C:25](=[O:33])[C:26]=1[NH:27][CH2:28][CH2:29][S:30]([CH3:32])=[O:31])=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:16])[CH3:15].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:12][N:13]([C:17]1[C:18](=[O:34])[C:19]2[C:24]([C:25](=[O:33])[C:26]=1[NH:27][CH2:28][CH2:29][S:30]([CH3:32])(=[O:9])=[O:31])=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)N(C)C1=C(NCCS(C)=O)C(=O)c2ccccc2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N(C)C1=C(NCCS(C)(=O)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
80% 3-chloroperbenzoic acid (0.78 g) was added to a solution of N-methyl-N-{3-[2-(methylsulfinyl)ethyl]amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl}acetamide (0.52 g) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (elution with chloroform-methanol 50:1 solution) to give N-methyl-N-{3-[2-(methylsulfonyl)ethyl]amino-1,4-dihydro-1,4-dioxo-2-naphthalenyl}acetamide (0.39 g) as an orange amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([Si:19]([CH3:21])([CH3:20])[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([CH3:18])([CH3:17])[CH3:16]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A mixture of 3-hydroxy-benzonitrile (5.0 g, 42.0 mmol) and imidazole (7.15 g, 105 mmol) in N,N-dimethylformamide (100 mL) was treated with tert-butyl-chloro-dimethyl-silane (7.6 g, 50.4 mmol) in N,N-dimethylformamide (50 mL) over 10 min. The reaction was stirred at rt overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (10:1) to give the title compound (9.27 g, 95%). MS (DCI/NH3) m/z 234 (M+1)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.26 (s, 6H) 1.00 (s, 9H) 7.26 (dq, J=7.93, 1.22 Hz, 1H) 7.35 (t, J=2.44 Hz, 1H) 7.50 (m, 2H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[N:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O>[N:15]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[N:3]=1)=[N+:16]=[N-:17]
Reactant: COc1cc([N+](=O)[O-])c(Br)nc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])c(N=[N+]=[N-])nc1OC
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a suspension of 22.0 g of 2-bromo-5,6-dimethoxy-3-nitropyridine (example E4) in 50 ml DMSO were added 16.0 g sodium azide. The reaction mixture was stirred for 24 h at 50° C. Additional 3.20 g sodium azide were added and after stirring for additional 44 h the reaction was completed. The solvent was removed under vacuum and the resulting residue was extracted with dichloromethane (3×100 ml). The solvent was removed and the residue was purified by flash chromatography (petroleum ether/ethyl acetate) to yield the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[N:11]([CH2:26][C:27]3[CH:31]=[C:30]([C:32]4[S:33][C:34]([Cl:37])=[CH:35][CH:36]=4)[O:29][N:28]=3)[C:8]2=[N:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>CO>[Cl:37][C:34]1[S:33][C:32]([C:30]2[O:29][N:28]=[C:27]([CH2:26][N:11]3[C:8]4=[N:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]4[CH:13]=[C:12]3[C:14](=[O:25])[NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:20][CH2:21]3)[CH:31]=2)=[CH:36][CH:35]=1
Reactant: COC(=O)c1cnc2c(c1)cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CCC(NC(=O)c2cc3cc(C(=O)O)cnc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 60 °C

Procedure:
To a solution of 630 mg of 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester in 60 mL MeOH, 8.7 mL of a 1M aqueous NaOH solution were added. The reaction mixture was heated to 60° C. for 3 h. After cooling to RT 8.8 mL of a 1M aqueous HCl were added and the solvents were removed under reduced pressure. The residue was stirred with water/MeCN 2:1 and the precipitated product was collected by filtration.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@H:13]1[CH2:17][CH2:16][C@@:15]([CH3:21])([C:18]([OH:20])=O)[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH:30][CH3:31]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@H:13]1[CH2:17][CH2:16][C@@:15]([CH3:21])([C:18]([N:30]([CH3:31])[CH3:29])=[O:20])[C:14]1([CH3:22])[CH3:23])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@H]1CC[C@@](C)(C(=O)O)C1(C)C
Reactant: CNC
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@H]1CC[C@@](C)(C(=O)N(C)C)C1(C)C

Procedure:
The product from Example 181 and dimethylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.26-1.33 (m, 2H), 1.37-1.46 (m, 1H), 1.57 (s, 9H), 1.57-1.70 (m, 3H), 1.98-2.10 (m, 1H), 2.62-2.67 (m, 2H), 2.74-2.83 (m, 1H), 2.83 (s, 3H), 3.05 (s, 3H), 3.33-3.39 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 422 (M+H)+. Anal. calcd. for C23H39N3O2S: C, 65.52; H, 9.32; N, 9.97. Found: C, 65.19; H, 9.18; N, 9.88.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si](=O)=O.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl.C(OCC)C>[C:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCOCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]=O
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCCCOCc1ccccc1
Yield: 78.7 %

Procedure:
Under a nitrogen atmosphere a mixture of 8.0 grams (0.041 mole) of 7-phenyl-6-oxaheptan-1-ol and 1.4 grams of 95% silicon dioxide in 125 ml of methylene chloride was stirred, and 19.8 grams (0.090 mole) of pyridinium chlorochromate was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for four hours. After this time the reaction mixture was diluted with diethyl ether and then was passed through a column of magnesium silicate. The eluate was concentrated under reduced pressure yielding 6.2 grams of 7-phenyl-6-oxaheptan-1-al. The reaction was repeated.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:7]([CH3:17])=[N:6][CH:5]=1)([O-:3])=[O:2]>C(O)C>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:7]([CH:17]=[CH:7][N:8]([CH3:9])[CH3:4])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ncc([N+](=O)[O-])n1CCc1ccncc1
Solvent: CCO
Product: CN(C)C=Cc1ncc([N+](=O)[O-])n1CCc1ccncc1

Procedure:
2.32 g. (0.01 mole) of 5-nitro-2-methyl-1-[2-(4-pyridinyl)-ethyl]-imidazole was reacted analogously to Example 1. After cooling, the reaction solution was mixed with ethanol and the precipitate vacuum-filtered; m.p. 190°-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1.[Sn](Cl)(Cl)(Cl)Cl.ClCCCl.[N+](=[CH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[N-]>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc[nH]c3=O)c(Cl)cc2F)c1=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCCl
Product: CCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 2 h

Procedure:
Into a mixture of 1.0 g of 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1, 2, 3, 6-tetrahydropyrimidin-1-yl)phenoxy]-1H-pyridin-2-one, 121 mg of tin tetrachloride and 40 ml of 1,2-dichloroethane, 0.4 ml of ethyl diazoacetate (purity: 90%) is dropped at room temperature over 2 hours. After dropping, the reaction mixture is further stirred for 2 hours, and subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to give 3-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)phenoxy]-2-(ethoxycarbonylmethoxy)pyridine.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:22])=[CH:15][CH:16]=1
Reactant: CCNCC
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of diethylamine (89.1 mL), triethylamine (120.2 mL) and CH2Cl2 (500 mL) cooled in an ice-bath was added dropwise p-anisoyl chloride (133.8 g) over 40 minutes. The reaction mixture was stirred at room temperature for 40 minutes, the mixture was filtered, washed with ether and the solvent was removed in vacuo. Ether was added, then water to the residue, then the organic layer was separate and washed with 5% NaOH, then in HCl, then brine and then was dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by kugelrohr distillation at 140°-180° C. under high vacuum to afford 163.8 g of 4-methoxy-N,N-diethylbenzamide, m.p. 40°-42° C.
Reaction SMILES: [OH-].[Na+].[C:3]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.O>[C:3]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 78.1 %

Procedure:
An aqueous solution of 5 M NaOH (17.5 mL, 87.5 mmol) was added to a stirring solution of 15a (20.1 g, 51.6 mmol) in 130 mL of THF and 52.5 mL of water at room temperature. After stirring for 2 days, 3.1 mL of 5 M NaOH (15.5 mmol) was added, and stirring was continued for another 2 days. The THF was removed under reduced pressure, then the aqueous residue was acidified with 1 M HCl to pH 5 and extracted with diethyl ether. The combined organic layers were washed with brine and dried over MgSO4. The diethyl ether was removed under reduced pressure, and the resulting crude powder was recrystalized in hexanes to yield 15.1 g (78%) of white powder 16a. Mp 114-116° C. 1H-NMR (400 MHz, CDCl3, δH ppm): 7.43 (6H, m, p-Ar), 7.28 (6H, m, m-Ar), 7.22 (3H, m, o-Ar), 3.05 (2H, t, 3JH—H=6.4 Hz, HO—CH2), 2.33 (2H, t, 3JH—H=7.5 Hz, CH2CO2), 1.56-1.68 (4H, m, 2CH2), 1.36-1.47 (2H, m, CH2). 13C-NMR (100 MHz, CDCl3, δH ppm): 180.26, 144.36, 128.62, 127.66, 126.79, 86.30, 63.24, 33.98, 29.63, 25.74, 24.48. HRMS (EI): m/z calcd 374.1882 (C25H26O3), found 374.1883 [M]+.