Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22]CC)=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>C1COCC1.C(O)C.O>[CH2:1]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([OH:22])=[O:21])[CH:12]([C:16]([F:19])([F:17])[F:18])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1=Cc2ccc(NCC(C)C)cc2OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)CNc1ccc2c(c1)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 55 °C
Reaction time: 18 h
Yield: 20.6 %

Procedure:
The ethyl 7-(isobutylamino)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.53 g, 1.54 mmole) was dissolved in a mixture of THF (5.0 mL) and ethanol (5.0 mL). 2.5N sodium hydroxide (1.54 mL) was added and the reaction was heated to 55° C. (oil bath) for 3 hours. The reaction was cooled to room temperature and stirred for 18 hours. The solution was condensed in vacuo to give a yellow oil. The oil was redissolved in water (20 mL), acidified with 2.4 N HCl to pH around 1 and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to prep HPLC (reverse phase) and eluted with 50-95% ACN/ water with 0.05% TFA to give a yellow solid (0.1 g, 21%). ESHRMS m/z 314.1023 (M−H, C15H15O3F3N, Calc'd 314.0999). 1H NMR (CDCl3/400 MHz) 7.78 (s, 1H), 7.01 (s, 1H), 6.24 (s, 2H), 5.60 (q, 1H, J=7.0 Hz), 2.97 (m, 2H), 1.91 (m, 1H), 0.98 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(OCC)(=O)C>[CH3:8][N:7]1[C@H:6]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:11][C:2]([C:2]4[CH:11]=[CH:10][CH:9]=[C:8]5[C:3]=4[CH:4]=[CH:5][CH:6]=[N:7]5)=[CH:3][C:19]=3[CH2:20][CH2:5]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: Brc1cccc2ncccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc5ncccc45)cc3CC[C@@H]12
Yield: 55 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 5-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 128 mg (55%) of the title compound as an amorphous foam. mp 100°-104°. FDMS: m/e=356. α[D]589 =+61.77 (c=0.35, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24]/[CH:25]=[CH:26]\[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24]/[CH:25]=[CH:26]\[CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OC/C=C\CCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OC/C=C\CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 65.4 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (1.8 g, 13 mmol) and (Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone (3.43 g, 9.7 mmol) in acetonitrile (100 ml) was heated at reflux for 11/2 hours. At the end of the reaction, the solvent was removed and the inorganics were filtered after addition of dichloromethane (250 ml). The dichloromethane solvent was removed again. The crude oil was purified on two flash chromatography columns to give a colorless oil (2.78 g). The oil was solidified by vigorously drying on a vacuum pump. Recrystallization from ethanol (10 ml) and hexane (2 ml) gave analytically pure (Z)-[4-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxy-phenyl]ethanone, 1.83 g,m.p.=57°-59° C.
Reaction SMILES: C([O:9][C:10](=[O:36])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([S:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:16][CH2:17][S:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C1C=CC=CC=1>O1CCOCC1.O>[C:28]([S:27][CH:15]([CH2:16][CH2:17][S:18][C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]([OH:36])=[O:9])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(CCCCC(CCSC(=O)c1ccccc1)SC(=O)c1ccccc1)OC(=O)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCC(CCSC(=O)c1ccccc1)SC(=O)c1ccccc1

Procedure:
In overview, 6,8-Bisbenzoylmercaptooctanoic acid was prepared by a three step procedure from commercially available α-lipoic acid. The lipoic acid was first reduced to 6,8-bismercaptooctanoic acid with sodium borohydride in water under slightly alkaline conditions. The product was benzoylated with three equivalents of benzoyl chloride in the presence of triethylamine to scavenge the HCl byproduct to produce 6,8-bisbenzoylmercaptooctanoic benzoic anhydride. The anhydride was selectively hydrolyzed with dioxane/water to produce 6,8-bisbenzoylmercaptooctanoic acid without any undesired hydrolysis of the benzoylthio ester groups. The product was purified by column chromatography on Silica Gel. The purified acid was dissolved in methanol and converted to the sodium salt by the slow addition of an aqueous solution containing one mole equivalent of sodium bicarbonate.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16]CC)(=[O:15])[CH3:14].[CH3:19][C@H:20]([C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[C:21](Cl)=[O:22]>C1COCC1>[CH3:19][C@H:20]([C@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])[C:21](=[O:22])[CH2:14][C:13]([OH:16])=[O:15]
Reactant: CCOC(C)=O
Reactant: CCC[C@@H](C)[C@@H](C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC[C@@H](C)[C@@H](C)C(=O)CC(=O)O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution containing 2.0 g (13.9 mmol) of (2R,3R)-2,3-dimethyl-hexanoic acid in 20 mL of dichloromethane was added 2.1 g (16.6 mmol) of chloromethylene dimethyl-ammonium chloride. After stirring the resulting solution under nitrogen for 1.5 hours, the solvent was evaporated to give (2R,3R)-2,3-dimethyl-hexanoyl chloride. Butyl lithium (32.7 ml, 52.4 mmol) was added to a solution of diisopropylamine (4.9 g, 48.5 mmol) in dry THF (20 mL) under nitrogen at 0° C. and stirred for 20 minutes. The solution was cooled to −78° C. and 4.3 g (48.5 mmol) of ethyl acetate was added. The solution was stirred at that temperature for 45 minutes. (2R,3R)-2,3-Dimethyl-hexanoyl chloride in dry THF (20 mL) was slowly added to the ethyl acetate enolate at −78° C. and the resulting reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 2.5 hours and was cooled to 0° C. The reaction was quenched with a saturated solution of ammonium chloride and extracted into ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated. The resulting residue was filtered through a silica plug, eluting with 60/40 solution of hexane/ethyl acetate to afford 2.7 g (89.2% yield) of the titled compound as an oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[O:16][CH2:15]2.Br[CH2:23][C:24]1([CH2:28][OH:29])[CH2:27][O:26][CH2:25]1.C([O-])([O-])=O.[K+].[K+].[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>CN(C=O)C.C(N(CC)CC)C.O>[CH3:9][O:8][C:7]1[C:6]([O:10][CH3:11])=[CH:5][CH:4]=[C:3]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[C:2]=1[O:1][CH2:23][C:24]1([CH2:28][O:29][C:39](=[O:40])[NH:38][CH2:36][CH3:37])[CH2:27][O:26][CH2:25]1
Reactant: OCC1(CBr)COC1
Reactant: CCN=C=O
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)OCC1(COc2c(-c3ccc4c(c3)COC4=O)ccc(OC)c2OC)COC1
Temperature: 100 °C

Procedure:
In a screw cap vessel Compound 306 (0.017 g, 0.06 mmol) and 3-bromomethyl-3-hydroxymethyl-oxetane (0.22 g, 0.12 mmol) were dissolved in DMF (0.5 mL) and K2CO3 (0.02 g, 0.15 mmol) was added. The suspension was heated at 100° C. for 3 h. H2O (3 mL) was added and the suspension was extracted with EtOAc (3×3 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. In a screw cap vessel the crude product was dissolved in CH3CN (0.2 mL). Triethyl amine (0.003 mL) and Ethyl isocyanate (0.044 mL, 0.6 mmol) were added. The mixture was heated at 50° C. for 18 h and the solvent was evaporated. The crude product was purified by flash chromatography using toluene:EOAc 60:40->40:60 as the eluent. This afforded the title compound as an oil.
Reaction SMILES: CO[C:3](=[O:7])[CH2:4][C:5]#[N:6].[NH3:8].C[O:10][C:11](=O)[CH2:12][C:13]([CH3:15])=O>O.S(=O)(=O)(O)O>[C:5]([C:4]1[C:3](=[O:7])[NH:8][C:11]([OH:10])=[CH:12][C:13]=1[CH3:15])#[N:6]
Reactant: COC(=O)CC(C)=O
Reactant: COC(=O)CC#N
Reactant: N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)[nH]c(=O)c1C#N
Temperature: 80 °C
Yield: 98 %

Procedure:
3-cyano-4-methyl-6-hydroxypyrid-2-one is prepared by running 99 parts of cyanoacetic acid methyl ester into 160 parts of 24% strength aqueous ammonia, while stirring, at 10° to 15° C. The mixture is stirred for approx. 1 hour at 20° C., 133.5 parts of acetoacetic acid methyl ester are then added and the reaction mixture is heated at 80° C. for 4 hours in an autoclave, a maximum pressure of 1.5 bars being generated. The reaction suspension is then diluted with 400 parts of water and 114 parts of 61% strength sulphuric acid are added at 50°-60° C. and the mixture is cooled to 20° C. The product precipitated is filtered off, washed with water and dried. This gives 147.0 parts (98% of theory) of 3-cyano-4-methyl-6-hydroxypyrid-2-one with a melting point above 305° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:43][O:44][CH2:45][CH2:46][NH2:47]>O1CCCC1.O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:47][CH2:46][CH2:45][O:44][CH3:43])=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
The title compound was prepared as described in Example 76. To a solution of 3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.200 g, 0.781 mmol) in tetrahydrofuran (5 mL) was added 1-hydroxybenzotriazole hydrate (0.316 g, 2.34 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.449 g, 2.34 mmol), 2-methoxyethylamine (0.203 mL, 2.34 mmol) and N,N-dimethylformamide (2 mL). The solution was stirred for 16 h at room temperature. Water (40 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (10–90% acetonitrile/water). The pure fractions were made basic with ammonium hydroxide, and the solution evaporated under reduced pressure, diluted with water and filtered to give the title compound (0.162 g, 66% yield): 1H NMR (DMSO-d6) δ 13.45 (s, 1H), 8.70 (t, 1H), 8.56 (s, 1H), 8.08 (AB quartet, 2H), 7.92 (dd, 1H), 7.63 (d, 1H), 7.40 (t, 2H), 3.49 (s, 3H), 3.34 (m, 2H), 3.28 (s, 2H); ES-MS (m/z) 314 [M+1]+.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[N:33]3[C:28]([CH:29]=[CH:30][CH:31]=[CH:32]3)=[CH:27][C:26]=2[CH3:34])=[O:24])=[CH:19][CH:18]=1.C(OC(C)C)(C)C>C1(C)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:34][C:26]1[CH:27]=[C:28]2[N:33]([C:25]=1[C:23]([C:20]1[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=1)[NH:16][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]3=[O:13])=[O:24])[CH:32]=[CH:31][CH:30]=[CH:29]2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cc2ccccn2c1C(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1c[nH]c2ccc(C(=O)c3c(C)cc4ccccn34)cc2c1=O
Temperature: 110 °C

Procedure:
1.69 ml of diethyl ethoxymethylene malonate are added, under an inert atmosphere at ambient temperature, to 1.83 g (6.8 mmol) of (4-aminophenyl)(2-methylindolizin-3-yl)methanone in 23 ml of toluene. The reaction medium is heated at 110° C. for 1 h 45 and then concentrated under reduced pressure. The residue obtained is dissolved in 45 ml of diphenyl ether and then heated at 230° C. for 30 minutes. After the addition of diisopropyl ether at ambient temperature, the precipitate formed is filtered off, rinsed with diisopropyl ether, with methanol and then with dichloromethane, and dried under reduced pressure at 50° C. overnight 1.2 g of a yellow powder are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]=O)[CH:12]=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:16]([NH2:24])(=[NH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:13])[NH:24][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:23][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: N=C(N)c1ccccc1
Reactant: COc1ccc(C(C=O)C=O)cc1OC
Product: COc1ccc(-c2cnc(-c3ccccc3)[nH]c2=O)cc1OC
Yield: 67 %

Procedure:
(3,4-Dimethoxyphenyl)malonaldehyde acid methyl ester (7.2 g) (30 mmol) and 10 g (42 mmol) of benzamidine are melted at 100° C. The reaction mixture is chromatographed on 250 g of silica gel (0.063-0.2 mm) and the product is eluted with dichloromethane/methanol (9:1 v/v). The eluate is concentrated in a vacuum at 45° C. and the crystalline product is filtered off under suction. The whole is washed with diethyl ether and dried in a high vacuum at room temperature. There are obtained 6.2 g of 5-(3,4-dimethoxyphenyl)-2-phenyl-6(1H)-pyrimidinone as yellow crystals of m.p. 230° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)=[CH2:12].C(N(CC)C(C)C)(C)C>CC(C)=O>[CH:11]([C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:6]2[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:15][CH:14]=1)=[CH2:12]
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Reactant: C=Cc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc(Nc2nc(Cl)nc(Cl)c2Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 21.8 g (0.1 moles) of 2,4,5,6-tetrachloropyrimidine in 150 ml of acetone being stirred at 0°-5° C. was added dropwise over a 1/2 hr. period a solution of 11.9 g (0.1 mole) of 4-vinylaniline and 12.9 g (0.1 mole) of N,N-di-iso-propylethylamine. After stirring for 2 hr. at room temperature, the product was isolated by pouring the reaction mixture into 1 of ice water. The solid was collected by filtration and dried in vacuo at room temperature to give 28 g. Recrystallization from a solution of 120 ml of benzene and 200 ml of ligroin gave 17.5 g (58%) (mp 112°-114°).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1C[CH2:26][CH2:25][CH2:24]1.C([Li])CCC.C(Br)C=C>C(OCC)(=O)C.CCCCCC>[C:1]([O:5][C:6]([N:8]([CH2:9][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:26][CH:25]=[CH2:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NCC(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C=CCBr
Solvent: CCCCCC
Product: C=CCN(CC(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine N-t-butoxycarbonyl-2,2-bis-phenyl-ethylamine (2.0 g, 7.73 mmol) and tetrahydrofuran (20 mL) and cool in a dry-ice/acetone bath to -78° C. Slowly, add n-butyllithium (4.4 mL, 1.6M in hexane, 7.04 mmol) and allow to stand for 30 minutes. Add allyl bromide (0.7 mL, 8.09 mmol) maintaining the temperature at -78° C. Warm to ambient temperature and allow to stand for 1.5 hour and then heat to reflux for 5 hours. Cool to ambient temperature and allow to stand for 18 hours. Extract the reaction mixture with a saturated ammonium chloride solution and separate the layers. Extract the aqueous layer with diethyl ether and combine the organic layers. Extract the combine organic layer with water and saturated sodium chloride solution. Separate the organic layer and dry over MgSO4, filter and evaporate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:28])[C@H:5]([CH3:27])[NH:6][C:7](=[O:26])[C@H:8]([CH3:25])[NH:9][C:10](=[O:24])[C@H:11]([CH3:23])[NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH3:2].[CH2:29](OC(N1CCC[C@H]1C(N[C@H](C(NN)=O)C)=O)=O)[C:30]1C=CC=CC=1.C(NC(=O)[C@H](C)N)C>CN(C)C=O>[CH2:1]([NH:3][C:4](=[O:28])[C@H:5]([CH3:27])[NH:6][C:7](=[O:26])[C@H:8]([CH3:25])[NH:9][C:10](=[O:24])[C@@H:11]1[CH2:23][CH2:30][CH2:29][N:12]1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH3:2]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)NN
Reactant: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CCNC(=O)[C@H](C)N
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 49 %

Procedure:
This product was prepared by a process analogous to that employed in preparing the corresponding benzyloxycarbonylalanylalanyl alanine ethylamide described in Example 1 from benzyloxycarbonylprolyl alanine hydrazide and alanine ethylamide in a 49% yield with a melting point of 219 to 220 degrees C. [α]D20 -36.2 degrees (c 0.3; dimethylformamide).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:23]=[N:24][N:25]=2)[C:5]([CH3:22])=[C:6]([CH3:21])[C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[C:26](=O)(O)[O-].[Na+].[CH:31]([Cl:34])(Cl)Cl>>[Cl:34][CH2:31][C:26]1[N:8]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:7]2[C:6]([CH3:21])=[C:5]([CH3:22])[N:4]3[N:23]=[N:24][N:25]=[C:3]3[C:2]=2[N:1]=1
Reactant: Cc1c(NCCCCNC(=O)OC(C)(C)C)c(N)c2nnnn2c1C
Reactant: ClC(Cl)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Product: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCNC(=O)OC(C)(C)C)c12
Reaction time: 72 h

Procedure:
Ethyl 2-chloroethanimidoate hydrochloride (ethyl chloroacetimidate hydrochloride) (2.58 g, 16.4 mmol) was added to a solution of tert-butyl 4-[(8-amino-5,6-dimethyltetraazolo[1,5-a]pyridin-7-yl)amino]butylcarbamate (3.80 g, 10.9 mmol) in chloroform (75 mL). The solution was stirred for 3 days, then saturated aqueous sodium bicarbonate (40 mL) was added. The aqueous phase was extracted with chloroform (3×40 mL). The organic phases were combined, washed with water (2×20 mL) and saturated aqueous sodium bicarbonate (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 4.3 g of tert-butyl 4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butylcarbamate, which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH:22]5[CH2:26][CH2:25][O:24][CH2:23]5)=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](Cl)(=O)[O:32]C1C=CC([N+]([O-])=O)=CC=1.N1C=CC=CC=1.Cl.[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[CH2:57][NH:56][CH2:55]2.C(N(CC)C(C)C)(C)C>ClCCl>[F:51][C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[CH2:57][N:56]([C:31]([NH:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]3[C:20]4[C:19]5[C:14](=[CH:15][C:16]([O:21][CH:22]6[CH2:26][CH2:25][O:24][CH2:23]6)=[CH:17][CH:18]=5)[NH:13][C:12]=4[C:11]([C:27]([NH2:29])=[O:28])=[N:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=1)=[O:32])[CH2:55]2
Reactant: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(OC4CCOC4)ccc3c12
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(NC(=O)N2Cc3ccc(F)cc3C2)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(OC4CCOC4)ccc3c12
Temperature: 50 °C
Yield: 55.6 %

Procedure:
To a heterogeneous mixture of 4-(3-amino-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxamide (38 mg, 0.081 mmol) and 4-nitrophenyl carbonochloridate (19.64 mg, 0.097 mmol) in dichloromethane (2 mL) at room temperature was added pyridine (0.013 mL, 0.162 mmol). The resulting homogeneous mixture was stirred at room temperature for 1 hr before 5-fluoroisoindoline hydrocloride (35.2 mg, 0.203 mmol) and N,N-diisopropylethylamine (0.053 mL, 0.305 mmol) was added. The mixture was heated at 50° C. for 1 hr. It was concentrated under vacuum, diluted with MeOH (1.8 mL), and was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with CH2Cl2 (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (26.4 mg, 0.045 mmol, 54.9% yield) as a yellow solid. LCMS (M+H)+=566.34. 1H NMR (500 MHz, DMSO-d6) δ: 11.67 (s, 1H), 8.36 (m, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.79 (s, 1H), 7.64 (d, J=6.9 Hz, 1H), 7.46-7.39 (m, 3H), 7.29 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 7.23-7.17 (m, 2H), 7.08 (d, J=8.6 Hz, 1H), 6.70 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 5.10 (m, 1H), 4.85 (s, 2H), 4.82 (s, 2H), 3.99 (dd, J1=10.5 Hz, J2=4.2 Hz, 1H), 3.92-3.83 (m, 2H), 3.84 (m, 1H), 2.32 (m, 1H), 2.09 (m, 1H), 2.01 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:23])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.CC[O:26][CH2:27][CH3:28].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1>[C:29]([NH:1][C:2]1[N:3]=[C:4]([OH:23])[C:5]2[CH:11]=[C:10]([CH:12]=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22][C:27](=[O:26])[CH3:28])=[O:21])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1)(=[O:31])[CH3:30]
Reactant: Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1
Reactant: CCOCC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)Nc1nc(O)c2cc(C=Cc3ccc(C(=O)OC(C)=O)cc3)cnc2n1
Temperature: 120 °C
Yield: 84 %

Procedure:
A suspension of 0.88 g of 2-amino-4-hydroxy-6-[2-(4-carboxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine in 20 mL of acetic anhydride containing 0.05 g of 4-dimethylaminopyridine was heated under nitrogen at 120° C. for 3 hours. The reaction mixture was cooled to room temperature. Fifty milliliters of ether were added and the resulting yellow solid was collected by filtration to yield 0.95 g (84%) of the title compound; mp>300° C.; IR (Nujol) 3350, 3150, 1800, 1670, 1600 cm-1.