Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[NH2:15])=[CH:5][C:4]=1[O:16][CH3:17].[CH3:18][O:19][C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:21]>C(Cl)Cl.C(N(CC)CC)C>[CH3:17][O:16][C:4]1[CH:5]=[C:6]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]([O:19][CH3:18])=[O:21])=[CH:30][CH:29]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([C@@H]2CCCC[C@@H]2N)cc1OC
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2c2ccc(OC)c(OC)c2)cc1
Reaction time: 1 h

Procedure:
2.6 g of (+/−)-cis-1,2-dimethoxy-4-(2-aminocyclohexyl)benzene are dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. At RT, a solution of 2.4 g of 4-methoxycarbonylbenzoyl chloride in 30 ml of methylene chloride is added dropwise over a period of 3 h, and the mixture is stirred for 1 h and then extracted with 50 ml each of water, 2 N hydrochloric acid, sat. sodium bicarbonate solution and once more with water. The organic phase is dried with sodium sulfate, concentrated and crystallized from ethyl acetate. This gives 2.0 g (45.5% of Th.) of the title compound of m.p. 139-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[CH:10]2)[CH2:6]1)=[O:4].C(OC)(C)(C)C>C(OC(=O)C)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:20]=3)=[CH:10]2)[CH2:8]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
The cis/trans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester mixture is prepared as described in Example 47(a) of WO 97/28161. The cis-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methyl ester is isolated from the cis/trans mixture by chromatography on silicagel (t-butyl-methyl-ether:ethylacetate=1:1). Analytical HPLC: tR=10.59 min (Grad 1); ES-MS m/eo=429.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]#[N:24])[CH:18]=2)=[CH:4][CH:3]=1.[OH-:25].[K+]>C(O)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:24])=[O:25])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(-c2[nH]c3cccnc3c2-c2ccc(F)cc2)ccn1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1cc(-c2[nH]c3cccnc3c2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.44 g (4.6 mmoles) of 4-[3-(4-Fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridine-2-carbonitrile is stirred at room temperature in 8 mL of t-butanol in the presence of 1.03 g (18.3 mmoles) of powdered potassium hydroxide. The reaction is stirred at room temperature for 4 hours, concentrated under vacuum and poured into water and ethyl acetate (1/1). Chlorhydric acid 2N is added to the solution to reach pH=5 and the solution is extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration 800 mg of 4-[3-(4-Fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-pyridine-2-carboxylic acid amide are obtained as white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[ClH:15].Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC>CN(C)C=O>[ClH:15].[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:21]4[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:19]([O:18][CH3:17])[CH:20]=4)[CH2:28][CH2:27]3)=[O:14])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(=O)c3ccc4c(c3)CCCC4=O)CC2)cc(OC)c1OC
Yield: 75.1 %

Procedure:
Using 1-oxo-1,2,3,4-tetrahydro-6-naphthoic acid [Itoh et al., Chem. Pharm. Bull., 32, 130 (1984)] (0.8 g), 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (2.25 g), triethylamine (1.7 g), N,N-dimethylformamide (10 ml) and diethyl phosphorocyanidate (1.6 ml), an amidation as that described in Example 6 is carried out. The product is purified by silica gel column chromatography (hexane:acetone=1:1), and converted to the hydrochloride in a mixture of ethanol, ethyl acetate and ethyl ether to give 1-(1-oxo-1,2,3,4-tetrahydro-6-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (1.5 g) as colorless crystals, m.p. 210°-215° C. (decomp.).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:33][CH3:34])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH3:34])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (200 mg, 0.86 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-methylquinolin-2-amine hydrochloride SLA 28154 (234 mg, 0.86 mmol) at RT followed by a 2 N aq. LiOH solution (0.86 mL, 1.72 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with a mixture CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 21 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.40 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 39 as a yellow solid (20.0 mg, 5% yield).
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH:6]1[C:14]2[CH:9]([CH2:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.CN([CH:18]=[O:19])C>>[NH:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]1[CH:18]=[O:19]
Reactant: C1=CCC2CCNC2=C1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c([nH]1)CCCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Anhydrous DMF 20 mL in a 250 mL flask was cooled on ice bath and neat POCl3 4.6 mL (50 mmol) was added dropwise under Ar. After 10 min, a solution of tetrahydroindole 3.83 g (32.14 mmol) in anh DMF 10 mL was gradually added over 10 min (exothermic) followed by additional anh DMF 2×5 mL to wash the flask and the syringe. The cooling bath was replaced with ambient water bath and the reaction was stirred at RT under Ar for 13 hours (overnight). The reaction was quenched by addition of water 20 mL followed by 15% wt NaOH solution 40 mL. After 10 min, additional 15% NaOH 25 mL was added, followed by water 100 mL and the mixture was stirred vigorously for 30 min on ambient water bath. The precipitated product was collected by filtration, compressed on the Buchner funnel, washed thoroughly with water, dried by suction and on highvac. Y=4.282 g (90.5%) of light tan shiny flakes. 1H-NMR (d6-DMSO, 400 MHz): 11.609 (br s, 1H), 9.268 (s, 1H), 6.679 (s, 1H), 2.557 (t, 5.9 Hz, 2H), 2.446 (t, 5.9 Hz, 2H), 1.693 (m, 4H)
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=3)[C:19](O)=O)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:26].C[Si](Cl)(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[N:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=3)[CH2:19][Cl:26])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)N3CCCC3)cc2)[nH]c1=O
Agent: C[Si](C)(C)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCCC3)cc2)ccc1CCl

Procedure:
From 4.4 g. of 6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 150 ml. of methylene chloride, 1.6 ml. of triethylamine, 1.45 ml. of trimethylsilyl chloride and 1.7 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: C1C2C(COC([NH:18][C:19]3[S:20][CH:21]=[C:22]([Br:28])[C:23]=3[C:24]([O:26][CH3:27])=[O:25])=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl.N1CCOCC1>[NH2:18][C:19]1[S:20][CH:21]=[C:22]([Br:28])[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(Br)csc1NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCN1
Solvent: ClCCl
Product: COC(=O)c1c(Br)csc1N

Procedure:
Methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-bromothiophene-3-carboxylate (1 g) was stirred in DCM/morpholine (12 mL, 1:1) at rt until all the ester was consumed. The crude mixture was concentrated under reduced pressure. The residue was dissolved in ethyl ether. The white solid was removed. The mother liquid was concentrated under reduced pressure and a 1:1 mixture of ethyl ether/pentane (20 mL) was added. An additional white solid was removed. The organic layer was concentrated under reduced pressure and the crude mixture was placed under high vacumn to remove the excess of morpholine. The crude amine was taken directly to the next reaction step without further purification. Method[1], MS(ESI) 235.9 [M+H], Retention time=1.919 min.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:8]2[CH:13]=[N:12][N:11]([CH:14]([CH3:16])[CH3:15])[C:9]=2[N:10]=1)CO>C1COCC1.O>[CH3:27][C:26]1[CH:25]=[C:24]([CH3:28])[NH:23][C:22](=[O:29])[C:21]=1[CH2:20][NH:19][C:17]([C:7]1[C:8]2[CH:13]=[N:12][N:11]([CH:14]([CH3:16])[CH3:15])[C:9]=2[N:10]=[C:5]([CH:2]=[O:1])[CH:6]=1)=[O:18]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C(O)CO)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(CNC(=O)c2cc(C=O)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 6-(1,2-dihydroxyethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.66 g, 1.65 mmol) in 50% THF/Water (12 mL), NaIO4 (1.06 g, 4.95 mmol) was added at 0° C. and stirred at room temperature for 1 h. After completion of reaction, solid was filtered and washed with water. Azeotrope it with toluene to obtain N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-formyl-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.515 g, 84.8%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1>O>[C:5]([NH:8][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Acetic anhydride (176 mL) was added slowly to a stirred mixture of 103.2 mL of m-toluidine in 300 mL of water. After complete addition, the mixture was stirred for 4 hours at room temperature. The mixture was cooled in an ice bath, then extracted with diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave an oily residue which solidified. The solid was collected, washed with water, then dissolved in diethyl ether. The etheral solution was dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated under reduced pressure to yield 3-acetamidotoluene as a solid, mp 59°-61° C.
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:18][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCCC(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(C)Br
Temperature: 0 °C

Procedure:
2-Pentadecanol of Example 5 (180 g) and dichloromethane (2500 ml) were added to a 5-litre three-necked flask. The mixture was cooled to 0° C., and carbon tetrabromide (313.6 g) was added and stirred until it dissolved. Triphenylphosphine (351.4 g) was then added dropwise. The resulting mixture was allowed to warm to ambient temperature and left stirring for two days. The reaction mixture was then filtered, and the solvent removed on a rotary evaporator at 56° C. The resulting solid was re-dissolved in heptane and left stirring for two days. It was then filtered through celite under vacuum, and the heptane removed on a rotary evaporator at 78° C. to yield the title compound.
Reaction SMILES: FC1C=CC(C#CCN2C=C([C:16]3[N:24](COCC[Si](C)(C)C)[C:23]4[C:22](=[O:33])[N:21]([CH2:34][CH2:35][CH3:36])[C:20]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[N:19][C:18]=4[N:17]=3)C=N2)=CC=1.Cl>C(O)C>[CH2:34]([N:21]1[C:22](=[O:33])[C:23]2[NH:24][CH:16]=[N:17][C:18]=2[N:19]=[C:20]1[N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:35][CH3:36]
Reactant: CCCn1c(N2CCCC2)nc2nc(-c3cnn(CC#Cc4ccc(F)cc4)c3)n(COCC[Si](C)(C)C)c2c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1c(N2CCCC2)nc2nc[nH]c2c1=O
Temperature: 85 °C
Yield: 197.5 %

Procedure:
A mixture of 8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1-propyl-2-pyrrolidin-1-yl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.025 g, 0.043 mmol), 2N HCl (0.5 ml), ethanol (2 ml) was heated at 85° C. for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was washed with n-pentane to obtain pure 8-{1-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl)}-1-propyl-2-pyrrolidin-1-yl-1,7-dihydro-purin-6-one (0.021 g, quantitative) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:5]([O:6][C:7]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][CH3:20])[C:8]=2[C:9]([NH2:11])=[O:10])=[C:4]([CH3:26])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]([O:6][C:7]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([NH:17][CH:18]([CH:21]=[O:22])[CH2:19][CH3:20])[C:8]=2[C:9]([NH2:11])=[O:10])=[C:23]([CH3:25])[CH:24]=1
Reactant: CCC(CO)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(N)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCC(C=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide and Dess-Martin reagent in methylene chloride/DMSO was stirred at rt for 4 hr. The title compound was isolated after standard work-up and silica gel Biotage purification. 1H NMR(CDCl3) d 9.52(s,1H), 8.00(brs,1H), 7.06(s,22H), 5.99(s,1H), 5.8(brs,1H), 3.85(m,1H), 2.09(s,3H), 2.08(s,6H), 1.8-2.2(m,2H), 1.08(t,3H) ppm.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([O:10][C:11](=[O:12])[C:6]=12)=O)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26].CC([O-])=O.[Na+]>C(O)(=O)C>[O:10]=[C:8]1[C:7]2[C:6](=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:15]=[CH:14][CH:13]=2)[C:11](=[O:12])[N:23]1[CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]
Reactant: CC(=O)Oc1cccc2c1C(=O)OC2=O
Reactant: NC1CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 57 %

Procedure:
1,3-Dioxo-2-(2,6-dioxopiperidin-3-yl)-4-acetoxyisoindoline was prepared and isolated as follows. A mixture of 3-acetoxyphthalic anhydride (40 mg), aminoglutarimide trifluoroacetate (47 mg), and NaOAc (32 mg) in acetic acid (2 mL) was refluxed for 5 h. The solvent was evaporated, water (10 mL) was added, and the resulting solution was stirred for several minutes. The solid was filtered out and recrystallized from ethyl acetate to give 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-acetoxyisoindoline as pale yellow crystals (35 mg, 66%): 1H NMR (DMSO) δ 11.16 (s, 1H), 11.07 (s, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.22-7.31 (m, 2H), 5.05 (dd, J=5.4 Hz, J=12.5 Hz, 1H), 2.87-2.92 (m, 2H), 2.48 (s, 3H), 2.08-2.00 (m, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[N+:52]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[S:61](Cl)(=[O:63])=[O:62])([O-:54])=[O:53]>>[N+:52]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[S:61]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])(=[O:63])=[O:62])([O-:54])=[O:53]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 48 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 2-nitrobenzenesulfonyl chloride as described in example 2, affording the title compound in 48% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1
Reactant: Cc1[nH]cnc1-c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1[nH]cnc1-c1cccc(N)c1
Yield: 87.3 %

Procedure:
Eighty-four grams of 5-methyl-4-(3-nitrophenyl)-1-H-imidazole [R. Morgenstern et al., Pharmazie 30, 103 (1975)] dissolved in methanol were hydrogenated in the presence of 0.8 gm of 5% Pd catalyst at atmospheric pressure and at room temperature. When the calculated amount of hydrogen was taken up, the catalyst was filtered off, and the remaining solution was evaporated to dryness to produce 62.5 gm of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COc1ccccc1Oc1ccc2ccc(N)nc2n1
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4OC)nc3n2)cc1
Temperature: 4 °C
Yield: 69.6 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (10.2 g), N,N'-carbonyldiimidazole (10.9 g) and 2-amino-7-(2-methoxyphenoxy)-1,8-naphthyridine (13.4 g). The product produced by precipitation in water (18 g; m.p. 167° C.) is dissolved in boiling ethanol (400 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×10 cc) and dried at 45° C. under reduced pressure (0.067 kPa). N-[7-(2-methoxyphenoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (14 g) is produced, m.p. 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15])[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([CH3:20])([CH3:19])[CH2:14][OH:15])[CH:3]=1
Reactant: CCOC(=O)C(C)(C)c1cc(N)n(-c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1cc(N)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
To a stirring solution of ethyl 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropanoate (DP-2440, 0.240 g, 0.86 mmol) in dry THF (8.0 mL) at RT was added LiAlH4 (1.0 M in THF, 2.6 mL, 2.6 mmol) and the resulting mixture was stirred at RT for 1 h. The reaction was carefully quenched by the addition of H2O (0.10 mL), 3M NaOH (0.10 mL) and H2O (0.20 mL), and the mixture was stirred at RT overnight. The suspension was filtered through Celite and rinsed with EtOAc (20 mL). The filtrate was dried (MgSO4) and concentrated to afford 2-(5-amino-1-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-ol (0.208, 105% yield) as a yellow oil. MS (ESI) m/z: 232.2 (M+H+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]2)OCC1.[OH:13][NH:14][C:15](=N)[CH2:16][CH2:17][CH3:18]>>[CH2:16]([C:15]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]2)[O:13][N:14]=1)[CH2:17][CH3:18]
Reactant: N#CN1CCC2(CC1)OCCO2
Reactant: CCCC(=N)NO
Product: CCCc1noc(N2CCC(=O)CC2)n1

Procedure:
The title compound is prepared from 1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Intermediate 5. LC (method 13): tR=1.16 min; Mass spectrum (ESI+): m/z=254 [M+H]+.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[F:22].[I:23]I>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([I:23])[C:15]=1[F:22]
Reactant: COc1ccc(Br)c(F)c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(Br)c(F)c1I
Temperature: -78 °C

Procedure:
Into a 25-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed (i-Pr)2NH (1.26 g, 12.48 mmol, 1.25 equiv), tetrahydrofuran (7 mL). This was followed by the addition of n-BuLi (2.5M in hexane) (4.8 mL) dropwise with stirring at −78° C. The mixture was stirred for 1 h at −78° C. Then this solution was added to the solution a solution of 1-bromo-2-fluoro-4-methoxybenzene (2.04 g, 9.95 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) at −78 degree C. and stirred for 30 min, then I2 (3.048 g, 12.00 mmol, 1.2 equiv) was added. The resulting solution was stirred for 30 min at −78° C. in a liquid nitrogen bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 2.0 g (61%) of 1-bromo-2-fluoro-3-iodo-4-methoxybenzene as a light yellow solid. Mass spectrum (GC, m/z): Calcd. for C7H5BrFIO, 330.9 (M). found 330.9.