Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:16][C:12]=3[CH:11]=[C:10](C(O)=O)[N:9]=2)[CH:5]=[N:6][CH:7]=1.C1(P([N:54]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][C@H:18]4[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:16][C:12]=3[CH:11]=[C:10]([NH2:54])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(C(=O)O)nc(-c4cncc(Cl)c4)c32)CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine-6-carboxylic acid (Example 3.22, prepared from Example 2.1, Step 4 using a procedure similar to that described for Example 1.1, Step 5; 500 mg, 0.91 mmol) in DMF (6 mL) was added TEA (0.2 mL, 1.83 mmol), and the reaction was deoxygenated by purging with nitrogen for 5 minutes. To this reaction mixture was added diphenyl phosphoryl azide (0.4 mL, 1.83 mmol) and the reaction flask was sealed. The mixture was stirred at rt for 1 h and then H2O (2 mL) was added. Again, the reaction flask was sealed and the reaction was heated at 90° C. for 1.5 h. The reaction was then diluted with water and EtOAc. The organic layer was separated and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (2% MeOH/CH2Cl2) to yield 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridin-6-amine. MS ES/APCI calc'd. for C29H33ClN6O [M+H]+ 517. found 517.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[CH:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:21][CH:20]=1)=[O:18]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: O=C(Nc1cc2c(Br)cccn2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1
Temperature: 25 °C

Procedure:
N-(4-Bromopyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (4.66 g, 17 mmol), 4-formylphenyl boronic acid (3.06 g, 20.4 mmol), PdCl2dppf (0.37 g, 0.45 mmol) and Na2CO3 (3.6 g, 34 mmol) were stirred in 1,4-dioxane (140 mL) and water (28 mL) at 100° C. for 3 h. The reaction mixture was cooled to room temperature, filtered through celite, washed through with DCM and concentrated in vacuo. The residue was triturated with EtOAc and dried in vacuo to afford N-(4-(4-formylphenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[C@@H:18]([O:24]C(=O)C)[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]32[O:31][CH2:30][CH2:29][O:28]3)[CH2:6]1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:30]1[CH2:29][O:28][C:14]2([CH2:13][CH2:12][C@H:11]3[C@H:10]4[C@H:19]([C@@H:18]([OH:24])[CH2:17][C@:15]23[CH3:16])[C@:20]2([CH3:23])[C:7]([CH2:6][C@@H:5]([OH:4])[CH2:22][CH2:21]2)=[CH:8][CH2:9]4)[O:31]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2[C@@H](OC(C)=O)C[C@@]2(C)[C@H]3CCC23OCCO3)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CCC21OCCO1

Procedure:
At an internal temperature of 5°-10°, a solution of 4.7 g of 3β,11β-diacetoxy-17,17-ethylenedioxyandrost-5-ene in 140 ml of tetrahydrofuran is added dropwise to a stirred suspension of 2.35 g of lithium aluminium hydride in 95 ml of tetrahydrofuran and then rinsed out with 9 ml of tetrahydrofuran, and the mixture is boiled under reflux for 12 hours. The reaction mixture is decomposed at an internal temperature of a maximum of 5° by the careful dropwise addition of a mixture of 9 ml of tetrahydrofuran and 14 ml of ethyl acetate followed by a mixture of 9 ml of tetrahydrofuran and 14 ml of water, and after the addition of 70 g of anhydrous sodium sulphate the mixture is stirred without cooling for a further 30 minutes. Solid portions are removed by filtration with suction over a layer of kieselguhr (subsequent washing with tetrahydrofuran) and the filtrate is concentrated under a water-jet vacuum. The amorphous residue is chromatographed over 50 times the amount by weight of silica gel. Elution with a mixture of methylene chloride/acetone (93:7) and evaporation of the solvent yield uniform 17,17-ethylenedioxyandrost-5-ene-3β,11β-diol which, after being dissolved and recrystallised once from methylene chloride/ether, melts at 123°-125°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][C:17]#[N:18])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][C:17]#[N:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[OH:15])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(CC#N)CCCCC2=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C2(CC#N)CCCCC2O)c1
Reaction time: 1 h
Yield: 98 %

Procedure:
243 g of 1-(m-methoxyphenyl)-2-oxo-cyclohexane-1-acetonitrile are dissolved in 2.5 liters of ethanol, whereupon a total of 25 g of sodium borohydride is added portionwise while stirring. The temperature rises to about 45° C. After 1 hour, 1-(m-methoxyphenyl)-2-oxo-cyclohexane-1-acetonitrile can no longer be detected by thin-layer chromatography. After distillation of the solvent, the residue is treated with 500 ml of ice water and extracted twice with 1.5 liters of ether each time. The combined extracts are washed once in succession with 0.5 liter of water, 0.5 liter of 1 N hydrochloric acid and 0.5 liter of water, dried over magnesium sulfate, and the solvent is removed by distillation, whereby there are obtained 240 g of 1-(m-methoxyphenyl)-2-hydroxy-cyclohexane-1-acetonitrile in the form of a colorless, viscous oil which is dissolved without purification in 2 liters of pyridine and treated with 130 ml of phosphorus oxychloride. The mixture is boiled at reflux for 3 hours and subsequently evaporated in a water-jet vacuum. The residue is treated with water while cooling with ice and extracted twice with 1.5 liters of ether each time, whereupon the ethereal phases are combined, washed once in succession with 0.5 liter of water and 0.5 liter of 1 N hydrochloric acid and subsequently twice with water, dried over magnesium sulfate and evaporated. The brown oil obtained is purified on a 10-fold amount of silica gel. After elution of the impurities with about 10 liters of ether/petroleum ether (1:9), 1-(m-methoxyphenyl)-2-cyclohexene-1-acetonitrile is eluted with about 10 liters of ether/petroleum ether (1:3). The fractions which are uniform in accordance with thin-layer chromatography are combined, and the solvent is removed by distillation and the product remains behind as a light yellow oil.
Reaction SMILES: [C:1]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:8]=2[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].C(O)(=O)/C=C\C(O)=O.ClC1[N:31]=[N:30]C2CCNCC=2C=1.C(Cl)(=O)CCC>C(#N)C>[C:1]([N:6]1[CH2:16][CH2:15][C:9]2[N:10]=[N:11][C:12]([NH:30][NH2:31])=[CH:13][C:8]=2[CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: CCCC(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC#N
Product: CCCC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 6-butyryl-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, requires as starting material, may be produced in a manner analogous to that described in Example 8 (g), from 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and butyric acid chloride. Reaction time 27 hours. M.P. 130°-133° from acetonitrile.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([F:12])[F:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:19]O.O>C(Cl)(Cl)Cl.C[Re](=O)(=O)=O.[O-2].[Mn+4].[O-2]>[Si:1]([O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][N+:16]([O-:19])=[CH:15][CH:14]=1)([F:12])[F:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(F)(F)c1ccncc1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCC(F)(F)c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[2-(tert-butyldimethylsilanyloxy)-1,1-difluoroethyl]pyridine (0.14 g) prepared in (3) in chloroform (3 mL) were added methyltrioxorhenium (VII) (0.0010 g) and aqueous 30% hydrogen peroxide (0.11 mL). The reaction mixture was stirred at RT for 4 hr. To the mixture was added manganese (IV) oxide. The reaction mixture was stirred at RT for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure to give the crude title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:14]([N:3]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCBr
Reactant: O=C1CCCCCCCN1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCN1CCCCCCCC1=O
Yield: 69.7 %

Procedure:
Following example 17, 4.2 g of 50% sodium hydride-mineral oil dispersion (2.1 g NaH, 0.0875M), 10 g (0.0708M) of azacyclononan-2-one and 15 g (0.0777M) of 1-bromooctane gave 12.5 g (70%) of product; b.p. 150°-160°/0.5 mm.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:41])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:34][CH2:35][C:36]([O:38]CC)=[O:37])=[C:23]([CH:33]=2)[C:24]([O:26]CC(OCC)=O)=[O:25])=[O:17])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].C(O)(=O)C>O>[CH2:1]([NH:8][C:9](=[O:41])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:34][CH2:35][C:36]([OH:38])=[O:37])=[C:23]([CH:33]=2)[C:24]([OH:26])=[O:25])=[O:17])[N:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC(=O)c1cc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)ccc1OCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)COc1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1C(=O)O
Yield: 95.3 %

Procedure:
378 mg of ethoxycarbonylmethyl 5-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-2-ethoxycarbonylmethoxy-benzoate, 6.5 ml of ethanol and 1.29 ml of 2N sodium hydroxide solution are stirred for 5 hrs. at RT. After the addition of 3 ml of acetic acid and 2 ml of water the mixture is warmed until a homogeneous solution is obtained. After cooling the precipitate is filtered off under suction, washed with acetic acid-water 1:1 and dried. There are obtained 290 mg of 5-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-2-carboxymethoxy-benzoic acid, m.p. 219° C., MS: 471 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[C:19]([NH:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[CH3:29])=[O:20])([CH3:15])[CH3:14])#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([C:13]([C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[C:19]([NH:21][C:22]1[CH:27]=[C:26]([O:28][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:25]=[CH:24][C:23]=1[CH3:29])=[O:20])([CH3:15])[CH3:14])#[N:12]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(O)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (1.41 g, 8.92 mmol) and 3-(1-cyano-1-methylethyl)-N-(5-hydroxy-2-methylphenyl)benzamide (2.5 g, 8.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.85 g, 13.3 mmol), and the mixture was stirred at 80° C. for 18 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), and washed with water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic layer was washed with water (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30→20/80). The obtained solution was concentrated under reduced pressure to give the title compound (2.68 g, 76%) as a yellow amorphous substance.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:14]I>C1COCC1.CCOC(C)=O>[CH3:14][O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CI
Reactant: O=C(O)c1cccc(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cccc(C(=O)O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 300 mg (1.96 mmol) 6-hydroxymethyl-pyridine-2-carboxylic acid in 20 mL THF was added 188 mg (4.31 mmol) NaH in mineral oil (55%) at 0° C. After gas formation ceased, 310 μL (4.90 mmol) methyl iodide was added dropwise, then the mixture was stirred for 1 h at 0° C. and for 1 h at RT. The reaction mixture was diluted with EtOAc, extracted with water, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1.[CH3:21][S:22][C:23]1[N:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][N:24]=1>C1COCC1>[CH3:20][O:19][C:17](=[O:18])[CH:16]([C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1)[CH:29]([C:27]1[CH:26]=[CH:25][N:24]=[C:23]([S:22][CH3:21])[N:28]=1)[OH:30]
Reactant: CSc1nccc(C=O)n1
Reactant: COC(=O)Cc1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(c1ccc(F)cc1)C(O)c1ccnc(SC)n1
Reaction time: 0.75 h
Yield: 76 %

Procedure:
To a cold (−78° C.) solution of lithium diisopropylamide (21.4 mL of 2M solution in THF, 42.8 mmol) in THF (70 mL) is added dropwise a solution of methyl 4-fluorophenyl-acetate (6.0 g, 35.7 mmol) in THF (30 mL). The solution is stirred for 1 hour at −78° C. after which a solution of 2-methylsulfanyl-pyrimidine-4-carbaldehyde, 1, (6.0 g, 39.3 mmol) in THF (30 mL) is added dropwise to the reaction mixture. Stirring is continued for 45 minutes at −78° C. then the reaction is quenched by pouring the reaction solution into aqueous saturated NH4Cl. The aqueous phase is extracted with ethyl acetate. The organic phases combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue is purified over silica (33% EtOAc/hexanes) to afford 8.7 g (76%) of the desired product as a mixture (1:1) of diastereomers.
Reaction SMILES: O=S(Cl)Cl.[N:5]1([C:10]2[CH2:11][CH2:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)[CH:9]=[CH:8][N:7]=[CH:6]1.[CH3:23][CH2:24]O>>[N:5]1([C:10]2[CH2:11][CH2:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=3)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCO
Reactant: O=C(O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)C=C(n1ccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EtOH absolute (14.4 ml) was added slowly to SOCl2 (2.2 ml) at 0° C. and the mixture was heated at room temperature and 1,2-dihydro-3-(1-imidazolyl)-6-carboxy-naphthalene (7 g) was added. The reaction mixture was refluxed for one day, then was stirred overnight at room temperature. The solvent and the excess of SOCl2 were evaporated under reduced pressure and the residue was chromatographed on silica gel using CHCl3 :CH3OH (50:5) as eluant to give 1,2-dihydro-3-(1-imidazolyl)-6-ethoxycarbonyl-naphthalene(6.8 g), m.p. 113°-116° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].[CH3:39][N:40](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:41].F[P-](F)(F)(F)(F)F.CNC>ClCCl.C1COCC1>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([N:40]([CH3:41])[CH3:39])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in dichloromethane (2 mL) were added HBTU (30 mg, 0.079 mmol) and dimethylamine (0.185 mL, 0.37 mmol, 2.0M soln in THF). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (42 mg, 99%). LC-MS m/z 549 (M+H)+.
Reaction SMILES: C(NC(C(N[C@@H](C(O)=O)CCSC)=O)CC1C(C)=CC(O)=CC=1C)(OC(C)(C)C)=O.[ClH:31].NCC(N[C@H](C(C1C2(N)CC3CC(CC1(C(OC)=O)C3)C2)=O)CC1C=CC=CC=1)=O.Cl.N[C@@H](C(OC)=O)CCSC.C([NH:80][CH:81]([C:92]([NH:94][C@@H:95]([C:100]([NH:102][CH2:103][C:104]([NH:106][C@H:107]([C:115]([CH:117]1[C:124]2([NH2:126])[CH2:125][CH:120]3[CH2:121][CH:122]([CH2:127][C:118]1([C:128]([O:130][CH3:131])=[O:129])[CH2:119]3)[CH2:123]2)=[O:116])[CH2:108][C:109]1[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=1)=[O:105])=[O:101])[CH2:96][CH2:97][S:98][CH3:99])=[O:93])[CH2:82][C:83]1[C:88]([CH3:89])=[CH:87][C:86]([OH:90])=[CH:85][C:84]=1[CH3:91])(OC(C)(C)C)=O.C(NCC(N[C@H](C(C1C2(N)CC3CC(CC1(C(OC)=O)C3)C2)=O)CC1C=CC=CC=1)=O)(OC(C)(C)C)=O>>[ClH:31].[CH3:91][C:84]1[CH:85]=[C:86]([OH:90])[CH:87]=[C:88]([CH3:89])[C:83]=1[CH2:82][CH:81]([C:92]([NH:94][C@@H:95]([C:100]([NH:102][CH2:103][C:104]([NH:106][C@H:107]([C:115]([CH:117]1[C:124]2([NH2:126])[CH2:123][CH:122]3[CH2:121][CH:120]([CH2:119][C:118]1([C:128]([O:130][CH3:131])=[O:129])[CH2:127]3)[CH2:125]2)=[O:116])[CH2:108][C:109]1[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=1)=[O:105])=[O:101])[CH2:96][CH2:97][S:98][CH3:99])=[O:93])[NH2:80]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C)C2
Agent: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CN)C2
Agent: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C2
Agent: COC(=O)[C@H](N)CCSC
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)C(N)Cc1c(C)cc(O)cc1C)C2

Procedure:
Substitution of equivalent quantities of Boc-2,6-dimethyl-DL-tyrosyl-D-methionine and methyl glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride for the Boc-2,6-diemthyl-DL-tyrosine and methyl D-methioninate hydrochloride respectively of Example 35 and substantial repetition of the procedures described therein affords methyl Boc-2,6-dimethyl-DL-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate. When this compound is substituted for the methyl Boc-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate of Example 38 and the procedures described therein substantially repeated there is obtained methyl 2,6-dimethyl-DL-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride which is represented by the following formula ##STR42##
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[CH:1]1([CH2:7][N:8]([CH2:9][CH2:10][OH:11])[C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCNCC1CCCCC1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC(=O)N(CCO)CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of 2-(cyclohexylmethylamino)-ethanol (600 mg, 3.8 mmol) in DCM (6 mL) at 0° C. was added DIPEA (588 mg, 4.6 mmol) and then acetoxyacetyl chloride (467 mg, 3.44 mmol) over 5 min. The resulting mixture was warmed to room temperature, stirred overnight under an atmosphere of nitrogen, diluted with DCM and washed successively with 1 N aqueous HCl, saturated NaHCO3, and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield the title compound (914 mg). (m/z): [M+H]+ calcd for C13H23NO4, 258.16. found, 258.0.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=O)[CH2:14][CH3:15].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH3:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC=O
Reactant: c1ccc(C2CCCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN1CCCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
3-Phenyl-piperidine (4.0 g, 24.81 mmol) and propionaldehyde (1.8 ml, 24.81 mmol) were dissolved in tetrahydrofuran (100 ml). Acetic acid (2.14 ml, 37.21 mmol) and sodium trisacetoxyborohydride (10.515 g, 49.61 mmol) were sequentially added to the reaction mixture and stirred for 1 hour at room temperature. The reaction mixture was concentrated and the residue was dissolved in aqueous NaHCO3 solution (50 ml) and diethyl ether (100 ml). The organic phases was dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product (4.6 g, 87% purity).