Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].Cl[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>CN1CCCC1=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH3:16])[CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:20][N:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[CH2:22][CH2:23]1)[N:7]=[C:6]2[NH2:30]
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Reactant: Clc1ccccn1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(c4ccccn4)CC3)nc(N)c2cc1OC

Procedure:
A solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (250 mg) and 2-chloropyridine in N-methylpyrrolidone (5 m) was stirred at 130° C. under nitrogen for 48 hours. The cooled reaction mixture was diluted with water and extracted with chloroform. The extract was chromatographed on silica gel to yield 6,7-dimethoxy-N2-methyl-N2-(4-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-quinazoline-2,4-diamine 22, MS: 485 ([M+H]+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[CH:10]=[N:9][C:8]=12)(O)=[O:2].[NH2:28][C:29]1([C:37]([O:39][CH3:40])=[O:38])[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:7]3[N:6]=[CH:5][C:4]([C:1](=[O:2])[NH:28][C:29]4([C:37]([O:39][CH3:40])=[O:38])[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[CH2:31][CH2:30]4)=[C:8]3[N:9]=[CH:10][C:11]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])=[C:14]([F:20])[CH:15]=1
Reactant: O=C(O)c1cnn2c(-c3ccc(Cl)cc3F)c(-c3ccccc3Cl)cnc12
Reactant: COC(=O)C1(N)CCS(=O)(=O)CC1
Product: COC(=O)C1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4F)c(-c4ccccc4Cl)cnc23)CCS(=O)(=O)CC1
Yield: 79 %

Procedure:
The compound obtained in Reference Example All (3-carboxy-7-(4-chloro-2-fluorophenyl)-6-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidine; 39 mg) and methyl 4-amino-1,1-dioxotetrahydrothiopyran-4-carboxylate (20 mg) were treated in the same manner as described in Example A1 to give 7-(4-chloro-2-fluorophenyl)-6-(2-chlorophenyl)-3-[N-(4-methoxycarbonyl-1,1-dioxotetrahydrothiopyran-4-yl)-carbamoyl]pyrazolo[1,5-a]pyrimidine (45 mg, yield: 79%) as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[OH:30][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:25][CH2:26][N:27]([C:42]([NH:41][CH3:40])=[O:43])[CH2:28][CH2:29]1
Reactant: CN=C=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNCC3)s2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)N1CCC(O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) was dissolved in CH2Cl2 (1 mL). N,N-diisopropylethylamine (30 μL, 0.172 mmol) and methyl isocyanate (7 μL, 0.130 mmol) were added sequentially. The solution was stirred overnight at rt, then concentrated in vacuo on a Genevac. The resultant residue was dissolved in DMSO and purified via HPLC (30-64% CH3CN:H2O) to provide 4-hydroxy-N-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide (36 mg, 0.073 mmol). MS ESI: +m/z 493.1. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 7.93 (s, 2H), 7.44 (s, 1H), 7.25 (d, J=5.1 Hz, 1H), 7.13 (s, 1H), 6.43 (d, J=4.8 Hz, 1H), 6.15 (s, 1H), 3.83-3.74 (m, 2H) (d, J=14.0 Hz, 2H), 3.07 (t, J=14.5 Hz, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 1.98-1.82 (m, 2H), 1.65 (d, J=13.9 Hz, 2H). rhSYK activity=+++
Reaction SMILES: O1CCCC1.Cl[Si:7]([CH2:10][Cl:11])([CH3:9])[CH3:8].[CH2:12]([Mg]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCCCCC>[CH2:12]([Si:7]([CH2:10][Cl:11])([CH3:9])[CH3:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: C[Si](C)(Cl)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(CCl)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 109.5 %

Procedure:
In a 2 L 3-necked flask equipped with a nitrogen inlet, a 500 ml dropping funnel and a thermometer, was placed 500 ml of tetrahydrofuran. Chloro(chloromethyl)-dimethylsilane (100 ml, 0.744 mol) was added by syringe and the colorless solution cooled to 0° C. in an ice/acetone bath. Then benzylmagnesium chloride (2.0 M solution, 400 ml, 0.8 mol) was transferred to the dropping funnel by syringe and added dropwise over 2 hours. A slightly exothermic reaction was observed and the temperature was maintained below 10° C. After addition of the benzylmagnesium chloride was complete, the ice bath was allowed to warm up to room temperature without heating, and the reaction mixture was stirred overnight. Thereafter hexane (300 ml) was added and the reaction mixture was worked up by dropwise addition of saturated aqueous ammonium chloride (300 ml) and transferred to a 2 L separatory funnel with additional hexane (300 ml). After partitioning, the organic layer was washed with saturated aqueous ammonium chloride (200 ml) and saturated aqueous sodium chloride (200 ml). The combined aqueous layers were backwashed with hexane (2×500 ml). The combined organic layers were dried over magnesium sulfate, evaporated on a rotary evaporator, and finally evaporated with an oil pump to give a colorless oil 162.0 g (109.5% yield). A quantitative yield was assumed with a purity of the crude product as 91.3%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (14 g, 42.68 mmol) and acetaldehyde (3.75 g, 85.36 mmol) in dichloroethane (150 mL), acetic acid (15.36 g, 256.08 mmol) was added and the reaction stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (27.01 g, 128.04 mmol) was then added at 0° C. and the reaction mixture stirred at room temperature for 2 h. The solvent was then removed under reduced pressure and water added to the residue. The mixture was extracted with DCM. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude product was purified by column chromatography to afford methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (14 g, 93.33%).
Reaction SMILES: [N+](=[CH2:3])=[N-].N(CNC(N)=O)=O.[OH-].[K+].[Cl:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>C(OCC)C>[Cl:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([O:18][CH3:3])=[O:17]
Reactant: O=C(O)c1cccnc1Cl
Reactant: C=[N+]=[N-]
Agent: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: COC(=O)c1cccnc1Cl
Reaction time: 8 h

Procedure:
To a cold diethyl ether solution containing about 2.8 g. (0.067 mole) of diazomethane generated from 10 g. of nitrosomethyl urea and 30 cc. of 40% potassium hydroxide (see Organic Synthesis, Col. 1, Vol. II, page 166) was added in portions 9.45 g. (0.06 mole) of 2-chloronicotinic acid. After the evolution of nitrogen had ceased the reaction mixture was allowed to stand at room temperature overnight. The solvent was removed in a rotary evaporator leaving 2-chloro-nicotinic acid, methyl ester as a residual oil whose infrared spectrum indicated no OH absorption was present. The oil was used directly in the next step. The above compound has also been described by F. G. Mann and J. A. Reid, J. Chem. Soc., 1952, 2057.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[CH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:21]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]#[CH:11]
Reactant: O=Cc1ccccc1O
Reactant: C#CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCCCCCCCCCOc1ccccc1C=O

Procedure:
To an ice-cold solution of 11-hydroxyundecyne (10 g, 59.4 mmoles) in 400 ml of methylene chloride under argon was added in one portion carbon tetrabromide (40.5 g, 0.1224 mole). The reaction mixture was stirred at 0° C. for 5 minutes and triphenylphosphine (29.43 g, 0.1122 mole) was added. The reaction was kept at 0° C. for an additional 15 minutes and stirred at room temperature for 3 hours. The methylene chloride was removed in vacuo. The residue was treated with hexane and the combined organic extract was concentrated in vacuo. The crude product was purified by flash chromatography on silica, eluting with straight hexane, to give 7.2 g (52%) of 11-bromoundecyne as a colorless oil. Following the procedures of Examples 20 and 39(a), a mixture of salicylaldehyde, 11-bromoundecyne and potassium carbonate in dimethylformamide is reacted to furnish 2-(10-undecynyloxy)benzaldehyde.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11].CCO>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:4]
Reactant: O=C(O)C(=NO)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCO
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of dichloroacetyl chloride (1.8 ml.) in methylene chloride (15 ml.) was added 2-hydroxyimino-(4-chlorophenyl)acetic acid (anti-isomer) (1.5 g.) and the suspension stirred for two hours at room temperature. During this time most of the material dissolved. The solid was removed, washed with petroleum (b.p. 40°-60°) and the washings and filtrate were combined, kept at 5° overnight and the resulting solid was collected and dried to give the title acid (2.0 g; 85%), m.p. 80°, λmax. (EtOH) 258 nm (ε 12,280), λmax. (Nujol) 1774 (ester), 1750 and 1722 cm.-1 (CO2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6](I)[N:5]=1)[CH3:2].[Cu](C#N)[C:14]#[N:15]>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: N#C[Cu]C#N
Reactant: CCOc1nc(I)ccc1OC
Solvent: CN(C)C=O
Product: CCOc1nc(C#N)ccc1OC
Temperature: 150 °C

Procedure:
To a solution of 2-ethoxy-6-iodo-3-methoxypyridine (10-2, 100 mg, 0.36 mmol, 1 equiv) in DMF (675 uL) was added copper cyanide (39 mg, 0.43, mmol, 1.2 equiv). The reaction mixture was heated in a microwave reactor at 150° C. for 20 minutes, and then was partitioned between DCM (50 mL) and water (50 mL). The aqueous layer was extracted with DCM (3×25 mL), and the organic phase was dried over Mg2SO4, concentrated and purified by normal phase column chromatography (20-50% EtOAc in hexanes) to yield the title compound (10-3) as a white solid. ESI+MS [M+H]+ C9H11N2O2: 179.1 found, 179.2 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]#[N:11].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([F:22])[CH:16]=1.C[Al](C)C.C1(C)C=CC=CC=1>CC1C=CC=CC=1C>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:10](=[NH:11])[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])([CH3:13])[CH3:12])=[C:17]([F:22])[CH:16]=1
Reactant: CC(C)(C#N)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: CC(C)(C(=N)Nc1ccc(Br)cc1F)c1c(Cl)cccc1Cl
Temperature: 100 °C
Yield: 46.6 %

Procedure:
2-(2,6-Dichlorophenyl)-2-methylpropanenitrile (20 g, 93 mmol) and 4-bromo-2-fluoroaniline (28.4 g, 149 mmol) were dissolved in anhydrous o-xylene (200 mL) and heated to 100° C. under N2. Trimethylaluminum (2 M) in toluene (140 mL, 280 mmol) was added drop-wise (˜0.9 mL per minute) over 2.5 hours while the reaction mixture was stirred at 100° C. After addition, the reaction mixture was stirred at 100° C. for 30 minutes, and then cooled to −5° C. The reaction mixture was very carefully quenched with potassium sodium tartrate (20 g in 100 mL water) (Caution: gas and heat formation). The reaction mixture was filtered through Celite 545. The filtrate was washed with 1N HCl (4×70 mL). The aqueous was neutralized with 2N NaOH and extracted with EtOAc (4×100 mL). The organics were combined, washed with brine, dried with Na2SO4, and concentrated on a rotary evaporator to afford 24 g of crude product. The crude product was recrystallized with 72 mL of MTBE and 240 mL of hexane to give N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (17.5 g, 43.3 mmol, 46.4% yield) as a white solid (purity: 99%). 1H-NMR (MeOD, 400 MHz) δ 7.42 (d, 2H, J=8.0 Hz), 7.30 (m, 2H), 7.16 (t, 1H, J=8.0 Hz), 6.93 (t, 1H, J=8.0 Hz), 2.11 (s, 6H); 13C-NMR (DMSO-d6, 100 MHz) δ 166.5, 156.1, 153.7, 140.6, 138.5, 135.9, 131.4, 128.6, 128.0, 125.7, 119.5, 112.9, 50.0, 29.2; MS m/e 403.09 (M+H+); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 2.32 minutes.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:24][NH2:25]>>[NH:24]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:3]=1)[NH2:25]
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccc(C(F)(F)F)cc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)-(4-trifluoromethyl-phenyl)-amine and hydrazine monohydrate.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[NH:19][CH:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]1)[CH3:6]
Reactant: CCOCCn1c(NC2CCNCC2)nc2cccnc21
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(NC2CCN(CC#N)CC2)nc2cccnc21
Temperature: 25 °C
Yield: 21 %

Procedure:
A mixture of 9.4 parts of 2-chloroacetonitrile, 30 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 11 parts of sodium carbonate and 658 parts of N,N-dimethylformamide was stirred over weekend at room temperature. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried in vacuo, yielding 7.2 parts (21.0%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidineacetonitrile; mp. 141.4° C. (compound 92).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:33]=[CH:32][C:14]3[CH2:15][CH2:16][C:17]4[C:18]([C:29]([NH2:31])=[O:30])=[N:19][N:20]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=5)[C:21]=4[C:13]=3[CH:12]=2)=[O:9])=[C:4]([CH3:34])[CH:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>CN(C)C(=O)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:21]3[C:13]4[CH:12]=[C:11]([NH:10][C:8]([C:5]5[CH:6]=[N:7][C:2]([N:35]6[CH2:40][CH2:39][O:38][CH2:37][CH2:36]6)=[CH:3][C:4]=5[CH3:34])=[O:9])[CH:33]=[CH:32][C:14]=4[CH2:15][CH2:16][C:17]=3[C:18]([C:29]([NH2:31])=[O:30])=[N:19]2)=[CH:23][CH:24]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)ncc1C(=O)Nc1ccc2c(c1)-c1c(c(C(N)=O)nn1-c1ccc(F)cc1)CC2
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(N2CCOCC2)ncc1C(=O)Nc1ccc2c(c1)-c1c(c(C(N)=O)nn1-c1ccc(F)cc1)CC2
Temperature: 100 °C
Reaction time: 27 h

Procedure:
The title compound of Example 246 (1.47 mmoles) and morpholine (23.1 mmoles) were dissolved in 10 mL of N,N-dimethylacetamide. The reaction mixture was then placed under nitrogen and stirred in an oil bath at 100° C. for 27 h. The mixture was partially stripped of solvent then added to water, filtered, and washed with water. The solid was recrystallized from acetonitrile, then dissolved in acetonitrile and dried over anhydrous MgSO4. The solvent was then stripped down to a solid. Mp: 301° C. (decomp.) 1H NMR (d6-DMSO, 400 MHz): δ 2.22 (s, 3H); 2.80-2.94 (m, 4H); 3.46 (t, 4H, J=4.8 Hz); 3.62 (t, 4H, J=4.8 Hz); 6.67 (s, 1H); 7.22-7.27 (m, 3H); 7.31-7.38 (m, 2H); 7.42 (dd, 1H, J=1.9 Hz, 8.2 Hz); 7.49-7.57 (m, 3H); 8.11 (s, 1H); 9.92 (s, 1H). 13C NMR (d6-DMSO, 100 MHz): δ 20.35, 20.38, 29.63, 45.55, 66.54, 108.46, 114.91, 117.02, 117.25, 119.91, 121.23, 122.78, 126.42, 128.64, 128.73, 129.36, 132.60, 136.82, 136.85, 138.38, 139.82, 143.15, 147.70, 148.03, 160.04, 161.39, 163.84, 164.47, 166.18. M+1=527
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH3:22])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(=O)(O)[O-].[Na+].[C:35]1([CH:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@@H:21]([C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH3:22])=[O:19])[NH:17][C:42](=[O:43])[CH:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: C[C@@H](NC(=O)[C@H](N)CCCNC(=O)OCc1ccccc1)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(O)cc1

Procedure:
(R)-N5 -(Cbz)-(R)-N-[1-(4-hydroxyphenyl)ethyl]ornithine amide hydrochloride (28.1 g; 66.6 mmol; from step (c) above) was dissolved in THF (500 mL) and solid sodium bicarbonate (22.4 g; 266.4 mmol; 4 eq.) was slowly added. A solution of diphenylacetylchloride (21.4 g; 66.60 mmol) in THF was then slowly added dropwise over 30 minutes. The reaction was monitored by TLC analysis. After the reaction was judged complete, the solvent was removed under vacuum and the residue was dissolved in a mixture of THF, EtOAc and MeOH and washed with saturated aqueous sodium bicarbonate, water, saturated KHSO4 and brine. The organics were dried over Na2SO4, filtered and concentrated to dryness to yield 29.2 g (0.050 mol; 76%) of the sub-title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C.[Cl:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[N:27][C:28]=1[Cl:29]>C(OCC)(=O)C>[Cl:29][C:28]1[C:23]([Cl:22])=[CH:24][C:25]([O:30][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[CH:26][N:27]=1
Reactant: CCOC(CBr)OCC
Reactant: Oc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(COc1cnc(Cl)c(Cl)c1)OCC
Temperature: 100 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
Bromoacetaldehyde diethyl acetal (2.74 ml, 18.3 mmol) and cesium carbonate (9.93 g, 30.5 mmol) were added to an N,N-dimethylacetamide solution (10 ml) of 5,6-dichloropyridin-3-ol (1.0 g, 6.10 mmol), and stirred under a nitrogen atmosphere at 100° C. for 16 hours. Saline solution and ethyl acetate were added to the reaction solution, the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=11:1 to 9:1) to obtain 2,3-dichloro-5-(2,2-diethoxyethoxy)pyridine (1.51 g, yield: 88%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20]C=3)[CH2:11][CH2:10][C:9]=2[N:8]=1.FC1C=C(C=CC=1)OCC1C=CC2C(=O)NCCC=2[N:35]=1.BrC1C=CC(F)=CN=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:35]=3)[CH2:11][CH2:10][C:9]=2[N:8]=1
Reactant: O=C1c2ccc(COc3cccc(F)c3)nc2CCN1c1ccc(F)cc1
Reactant: O=C1NCCc2nc(COc3cccc(F)c3)ccc21
Agent: Fc1ccc(Br)nc1
Product: O=C1c2ccc(COc3cccc(F)c3)nc2CCN1c1ccc(F)cn1

Procedure:
Prepared in a manner similar to the preceding example, 2-((3-fluorophenoxy)methyl)-6-(4-fluorophenyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one, using the common intermediate 2-((3-fluorophenoxy)methyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one as described above and 2-bromo-5-fluoropyridine. 1H NMR (400 MHz, CDCl3) δ 8.49 (1H, d, J=8), 8.32 (1H, d, J=3), 8.03 (1H, dd, J=9.2, 4.0), 7.60 (1H, d, 8), 7.54 (1H, dd, J=23, 8), 7.28 (1H, dd, J=16, 7.6), 6.80 (1H, dd, 7.6, 1.6), 6.74 (1H, ddd, J=23, 8.0, 1.6), 5.26 (1H, s), 4.41 (2H, t, J=6.8), 3.38 (2H, t, J=6.8); LC-MS (M+H)=368.2.
Reaction SMILES: [CH2:1]([C:3]1[C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[C:14]([CH2:15][CH2:16][NH:17][C:25](=[O:27])[CH3:26])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nn2ccc3c(c2c1CCN)CCO3
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nn2ccc3c(c2c1CCNC(C)=O)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.1 %

Procedure:
To a solution of 2-(2-ethyl-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl)ethanamine (110 mg, 0.476 mmol) and triethylamine (133 μL, 0.954 mmol) in tetrahydrofuran (5 mL) was added acetic anhydride (90.0 μL, 0.952 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution (50 μL) was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=90/10→100/0) and recrystallization (ethyl acetate/diisopropyl ether) to give the title compound (67.8 mg, yield 52%).