Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1>[OH-].[Na+].C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[O:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCN1CCC(OC(c2ccc(Cl)cc2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
1.00 g (2.48 mmol) of ethyl 3-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]propionate obtained in Example 24 was dissolved in a mixed solution of 1 ml of 50 wt % of aqueous sodium hydroxide and 8 ml of ethanol, and the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, neutralized with dil. hydrochloric acid and then extracted with chloroform. The chloroform extract was dried over anhydrous sodium sulfate and then concentrated to give 0.86 g (92%) of 3-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]propionic acid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:26]([N:33]1[C:37](=[O:38])[CH2:36][C:35]([C:44]([O-:46])=O)([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>O1CCCC1>[CH2:26]([N:33]1[C:37](=[O:38])[CH2:36][C:35]([C:44](=[O:46])[NH:54][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)C1(C(=O)[O-])CC(=O)N(Cc2ccccc2)C1
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)NCc2ccccc2)CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
1-Hydroxybenztriazole (2.78 g) and dicyclohexylcarbodiimide (42.5 g) were added to a mixture of monoethyl 1-benzyl-5-oxopyrrolidine-3,3-dicarboxylate (60.0 g), benzylamine (23.2 g) and tetrahydrofuran (500 ml), and the mixture was stirred at room temperature overnight. The insoluble matter was removed by filtration and the filtrate was concentrated. Ethyl acetate (400 ml) was added and the mixture was sequentially washed with an aqueous solution of potassium carbonate, water, dilute hydrochloric acid and saturated brine, dried, and concentrated to give 78 g of the object compound as white crystals, melting point 63°-65° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc(NC(=O)OC(C)(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)cn1
Temperature: 70 °C
Yield: 87.1 %

Procedure:
A mixture of 200 mg of ethyl 2-tert-butoxycarbonylamino-5-pyrimidinecarboxylate, 125 mg of potassium hydroxide and 15 mL of ethanol was heated to 70° C. for 3 h, cooled and concentrated under reduced pressure. The residue was dissolved in 50 mL of ice water, washed with 50 mL of ether, acidified to pH=3 with conc. HCl and extracted with 3×50 mL of chloroform. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Drying under vacuum gave 156 mg of 2-tert-butoxycarbonylamino-5-pyrimidinecarboxylic acid as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[O:16]=[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1
Yield: 99 %

Procedure:
A mixture of ethyl p-hydroxybenzoate (4.98 g), benzyl bromoacetate (4.75 ml) and K2CO3 (4.14 g) was stirred for 15 hr in 30 ml of DMF. The reaction mixture was diluted with water (200 ml) and extracted with a 1:1 ether:hexane mixture. The combined organic extracts were washed (water, brine), dried (Na2SO4), filtered, and evaporated leaving 9.3 g, (99%) of the title compound as a heavy oil; TLC, Rf =0.71, Et2O: hexane (1:1).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:20](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:22])=[O:21])=[C:16]([F:19])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:35])=[C:4]([O:36][CH3:37])[CH:3]=1.[NH2:38][C:39]1[CH:43]=[CH:42][O:41][N:40]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:20]([NH:38][C:39]4[CH:43]=[CH:42][O:41][N:40]=4)(=[O:22])=[O:21])=[C:16]([F:19])[CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:35])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: Nc1ccon1
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)c(F)cc21
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of perfluorophenyl 1-(4-bromo-5-chloro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate (0.440 g, 0.700 mmol), 3-aminoisoxazole (0.057 ml, 0.770 mmol) and THF (7.0 ml) was cooled in an ice-bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in TI-IF) (1.47 ml, 1.47 mmol) was added dropwise. After 60 min, the mixture was diluted with 1N aq. HCl and EtOAc. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was concentrated and then triturated with in Et2O. The resulting suspension was sonicated, then filtered. The collected solid was washed with Et2O (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-bromo-5-chloro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.370 g, 0.700 mmol, 100% yield) as an off white solid. m/z (ESI) 527.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4](I)[CH:3]=1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>COCCOC.[Cu]I.[Pd](Cl)Cl.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)Cc1ccc(F)cc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(F)cc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of ester 325 (3.80 g, 12.9 mmol) in dry DME (100 mL) at 0° C. was added triethylamine (4.5 mL, 3.3 g, 33 mmol), copper (I) iodide (0.50 g, 2.6 mmol), and bis(triphenylphosphine) palladium (II) chloride (0.38 g, 0.54 mmol). The mixture was degassed with a stream of N2 for 5 min, then trimethylsilylacetylene (4.0 mL, 2.8 g, 29 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 3 h. It was then concentrated under reduced pressure, re-dissolved in ether, filtered and concentrated. Silica gel chromatography of the residue (eluent 10% ethyl acetate/hexanes) afforded 326 (3.30 g, 97% yield). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.23 (dd, J=8.6, 5.7 Hz, 1H); 7.14 (dd, J=9.0, 2.7 Hz, 1H); 7.00 (dt, J=8.4, 2.7 Hz, 1H); 3.79 (s, 2H); 3.70 (s, 3H); 0.25 (s, 9H). LCMS: (M+H) 265.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH:55]1([C:58]2[O:62][N:61]=[C:60]([CH2:63][NH2:64])[N:59]=2)[CH2:57][CH2:56]1>CN(C)C=O>[CH:55]1([C:58]2[O:62][N:61]=[C:60]([CH2:63][NH:64][C:20]([C:10]3[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:9]=3)=[O:21])[N:59]=2)[CH2:57][CH2:56]1
Reactant: NCc1noc(C2CC2)n1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1noc(C2CC2)n1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Yield: 66.8 %

Procedure:
To a stirred solution of 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M, 100 mg, 0.300 mmol) in dimethylformamide (4 mL, dried), was added 4-methylmorpholine (CAS No. 109-02-4, 0.09 mL 0.901 mmol), HBTU (CAS No. 94790-37-1, 171 mg, 0.450 mmol), 5-cyclopropyl-[1,2,4]oxadiazol-3-methanamine hydrochloride (Chembridge, MFCD09864586, 52 mg, 0.300 mmol) at rt and this mixture was stirred for 12 h at rt. Volatile were removed under reduced pressure and the residue was extracted with ethyl acetate. The combined organic layer was washed with aq. NaHCO3 soln, brine and concentrated to afford the crude residue which was purified by column chromatography (100-200 silica gel, elution with ethyl acetate/hexane). The title compound (91 mg, 66.0% yield) was obtained as a white solid; LC-MS (UV peak area/ESI) 96.8%, 454.6 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][C:17]#[N:18])[CH2:11][CH2:10]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1CCN(c2cccc(Cl)c2Cl)CC1
Yield: 93.4 %

Procedure:
2,3-Dichlorophenyl piperazine (5.0 g, 0.0216 mol), chloroacetonitrile (1.37 mL, 0.0216 mol), and potassium carbonate (K2CO3) (14.95 g, 0.108 mol) are combined in acetonitrile and heated to reflux for 18 hours. The reaction mixture is concentrated in vacuo and the resulting residue is partitioned between water (H2O) and dichloromethane. The organic layer is dried (sodium sulfate) and concentrated to give 5.45 g of the title compound as a yellow solid; mp 89°-92° C.
Reaction SMILES: [F: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]1([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH3:29].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][N:15]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:14][CH2:13]1
Reactant: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1
Reactant: CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.31 g, 1.18 mmol), acetonitrile (20 ml), potassium carbonate (0.3 g, 2.9 mmol), bromobutane (0.16 ml, 1.3 mmol). Yield: 0.26 g, 70%. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 138° C. MS m/z (relative intensity, 70 eV) 319 (M+, 6), 277 (14), 276 (bp), 258 (23) 185 (9).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O>C(O)C>[CH3:12][C:3]1[C:4]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[N:1]=[C:19]=[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][NH:13]1
Reactant: O=Cc1ccccn1
Reactant: Cc1ccc(N)c(C)c1[N+](=O)[O-]
Solvent: CCO
Product: Cc1ccc(N=C=C2C=CC=CN2)c(C)c1[N+](=O)[O-]

Procedure:
3.3 g of 4-amino-2-nitro-m-xylene and 2.1 g of 2-pyridinealdehyde were dissolved in 50 ml ethanol and left to stand. Crystals slowly precipitated and were filtered off under suction and washed with ethanol. The dried product (3.0 g) had a melting point of 114° to 116° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20](=[O:22])[C:19]([CH2:29][C:30](Cl)=[O:31])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH:33]=1.Cl>O.O1CCCC1>[CH3:3][N:4]([C:30](=[O:31])[CH2:29][C:19]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]2[CH:33]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=2[O:21][C:20]1=[O:22])[C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CN[C@@H](CC(C)C)C(=O)O
Reactant: O=C(Cl)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 3 h

Procedure:
0.9 g of sodium hydroxide is added to a solution of 3 g of N-methylleucine in 70 ml of water and 40 ml of tetrahydrofuran. The medium is then cooled to 5° C. and a solution of 7.3 g of 2-(5-chloro-2,3-dihydro-2-oxo-3-phenyl-3-benzofuranyl)acetyl chloride in 50 ml of tetrahydrofuran and a solution of 0.9 g of sodium hydroxide in 22.7 ml of water are then added simultaneously in small portions so as to maintain the pH at 12. The mixture is stirred for 3 hours at room temperature and 22.7 ml of N hydrochloric acid are added. The medium is concentrated and the precipitate obtained is filtered off and dissolved hot in an ethanol/methanol (50:50) mixture. The solution is filtered and the filtrate evaporated. A crystalline product is obtained.
Reaction SMILES: [H-].[Na+].CC(C)([O-])C.[K+].[C:9](=[O:14])([O:12][CH3:13])OC.[C:15]1(=[O:26])[C:20]2([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1.[Cl-].[Na+].O.C(O)(=O)C>[CH3:13][O:12][C:9]([CH:16]1[CH2:17][CH2:18][CH2:19][C:20]2([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:15]1=[O:26])=[O:14]
Reactant: O=C1CCCCC12CCCCC2
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [H-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1CCCC2(CCCCC2)C1=O

Procedure:
To a suspension of 60% sodium hydride (5.7 g) and potassium tert-butoxide (1.6 g) in tetrahydrofuran (200 mL) was added dimethyl carbonate (9.6 mL) at room temperature while stirring. The reaction mixture was heated under reflux. To the reaction mixture was added dropwise a solution of spiro[5.5]undecan-1-one (11.85 g) obtained in Step 1 in tetrahydrofuran (40 mL) over 1 hour, followed by heating the reaction mixture under reflux for 2 hours. After ice-cooling, acetic acid (14.6 mL) was added dropwise to the reaction mixture. Then, the reaction mixture was poured into saturated brine, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:15) to give 1-oxo-spiro[5.5]undecane-2-carboxylic acid methyl ester (13.02 g).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][N:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1 mmol) and commercially available 2-amino-5-bromopyridine (157 mg, 1 mmol) according to general procedure II. Obtained as a dark red solid (13 mg, 3%). MS (ISP) 430.3 [(M+H)+]; mp 216° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][C:15](=[O:17])[CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.N1([C:33](=[O:35])[CH3:34])C=CC=N1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH:14]([C:33](=[O:35])[CH3:34])[C:15](=[O:17])[CH2:16][CH:9]1[CH2:10][O:11][CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)n1cccn1
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C1C(=O)CC2COCC1N2C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (482 mg, 2 mmol) in THF (5 mL) was added LiHMDS (3 mL, 3 mmol) slowly at −78° C. After 15 mins, 1-pyrazol-1-yl-ethanone (264 mg, 2.4 mmol) was added, and the resulting mixture was stirred at −78° C. for 1 hour and then at room temperature for 1 hour. The reaction mixture was quenched with water, and then extracted with EA (20 mL×2). The organic layer was concentrated in vacuo. The residue was purified by flash chromatography (EA in PE 0%˜70%) to afford 6-acetyl-7-oxo-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (compound AL) as light yellow oil (56 mg, 20%). LC/MS: calc'd 284 (MH+), exp 284 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C@@H:19]([CH3:20])[CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][C@@H:15]2[CH3:31])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C@@H:19]([CH3:20])[CH2:18][NH:17][CH2:16][C@@H:15]2[CH3:31])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H](C)N1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CNC[C@H](C)N1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 53.9 %

Procedure:
A solution of benzyl (3S,5S)-4-[(4-tert-butylphenyl)sulfonyl]-3,5-dimethylpiperazine-1-carboxylate (340 mg, 0.77 mmol) in anhydrous MeOH was hydrogenated at 1 atmosphere for 2 days using palladium, 10% wt. on activated carbon (144 mg) as catalyst. Reaction was complete as determined by TLC. The reaction mixture was then filtered through a celite bed. After solvent evaporation crude product was purified via flash column chromatography to afford (2S,6S)-1-[(4-tert-butylphenyl)sulfonyl]-2,6-dimethylpiperazine in 53.9% yield (128 mg) as pale yellow oil.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]=[C:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]2[C:18]3[N:19]([CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:28]=3)[N:20]=[CH:21][C:22]=2[C:23]([NH2:25])=[O:24])[C:12]1([CH3:36])[CH3:35])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([NH:10][C@@H:11]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]2[C:18]3[N:19]([CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:28]=3)[N:20]=[CH:21][C:22]=2[C:23]([NH2:25])=[O:24])[C:12]1([CH3:36])[CH3:35])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC1(C)C(=NCc2ccccc2)CCC1Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)[C@@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)CC[C@H]1NCc1ccccc1
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
Sodium borohydride (1.5 mg, 0.040 mmol) was added to a solution of 4-(3-(benzylimino)-2,2-dimethylcyclopentylamino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (6 mg, 0.013 mmol, from Step 1) in methanol (1 mL) at 0° C. After 30 min at 0° C., the mixture was quenched with saturated ammonium chloride (1 mL), diluted with ethyl acetate (60 mL), washed with water, brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography, eluting with 0 to 10% methanol in dichloromethane, to give the title compound (4.0 mg, 60% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 8.13 (1 H, s), 7.91 (1 H, d, J=1.54 Hz), 7.56-7.84 (2 H, m), 7.04-7.53 (9 H, m), 4.32 (1 H, t, J=8.91 Hz), 3.69-4.04 (2 H, m), 2.77-2.95 (1 H, m), 2.08-2.52 (2 H, m), 1.43-1.81 (2 H, m), 0.97-1.15 (6 H, m); MS (ES+) m/z: 454.4 (M+H); HPLC retention time: 6.605 min (analytical HPLC Method L).
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:22]([O:24]CC[Si](C)(C)C)=[O:23])=[CH:16][CH:15]=2)[CH3:8])=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:2]=[CH:3][C:4]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)[CH3:8])=[CH:5][CH:6]=1
Reactant: CC(=NOCCOc1ccc(C[C@H](Oc2ccc(F)cc2)C(=O)OCC[Si](C)(C)C)cc1)c1ccc(-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(=NOCCOc1ccc(C[C@H](Oc2ccc(F)cc2)C(=O)O)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
The target compound (568 mg) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 7 using 2-trimethylsilylethyl (S)-3-[4-[2-[[1-(4-biphenylyl)ethylidene]aminoxy]ethoxy]phenyl]-2-(4-fluorophenoxy)propionate (938 mg) obtained from Reference example 14 and a 1M solution of tetrabutylammonium fluoride in tetrahedrofuran (3.8 ml).
Reaction SMILES: C=CCC.[CH2:5]1[CH:9]2[CH:10]3[CH:14]=[CH:13][CH:12]([CH:8]2C=[CH:6]1)[CH2:11]3>>[CH2:5]([CH:9]1[CH2:8][CH:12]2[CH2:11][CH:10]1[CH:14]=[CH:13]2)[CH3:6]
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: C=CCC
Product: CCC1CC2C=CC1C2
Reaction time: 25 h
Yield: 53 %

Procedure:
In a 1000-ml stainless steel magnetic stirrer type autoclave in which the atmosphere had been replaced with nitrogen, 162 g of 1-butene and 198 g of dicyclopentadiene were placed, and the reaction was carried out at 170° C. for 25 hours. After the completion of the reaction, unreacted 1-butene was collected by a trap in a bath including dry ice and methanol. Afterward, the resultant reaction liquid was subjected to a vacuum distillation in order to recover 52 g of unreacted dicyclopentadiene and to obtain 97 g of 5-ethyl-2-norbornene and 8 g of a fraction of a boiling point of 87° C./1 mmHg. In this case, the amount of recovered 1-butene was 112 g. Therefore, in this Diels-Alder reaction, the conversion of 1-butene was 31% and the selectivity of 5-ethyl-2-norbornene to reacted 1-butene was 89%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)[C:5]([F:22])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[NH2:28].O.[OH-].[Na+]>CN1CCCC1=O>[F:22][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)=[N:7][C:2]([NH:28][C:27]2[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:25]([O:24][CH3:23])[CH:26]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CC1(C)Oc2ccc(Nc3nc(Cl)ncc3F)nc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)NC(=O)C(C)(C)O4)n2)cc(OC)c1OC
Temperature: 120 °C
Yield: 160270.8 %

Procedure:
6-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (Step A) (568 kg, 1.00 mol eq) is mixed with 3,4,5-trimethoxyaniline (402 kg, 1.25 mol eq) in N-methylpyrrolidin-2-one (2835 kg) with stirring under a nitrogen atmosphere. To this is added water (11 kg) and the mixture heated to about 120° C. and stirred for about 10 hours. This is then cooled to about 65° C. and the pH adjusted to pH 8.5 with 4% w/w aqueous sodium hydroxide solution. The resulting slurry is further cooled to about 20° C., stirred for at least 6 hours and then filtered. The filtered solid is washed twice with water (2×1440 kg) then twice with acetone (2×1140 kg) and finally dried under vacuum at about 40° C. to give the title compound (754 kg, 91%) as a colored solid.