Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([NH:12][C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].I[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].[NH4+].[Cl-]>CN(C=O)C.C(OCC)C>[Cl:3][C:4]1[CH:11]=[C:10]([N:12]([C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[CH2:14]2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CN1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Reactant: Cc1ccccc1CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccccc1CN(c1ccc(C#N)c(Cl)c1)[C@H]1CC(=O)N(C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
NaH (60% in mineral oil, 0.857 g, 21.4 mmol) was washed with pet ether (3×), suspended in DMF (50 mL), and cooled to 0° C. To this suspension was added a solution of 2-chloro-4-{[(3S)-1-methyl-5-oxo-3-pyrrolidinyl]amino}benzonitrile (5.08 g, 20.0 mmol) and DMF (25 mL) dropwise over 20 min. After stirring at 0° C. for 30 min, this solution was added dropwise to a pre-cooled (0° C.) solution of 1-(iodomethyl)-2-methylbenzene (7.0 g, 30.0 mmol) in DMF (75 mL) over 30 min. The reaction was stirred at 0° C. for an additional 20 min and then poured into a solution of aq. NH4Cl (300 mL) and diethyl ether (300 mL). The layers were separated and the aqueous layer was extracted with Et2O (2×300 mL). The organic extracts were washed with H2O, aq. NaHSO3, dried over Mg2SO4, filtered, and concentrated. The oil was triturated with isopropanol (1 mL) and diethyl ether (75 mL) and the solid filtered to give the titled compound (5.4 g., 76%) as a white solid. LC-MS (ES) m/e 354.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15][CH3:16])=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].CN(C)C=O.C([O-])([O-])=O.[K+].[K+].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Cl>O>[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36][O:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15][CH3:16])=[O:14])[C:3](=[O:21])[C:2]=1[Br:1]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Reactant: Fc1ccc(CCl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
Methyl 3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-4-methylbenzoate (4) (1.9 kg, 5.4 moles), N,N-dimethylformamide (4.8 L) and powdered K2CO3 (1.1 kg, 8.1 moles) were mixed together and heated to 55° C. under nitrogen. 2,4-difluorobenzyl chloride (964 g, 5.9 moles) was added at a rate such that the temperature was maintained below 65° C. After the addition, the mixture was heated at 65° C. for 3.5 hours. After 3 hours the reaction was complete and the reaction mixture was cooled to 20-25° C. with the addition of 19 L water. The solid was filtered and washed with 15 L water. The crude product was then purified by trituration in refluxing methanol (4 L). The mixture was cooled and the solid filtered to yield 2.32 kg (90%) product. 1H NMR (300 MHz, CDCl3) δ 1.90 (s, 3H), 2.11 (s, 3H), 3.87 (s, 3H), 5.25 (s, 2H), 6.11 (s, 1H), 6.88 (dt, J=4.8, 1.8 Hz, 1H), 6.96 (t, J=4.8 Hz, 1H), 7.42 (d, J=6 Hz, 1H), 7.59 (q, J=4.8 Hz, 1H), 7.74 (s, 1H), 8.02 (d, J=6 Hz, 1H). Anal. Cald. for C22H18BrF2NO4: C, 55.25; H, 3.79; N, 2.93. Found: C, 55.34; H, 3.83; N, 3.14.
Reaction SMILES: [H-].[Na+].C1COCC1.C(OCC)(=O)CC(OCC)=O.[C:19]12([C:29]3[CH:49]=[CH:48][C:32]([C:33]([NH:35][C:36]4[CH:47]=[CH:46][C:39]([C:40]([O:42]CC=C)=[O:41])=[CH:38][CH:37]=4)=[O:34])=[CH:31][C:30]=3[O:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH3:56])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>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.O>[C:19]12([C:29]3[CH:49]=[CH:48][C:32]([C:33]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([C:40]([OH:42])=[O:41])=[CH:46][CH:47]=4)=[O:34])=[CH:31][C:30]=3[O:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH3:56])[CH2:28][CH:23]3[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]3)[CH2:26]1)[CH2:20]2
Reactant: C=CCOC(=O)c1ccc(NC(=O)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OCOCCOC)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1cc(C(=O)Nc2ccc(C(=O)O)cc2)ccc1C12CC3CC(CC(C3)C1)C2

Procedure:
107 mg (3.5 mmol) of sodium hydride (80% in oil) and 5 ml of THF were introduced into a round-bottomed flask under a stream of nitrogen. 535 μl (3.5 mmol) of diethyl malonate were then added dropwise and the mixture was stirred until the evolution of gas had ceased. This solution was introduced dropwise into a mixture of 1.67 g (3.2 mmol) of allyl 4-[4-(1-adamantyl)-3-methoxyethoxymethoxybenzamido]benzoate, 40 ml of THF and 184 mg (0.18 mmol) of tetrakis(triphenylphosphine)palladium(0) and the mixture was stirred at room temperature for three hours. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of dichloromethane and ethyl acetate (80/20). After evaporation of the solvents, 630 mg (41%) of 4-[4-(1-adamantyl)-3-methoxyethoxymethoxybenzamido]benzoic acid, having a melting point of 189°-91° C., were recovered.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH:28]=O>CN(C)C(=O)C>[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH:28]=[N:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2
Reactant: CC(C)(C)CC=O
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CC(C)(C)CC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 60 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with 3,3-dimethylbutanal (0.5 g, 5.0 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.072 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11](=[O:30])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:19]2=[O:29])[CH2:14][CH2:13]1)[C:7]([OH:9])=O.[NH:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:19]2=[O:29])[CH2:16][CH2:17]1)=[O:30])[C:7]([N:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1)=[O:9]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=C(O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Product: O=C(C[C@H](Cc1cc(Cl)c(O)c(C(F)(F)F)c1)C(=O)N1CCC(N2CCOCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
Prepared analogously to Example (1 g) from 70 mg (0.126 mmol) (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-piperidin-1-yl]-butanoic acid and 22 mg (0.130 mmol) 4-piperidin-4-yl-morpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([OH:26])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22]C(=O)C)[CH2:8][CH2:7]1>Cl>[ClH:1].[ClH:1].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH:13]([OH:26])[CH2:12][N:9]1[CH2:8][CH2:7][CH:6]([O:5][C:4]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:2]([Cl:1])[CH:3]=2)[CH2:11][CH2:10]1
Reactant: CC(=O)Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Product: Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 165.3 %

Procedure:
N-(2-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide (1.418 g, 3.13 mmol) was dissolved in 50 ml HCl (35%/aq, puriss) and refluxed overnight. The product precipitated and was filtered and dried to give 0.835 g (65%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[N+:24]([O-:26])=[O:25])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Temperature: 70 °C

Procedure:
To a solution of 3-(benzyloxy)phenol (1.145 g, 5.72 mmol) and 2,5-dichloronitrobenzene (1.154 g, 6.01 mmol) in 15 mL of DMSO was added cesium carbonate (3.72 g, 11.4 mmol). The reaction was heated to 70° C. under argon for one hour, then cooled to room temperature. The solution was poured into EtOAc, washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:9]1[N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C(=O)OCC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)nc1C(=O)OCC
Temperature: 60 °C

Procedure:
100 g (0.352 mol) of diethyl 5-nitropyridine-2,3-dicarboxylate were added to 500 ml of phosphoryl chloride in the course of 15 minutes with stirring at 60° C., heated to reflux and stirred for 1 1/2 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue dissolved again in methylene chloride. After stirring with ice-water, the aqueous phase was washed again with methylene chloride and the organic extracts were then washed in succession with water, saturated sodium hydrogencarbonate and sodium chloride solution and dried over magnesium sulfate. After filtering off with suction through neutral alumina and concentrating, 68.8 g (64.6% of theory) of the title compound of m.p. 70°-72° C. were obtained. (Not claimed according to the invention)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10](OC)=[O:11].O.[H-].[Na+]>C1COCC1>[F:7][C@@H:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][OH:11]
Reactant: CCCCC(F)CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](F)CCO
Temperature: 5 °C
Reaction time: 2 h
Yield: 107.4 %

Procedure:
To a 1 l flask were added 154 ml of THF and 2.3 g of lithium aluminum hydride under a nitrogen atmosphere, and the solution was kept at 5° C. To the solution was added dropwise a solution of 9 g of methyl 3-fluoroheptanoate in 43 ml of THF over 2 hours at 5° C. After the addition, the temperature was gradually elevated up to room temperature, and the mixture was stirred for 2 hours After cooling to 5° C., 2 3 g of water, 2.3 g of a 15% sodium hydride aqueous solution, and 6.9 g of water were added thereto dropwise in this order, followed by stirring at that temperature for 15 minutes. The thus formed precipitate was removed by filtration, and the filtrate was subjected to liquid-liquid separation. The organic layer was dehydrated over potassium carbonate and the solvent was removed by distillation at 30° C. or less to obtain 8.0 g (yield=98.0%) of the titled compound. NMR (ppm): 0.92 (3H, t, J=7.2 Hz), 1.3-1.9 (8H, m), 3.81 (2H, m), 4.70 (1H, m)
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccccc1C1=CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1C1CCCCC1
Yield: 65 %

Procedure:
16.3 g. (0.1 mol) o-(1-Cyclohexenyl)-benzaldehyde were heated for 4 hours in a Dean and Stark apparatus with 6.85 g. (0.11 mol) ethyleneglycol and 1 g. p-toluenesulphonic acid in 400 ml. toluene. Thereafter, the calculated amount of water had separated off. The isolated protected aldehyde was taken up in ethanol and hydrogenated over platinum oxide as catalyst. After filtering and evaporating off the solvent, the crude product was taken up in 300 ml. dioxan, mixed with 80 ml. of a 10% aqueous solution of oxalic acid and heated under reflux for 2 hours. After extraction with ethyl acetate, the organic phase was washed with water, dried over anhydrous magnesium sulphate and evaporated. Flash chromatography (hexane/ethyl acetate 5:1 v/v) gave the aldehyde in pure form in a yield of 65% of theory.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15]S(C(F)(F)F)(=O)=O)[CH:12]=[C:11](OCC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[Cl:32][C:33]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:10]=[C:11]([C:36]2[CH:35]=[CH:34][C:33]([Cl:32])=[C:38]([C:39]([F:42])([F:41])[F:40])[CH:37]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 15, step (d)) under the conditions described in Example 15 step (e-f) using 4-chloro-5-trifluoromethylphenylboronic acid in step (e). 1H-NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 7.65 (d, 1H), 7.55 (d, 1H), 7.04 (s, 1H), 6.92 (m, 1H), 6.86 (m, 1H), 4.98 (br s, 1H), 3.68 (m, 4H), 1.97 (m, 1H), 1.68 (m, 1H), 1.49 (m, 1H), 0.92 (d, 6H); Mass Spectrum (m/z, ESI) 399 (M−H)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:25][CH3:26])[C:16]2[C:21]([NH:22][CH2:23][CH3:24])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:25]([N:15]([CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:16]1[C:21]([NH:22][CH2:23][CH3:24])=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:26]
Reactant: [H][H]
Reactant: CCNc1cccnc1N(CC)CC1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCNc1cccnc1N(CC)CC1CCNCC1

Procedure:
1-Benzyl-4-[N-ethyl-N-(3-ethylamino-2-pyridinyl)aminomethyl]piperidine (EXAMPLE 187, 2.38, 6.75 mmol) and palladium hydroxide on carbon (1.5 g) in 100 ml ethanol is hydrogenated under 40 p.s.i. hydrogen for 42 hr. Filtration and evaporation of the solvent gives 4-[N-ethyl-N-(3-ethylamino-2-pyridinyl)aminomethyl]piperidine.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[CH3:33][Si:34]([CH3:73])([CH3:72])[CH2:35][CH2:36][O:37][CH2:38][N:39]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:40]1[N:45]2[N:46]=[CH:47][C:48](I)=[C:44]2[N:43]=[C:42]([CH2:50][CH:51]2[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]2)[CH:41]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:71][Si:68]([CH3:69])([CH3:70])[CH2:67][CH2:66][O:65][CH2:64][N:39]([CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:33])([CH3:72])[CH3:73])[C:40]1[N:45]2[N:46]=[CH:47][C:48]([C:10]3[CH:9]=[N:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:11]=3)=[C:44]2[N:43]=[C:42]([CH2:50][CH:51]2[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]2)[CH:41]=1
Reactant: CC1(C)OB(c2ccc(-c3ccccc3)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
2-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.32 mmol, 370 mg), K3PO4 (3.04 mmol, 644 mg), and PdCl2(dppf).CH2Cl2 (0.10 mmol, 83 mg) was added to a solution of tert-butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Int-12e, 1.02 mmol, 726 mg) in dioxane (6 mL) and H2O (1 mL). The resulting solution was stirred at 100° C. under argon for 18 hours. The mixture was diluted with H2O and then extracted with ethyl acetate (x2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Int-12f): LCMS tR=3.47 Min (5 min run, UV254nm). Mass calculated for, M+744.2, observed m/z 745.2 (M+H).
Reaction SMILES: CO[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.C([O-])(=O)C.[NH4+:16]>O>[N+:9]([C:8]1[C:3]([NH2:16])=[N:4][CH:5]=[CH:6][CH:7]=1)([O-:11])=[O:10]
Reactant: [NH4+]
Reactant: COc1ncccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Solvent: O
Product: Nc1ncccc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 23.2 %

Procedure:
One gram (6.5 mmol) of 2-methoxy-3-nitropyridine and 5.0 g (65 mmol) of ammonium acetate were added to a 100 ml round bottom flask. The reaction mixture was heated at 150° C. for approximately 16 hours under an argon atmosphere. An additional 5 g of ammonium acetate was added to the reaction mixture which was allowed to heat for an additional 8 hours. Thin layer chromatography of the mixture indicated that both product and starting material were present. The reaction mixture was cooled and poured into approximately 100 ml of water. The precipitated solid was collected by filtration to provide 209.8 mg of 3-nitro-2-aminopyridine. m/e 139. The NMR spectrum of the collected produot was identical to that of an authentic reference standard.
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[OH-].[Na+]>O.O1CCOCC1>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C:13]2([NH:12][C:11](=[O:27])[C:10]3[CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=[CH:8][C:9]=3[O:26]2)[CH2:14]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Yield: 92.2 %

Procedure:
A solution of (±)-(E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (Intermediate 5, Step B, 270 mg, 0.67 mmol) in water (3 ml) and dioxane (6 ml) was treated with 1 M NaOH (0.75 ml) as described in Example 30, Step A to give (±)-(E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (240 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=O.[CH3:10][CH2:11]C(=O)CC.B(F)(F)F.CCOCC.O>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:10]/[CH3:11]
Reactant: CCC(=O)CC
Reactant: O=Cc1ccccc1Cl
Agent: FB(F)F
Solvent: CCCCCC
Solvent: CCOCC
Solvent: O
Product: C/C=C/c1ccccc1Cl
Yield: 59.3 %

Procedure:
48 ml of 2-chlorobenzenaldehyde (0.42 mol) and 49.7 ml of 3-pentanone (0.47 mol) were dissolved in 600 mL of hexane in flask, and then stirred with raising the temperature. 53.6 ml of Boron trifluoride etherate (BF3OEt2, 0.42 mol) was added to the resultant under reflux conditions. When the reaction was completed, water was added thereto. After layer separation, the obtained organic layer was washed twice with 1M sodium hydroxide solution (1M NaOH), and then the separated organic layer was washed with water. The separated organic layer was dehydrated with anhydrous magnesium sulfate (MgSO4) and concentrated. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (38 g, yield 58%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:18][C:15]1[CH:16]=[CH:17][C:9]2[CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:11](=[O:13])[C:10]=2[CH:14]=1
Reactant: Cc1ccc(COc2ccccc2)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)C(=O)c1ccccc1OC2
Reaction time: 0.17 h

Procedure:
Mix 0.2 gm of the phenoxymethylbenzoic acid of Step A, 1 ml of thionyl chloride and 10 ml of dry benzene. Reflux for 1 hour and concentrate to dryness in vacuo. Dissolve the residue in 10 ml of dry 1,2-dichloroethane and add 0.3 gm of anhydrous aluminum chloride while stirring in an ice bath. After 10 minutes, pour the reaction mixture into ice water, extract with chloroform, wash with water and dry over magnesium sulfate. Concentrate to dryness and chromatograph the residue over silica gel eluting with chloroform. Concentrate the eluate to dryness and crystallize from hexane to obtain the title product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6]C)[CH3:5].[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=O)=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)=[CH:13][CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10]2)[N:16]=1)=[O:18])=[O:24])[CH3:5]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CNC(C)COC
Product: COCC(C)NC(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 32 %

Procedure:
According to the general method described in step 3 of example 53, reaction of (2-methoxy-1-methyl-ethyl)-methyl-amine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (32%) as amorphous yellow solid.