Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13](=[O:22])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13](=[O:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CC(C)COc1ccc(C(=O)/C=C/c2ccccn2)c(O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(C(=O)CCc2ccccn2)c(O)c1
Yield: 84.7 %

Procedure:
In a 200 mL round-bottomed flask, (E)-1-(2-hydroxy-4-isobutoxyphenyl)-3-(pyridin-2-yl)prop-2-en-1-one (1.08 g, 3.63 mmol) and 80 mg of 10% Pd/C was mixed together in wet EtOAc (50 ml). Hydrogenation was conducted at atmospheric pressure room temperature until the starting material was gone. The catalyst was filtered and the crude was purified by chromatography on silica gel (25% EtOAc/hexane) to provide 0.92 g of final compound (82%) as off white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:30]=[CH:31][CH:32]=1)[CH2:10][N:11]1[CH2:29][CH2:28][C:14]2([O:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[S:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)C>C(O)(=O)C.O>[CH3:27][C:24]1[S:23][C:22]([C:20]([N:16]2[CH2:15][C:14]3([CH2:13][CH2:12][N:11]([CH2:10][C:9]4[CH:8]=[C:7]([CH:32]=[CH:31][CH:30]=4)[O:6][CH2:5][CH:4]=[O:3])[CH2:29][CH2:28]3)[O:19][CH2:18][CH2:17]2)=[O:21])=[CH:26][CH:25]=1
Reactant: CCOC(COc1cccc(CN2CCC3(CC2)CN(C(=O)c2ccc(C)s2)CCO3)c1)OCC
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C(=O)N2CCOC3(CCN(Cc4cccc(OCC=O)c4)CC3)C2)s1
Temperature: 65 °C

Procedure:
A solution of (9-(3-(2,2-diethoxyethoxy)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(5-methylthiophen-2-yl)methanone (example 38, step b) (0.45 g) in a mixture of acetic acid (25 mL) and water (25 mL) was heated at 65° C. under nitrogen for 16 hours. Most of the solvents were removed under reduced pressure and the residue partitioned between ethyl acetate and excess saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate and filtered, acetic acid (0.051 mL) was added and the solvent removed under reduced pressure to afford the subtitled compound. Yield 0.38 g. Used directly.
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.N1C(C)=CC=CC=1C.[CH3:25][OH:26]>[B-](F)(F)(F)F.[Ag+]>[CH3:25][O:26][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: CO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: Cc1cccc(C)n1
Product: COC1C=C(CCCCCCC(=O)O)C(=O)C1
Reaction time: 0.03 h

Procedure:
To a stirred solution of 5.30 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 8) in 85ml. of methanol at 0°-3° C. is added 4.40 g. (22.6 mmole) of silver fluoborate in one portion. After 2 minutes, the mixture is treated with 2.66 g. (24.8 l mmoles) of 2,6-lutidine. After stirring for 30 minutes at 0°-3° C. the mixture is stirred at ambient temperature for 45 minutes. Silver bromide is removed by filtration, and the filtrate is concentrated to a volume of 40 ml. The solution is treated with saturated sodium chloride solution and extracted with ether. The extract is washed successively with 0.5 N hydrochloric acid solution, water, and saturated sodium chloride solution; dried over magnesium sulfate; and concentrated. Partition chromatography of the residue on Celite gives an oil, λmax.MeOH =220 mμ (7450); νmax.=1715 (carbonyl groups) and 1095 cm-1 (methoxy group).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([CH:20]=[C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:22]#[N:23])[C:11]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl>CO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:12]([CH:20]=[C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:22]#[N:23])[C:11]2=[O:30])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CC(=Cc1cc2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O)c1cccnc1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: N#CC(=Cc1cc2cccnc2n(-c2cccc(N)c2)c1=O)c1cccnc1
Temperature: 50 °C
Yield: 43.3 %

Procedure:
0.5 g of 3-[1,2-dihydro-1-(3-nitrophenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(3-pyridyl)prop-2-enenitrile, prepared in Example 111, is suspended in 15 ml of methanol and 10 ml of water, in the presence of 0.5 g of iron powder. The suspension is heated to about 50° C. and 0.5 ml of concentrated hydrochloric acid is added dropwise. The reaction mixture is refluxed for 45 minutes and then cooled to room temperature. The residual iron is removed and the filtrate is diluted with water, treated with 0.5 g of potassium carbonate and extracted with dichloromethane. The organic phase is decanted, washed with water, dried and concentrated to give 0.2 g of 3-[1-(3-aminophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-2-(3-pyridyl)prop-2-enenitrile in the form of a bright yellow solid melting at 280° C., after purification on a silica column (eluent: dichloromethane/methanol 98.5/1.5). Yield 40%.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11](OC3C=CC=CC=3)[C:10]=2[N:24]=1>C(OCC)(=O)C>[CH3:6][C:7]1[N:8]([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH2:5])[C:10]=2[N:24]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOc3ccccc3)c2c1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: Cc1nc(N)c2nc(C)n(CCOc3ccccc3)c2c1C
Temperature: 150 °C

Procedure:
A sealed tube containing anhydrous ammonium acetate (11.4 g) and 2,6,7-trimethyl-4-phenoxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridine (1.14 g) from Part C was heated to 150° C. for 40 hours. The reaction was allowed to cool to room temperature. The resulting reaction mixture was then dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The basic layer was washed twice with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, and the solvents were removed under reduced pressure. The resulting orange solid was passed through a silica gel column using 94/6 dichloromethane/methanol as the eluant. Because NMR analysis indicated that the white solid contained ammonium acetate, the product was dissolved in chloroform and washed with 25% aqueous sodium hydroxide. The resulting basic aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with water, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting white solid was dried under vacuum at 60° C. for 24 hours to provide 2,6,7-trimethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 176.0–177.0° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]1([C:12](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][CH2:4][OH:5]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCO)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A mixture of 2-methylamino-ethanol (5.0 gr, 66.6 mmol) and triphenylmethyl chloride (18.6 g, 66.6 mmol) in 150 mL of CH2Cl2 was treated with triethylamine (9.3 mL, 66.6 mmol) and stirred at room temperature for 2 h. The solvent was removed in vacuum and the residue was dissolved in EtOAc (200 mL). The organic solution was washed with water (100 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with 20% EtOAc in n-heptane, and those fractions with Rf=0.5 by TLC (EtOAc/hexane, 3/7) were combined and concentrated in vacuo to give 18.7 g of the product as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[C:18](=[O:19])[CH:17]=[CH:16][N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:14]=1.CCN(CC)CC>C1COCC1.Cl>[O:19]=[C:18]1[CH:17]=[CH:16][N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:14]=[C:13]1[CH:12]=[O:11]
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1CO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of oxalyl chloride (0.175 mL, 2.07 mmol) in THF (7.5 mL) was added DMSO (0.294 mL, 4.14 mmol) at −78° C. To the suspension was added a solution of 3-(hydroxymethyl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (509 mg, 1.88 mmol) in THF (7.5 mL) at −78° C. The suspension was stirred at −78° C. for 1 h. To the mixture was added Et3N (1.05 mL, 7.52 mmol) at −78° C. The mixture was gradually warmed to room temperature, stirred at room temperature for 18 h, diluted with 1 M HCl aqueous solution, extracted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 70/30). To a solution of oxalyl chloride (0.477 mL, 5.64 mmol) in THF (19 mL) was added DMSO (0.801 mL, 11.3 mmol) at −78° C. To the suspension was added a mixture of the above residue in THF (9.5 mL) at −78° C. The suspension was stirred at −78° C. for 2 h. To the mixture was added Et3N (3.14 mL, 22.6 mmol) at −78° C. The mixture was gradually warmed to room temperature, stirred at room temperature for 17 h, diluted with 1 M HCl aqueous solution, extracted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (257 mg, 51% yield) as a yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 6.87 (1H, d, J=8.2 Hz), 7.81-7.91 (2H, m), 8.08-8.15 (1H, m), 8.16 (1H, s), 8.98 (1H, d, J=8.0 Hz), 10.07 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11].[N+:12]([O-])([OH:14])=[O:13].C1(O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([N+:12]([O-:14])=[O:13])[C:4]=1[OH:11]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(O)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(O)c1OC
Temperature: 5 °C

Procedure:
2,3-Dimethoxyphenol (79) (5.00 g, 0.032 mol) was dissolved in glacial acetic acid (50 ml) and the resultant, stirred solution was cooled to 5° C. A cooled (5° C.) mixture of concentrated nitric acid (10 ml) and water (10 ml) was added in one portion to the phenol solution which immediately turned dark red-brown. The mixture was stirred for a further minute and poured into water (200 ml), this solution was neutralised with saturated sodium bicarbonate solution until all effervescense had ceased. The resultant yellow solution was extracted with several portions of diethyl ether until the ether remained almost colourless. The combined extracts were washed with water until the water remained almost colourless, dried (MgSO4) and the ether evaporated off in vacuo to leave a brown oil. This was purified by column chromatography (10% petrol/dichloromethane) to give a bright yellow solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([OH:19])[CH2:17][OH:18].N1C=CC=CC=1.[Br:26][CH:27]([CH3:31])[C:28](O)=[O:29].[Na+].[Cl-].O>CCOC(C)=O.CC(C)=O>[Br:26][CH:27]([CH3:31])[C:28]([O:18][CH2:17][CH2:16][OH:19])=[O:29]
Reactant: OCCO
Reactant: CC(Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(Br)C(=O)OCCO
Reaction time: 8 h
Yield: 42.5 %

Procedure:
Dicyclohexylcarbodimide (4.1 g, 20 mmol), anhydrous ethylene glycol (5.0 g, 81 mmol), and pyridine (1 ml, 12 mmol) were charged into a vial. Acetone (14 ml) and 2-bromopropionic acid (1.5 ml, 16.7 mmol) were added while cooling the vial down with an ice bath to control the exothermic reaction. After stirring the vial's contents overnight, undissolved by-products were removed by filtration. To the filtered reaction mixture were added AcOEt (20 ml) and saturated NaCl water (15 ml) followed by shaking well. The reaction mixture separated into 2 layers. The upper AcOEt layer was washed with dilute HCI once and saturated NaCl water (15 ml) two more times and then dried with MgSO4. After removing MgSO4, AcOEt was rotary evaporated to obtain a crude product. This crude product was purified by silica gel chromatography (eluent: AcOEt:hexane=1:1 by weight) to yield 1.4 g (43% yield) product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25]>C1C=CC=CC=1>[C:22]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)(=[O:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1
Reaction time: 0.03 h

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and cooled to -10° with stirring. 0.255 G. of butyric acid chloride are added dropwise thereto over a period of 2 minutes. The temperature rises to 0° and pyridine hydrochloride precipitates out. Subsequently, the mixture is stirred overnight at room temperature and the suspension poured on to a mixture of 12 g. of ice and 12 ml. of 20% hydrochloric acid. Thereafter, this mixture is extracted three times with ethyl acetate, washed with water, dried over sodium sulfate and evaporated in vacuum. The 0.552 g. of yellowish crystals obtained as the residue are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.521 g. of yellowish crystals which are recrystallized from acetone-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl butyrate obtained melts at 77.9°-78.2° and is liquid crystalline (monotrope) upon cooling to 74.7°. UV (EtOH): ε272 = 26,100.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[O:41])[NH:39][CH3:40])[CH:33]=2)[CH:29]=[CH:28][C:27]=1[O:42][CH3:43])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8].[H-].[Na+].I[CH3:53]>C1COCC1.O>[Cl:1][C:2]1[C:3]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[O:41])[N:39]([CH3:53])[CH3:40])[CH:33]=2)[CH:29]=[CH:28][C:27]=1[O:42][CH3:43])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8]
Reactant: CNC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnc(C(=O)N(C)C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of amide 158 (125 mg, 0.175 mmol) in THF (5 mL) is treated with sodium hydride (11 mg, 0.26 mmol, 60% dispersion in mineral oil) at 0° C. After warming to RT and stirring 0.5 h, iodomethane (0.13 mL, 0.26 mmol, 2 M solution in TBME) is added via syringe and the reaction stirred 1 h. Analysis by LC/MS at this juncture revealed the reaction is only 75% complete. Hence more sodium hydride (11 mg, 0.26 mmol, 60% dispersion in mineral oil) is added, followed after 0.5 h by iodomethane (0.13 mL, 0.26 mmol, 2 M solution in TBME). After a further hour at RT, the reaction is diluted with water (10 mL) and extracted into EtOAc (3×20 mL). The combined EtOAc phases are dried (Na2SO4) and the solvent removed in vacuo. The title compound is obtained after chromatography (gradient elution—50-80% EtOAc in heptane with 0.5% triethylamine).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:14]3[S:15][C:16]([C:18]([N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[CH3:21])=[O:19])=[CH:17][C:13]=3[CH2:12][CH2:11][O:10][C:9]=2[CH:29]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:14]3[S:15][C:16]([C:18]([N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[CH3:21])=[O:19])=[CH:17][C:13]=3[CH2:12][CH2:11][O:10][C:9]=2[CH:29]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(CN=[N+]=[N-])cc1OCC2)c1ccccc1Cl
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)c1cc2c(s1)-c1ccc(CN)cc1OCC2)c1ccccc1Cl
Temperature: 40 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
8-(Azidomethyl)-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (100 mg, 0.23 mmol) was dissolved in 10 mL of MeOH. To the solution was added Pd/C (10 mg) and charged with H2. The mixture was stirred at 40° C. for 3 h. Filtered and concentrated in vacuo to obtain 244 (54.1 mg, yield 59%). 1H NMR (CDCl3, 400 MHz) δ 8.48-8.52 (m, 2H2), 6.55-7.47 (m, 8H), 4.15 (t, J=4.8 Hz, 2H), 3.91-3.95 (m, 2H), 3.28 (s, 3H), 2.94 (t, J=4.8 Hz, 2H). MS: (ESI+) 382.1
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[N:3]=1.[NH2:28][C:29]1[CH:30]=[CH:31][C:32]([C@H:40]2[CH2:45][CH2:44][C@@H:43]([O:46][CH2:47][CH3:48])[CH2:42][CH2:41]2)=[C:33]2[C:37]=1[C:36](=[O:38])[N:35]([CH3:39])[CH2:34]2>>[CH2:47]([O:46][C@@H:43]1[CH2:42][CH2:41][C@H:40]([C:32]2[CH:31]=[CH:30][C:29]([NH:28][C:2]3[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=4)[N:3]=3)=[C:37]3[C:33]=2[CH2:34][N:35]([CH3:39])[C:36]3=[O:38])[CH2:45][CH2:44]1)[CH3:48]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: CCO[C@H]1CC[C@@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](OCC)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title product was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (40.0 mg, 0.0944 mmol) and 7-amino-4-(cis-4-ethoxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 166A, 32.67 mg, 0.1133 mmol). The reaction mixture was concentrated under reduced pressure to yield a yellow oil. The material was purified by silica gel chromatography on the combi-flash Rf system using 1:1 EtOAc-DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 44.3 mg (69% yield). 1H NMR (DMSO-d6, 400 MHz): δ=1.13-1.22 (m, 9H), 1.46-1.59 (m, 4H), 1.70-1.84 (m, 2H), 1.91-2.01 (m, 2H), 2.56-2.68 (m, 1H), 3.08 (s, 3H), 3.16-3.24 (m, 2H), 3.45 (q, J=6.91 Hz, 2H), 3.61 (br. s., 1H), 3.91-4.01 (m, 4H), 4.53 (s, 2H), 7.25 (dd, J=8.59, 2.27 Hz, 2H), 7.30 (d, J=7.58 Hz, 1H), 7.60 (d, J=4.55 Hz, 2H), 8.46 (s, 1H), 8.51-8.88 (m, 1H), 9.87 (br. s., 1H), 10.58 (br. s., 1H). MS (ES+): m/z 676.30 [MH+] (TOF, polar).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:34])[N:14]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:34])[N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1c(CCc2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(CCc2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3-benzyloxycarbonylamino-2-oxo-6-phenethyl-1,2-dihydro-1-pyridyl)acetate (0.554 g) in dichloromethane (distilled from CaH) was added trifluoroacetic acid (1.50 ml); and the mixture was stirred overnight, evaporated, and dried under vacuum to afford (3-benzyloxycarbonylamino-2-oxo-6-phenethyl-1,2-dihydro-1-pyridyl)acetic acid; MS: m/z=407(M+1).
Reaction SMILES: Br.[CH3:2][CH:3]1[CH2:14][C:13]2[NH:12][CH:11]=[C:10]([C:15]([OH:17])=O)[C:9]=2[C:8]2[N:4]1[CH:5]=[CH:6][N:7]=2.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>O.O1CCOCC1>[C:19]1([NH:18][C:15]([C:10]2[C:9]3[C:8]4[N:4]([CH:5]=[CH:6][N:7]=4)[CH:3]([CH3:2])[CH2:14][C:13]=3[NH:12][CH:11]=2)=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC1Cc2[nH]cc(C(=O)O)c2-c2nccn21
Reactant: Nc1ccccc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC1Cc2[nH]cc(C(=O)Nc3ccccc3)c2-c2nccn21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 4-methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid hydrobromide (25 mg), aniline (12 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (23 mg), 1,4-dioxane (1.5 mL), and water (1.5 mL) is stirred at room temperature for 4 days. 0.5N sodium hydroxide solution (3 mL) is added and the mixture is extracted with dichloromethane (3×50 mL). The combined organic layers are washed with brine (1×10 mL), dried over magnesium sulfate and concentrated in vacuo. The residue is purified by preparative thin layer chromatography on silica gel, eluting with 5% methanol in dichloromethane, to give 4-methyl-5,6-dihydro-4H-1,3a,6-triaza-as-indacene-8-carboxylic acid phenyl amide, cream solid, 7 mg: LRMS calcd 292.34, found [M+H] 293.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([C:11](=O)[NH:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][NH:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCC2CN(Cc3ccccc3)CC12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CC3CCNCC3C2)cc1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 102.3 %

Procedure:
To a solution of the lactam from Example 22C (0.46 g) in THF (5 mL) was added 1M LiAlH4 (4.0 mL). The mixture was heated at 50° C. for 2 h, cooled to 15° C., and quenched by cautious addition of water (0.15 mL), followed by 15% NaOH (0.15 mL), then water (0.456 mL). The mixture was stirred for 5 minutes and filtered and washed with THF (3×5 mL). The filtrate was concentrated in vacuo to afford 442 mg of the title compound as a clear oil (quantitative yield). MS (CI) m/z 217 (M+H)+; 1H NMR: δ 1.8-1.5 (m, 3H), 2.33-2.10 (m, 2H), 2.8-2.4 (m, 8H), 3.75 (s, 2H), 7.25 ppm (m, 5H).