Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:14][C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(-c2ccc3ccccc3c2)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccnc1Nc1cccc(-c2ccc3ccccc3c2)c1
Yield: 67.2 %

Procedure:
A mixture of 3-(2-naphthyl)aniline (5.0 g), 2-chloro-3-nitropyridine (3.62 g) and potassium carbonate (6.31 g) in dioxane (50 ml) was stirred under reflux for 6 days. The reaction mixture was extracted with chloroform and evaporated. Crude residue was chromatographed on silica gel to give 2-[3-(2-naphthyl)phenylamino]-3-nitropyridine as an orange crystal (5.23 g).
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[OH-].[Na+].[N:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30](O)=[O:31])=[N+:20]=[N-:21].Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[N:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:11][N:12]=[N:13][N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12)=[O:31])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=NCc1ccccc1CC(=O)O
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3CN=[N+]=[N-])C(=O)N2C1c1nnn[nH]1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A stirred suspension of 21.73 g. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 400 ml. of a 50:50 mixture of tetrahydrofuran-water is cooled to ca. 0° C. and the pH is adjusted to 7.5 using 1.0 N sodium hydroxide. To the solution thus obtained, is added 17.3 g. of 2-(2-azidomethylphenyl)acetic acid (U.S. Pat. No. 3,766,175), followed by 17.4 g. of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The pH drops to 5.5. The reaction mixture is then stirred at ambient temperature, at pH 6, for 3 hours. At this point, the bulk of the tetrahydrofuran is removed by evaporation in vacuo, and the residual aqueous phase is extracted with ethyl acetate. The organic extract is discarded and the aqueous phase is cooled to ca. 0° C. The pH is then adjusted to 2 and the product is extracted into ethyl acetate. The ethyl acetate is dried and evaporated, leaving 34.8 g. of the title compound as a tan solid. IR(CHCl3) 2100, 1790, 1680 and 1515 cm.-1NMR (DMSO-d6): 7.37 (s, 4H), 5.60 (m, 2H, 5.23 (s, 1H), 4.55 (s, 2H), 3.70 (s, 2H), 1.66 (s, 3H) and 1.06 ppm (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH2:26])=[CH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=3)=[CH:23]2)=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc4ccc(N)cc4c3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4ccc(NC(=O)c5ccc(Cl)cc5)cc4c3)c2cc1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-2-amine (0.110 g, 0.31 mmol) in 10 ml of CH2Cl2 was added K2CO3 (0.086 g, 0.62 mmol). The mixture was cooled to 0° C. and 4-chlorobenzoyl chloride (44 mL, 0.34 mmol) was added. The solution was stirred for 16 h and allowed to gradually warm up to RT. The reaction was diluted with water and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified using a Gilson Prep HPLC system. The fractions were collected, combined, and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated to afford the desired compound. MS (ESI, pos. ion) m/z: 485.0 (M+1). Mass Calc'd for C29H21ClN2O4: 484.937.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl>[C:38]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:12][CH2:13][N:14]([S:17]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:30])[CH:26]=4)[CH:21]=3)(=[O:18])=[O:19])[CH2:15][CH2:16]2)=[O:10])[CH2:5][CH2:4]1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(trans-4-aminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (50 mg) and triethylamine (30 mg) in dichloromethane (10 ml) was added acetic anhydride (50 mg), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (41 mg).
Reaction SMILES: [N:1]1([C@H:14]([CH2:17][CH3:18])[CH2:15][OH:16])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].[CH2:21](Br)[C:22]#[CH:23]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl.O>[CH2:23]([O:16][CH2:15][C@H:14]([N:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1)[CH2:17][CH3:18])[C:22]#[CH:21]
Reactant: CC[C@H](CO)n1cnc2cnc3ccccc3c21
Reactant: C#CCBr
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C#CCOC[C@@H](CC)n1cnc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
(2R)-2-(1H-Imidazo[4,5-c]quinolin-1-yl)butan-1-ol (19 g, 78.8 mmol) was added to a mixture of sodium hydroxide (124 mL of 50%), dichloromethane (150 mL), benzyltrimethyl ammonium chloride (0.73 g), and propargyl bromide (11.4 mL, 102 mmol). The reaction mixture was allowed to stir at ambient temperature overnight. The reaction mixture was diluted with dichloromethane and water. The aqueous fraction was extracted multiple times with dichloromethane. The organic fractions were combined, washed with water, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate to provide 20.9 g of 1-{(1R)-1-[(prop-2-ynyloxy)methyl]propyl}-1H-imidazo[4,5-c]quinoline as a brown liquid.
Reaction SMILES: BrC1C=CC(C2C3C=CC(O)=CC=3OC=2)=CC=1.BrC/C=C/CBr.Br[CH2:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]1[CH:45]=[CH:44][C:33]2[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=3)=[CH:35][O:36][C:32]=2[CH:31]=1.[CH2:46]([NH:49][CH3:50])[CH:47]=[CH2:48]>>[CH2:46]([N:49]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][O:29][C:30]1[CH:45]=[CH:44][C:33]2[C:34]([C:37]3[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=3)=[CH:35][O:36][C:32]=2[CH:31]=1)[CH3:50])[CH:47]=[CH2:48]
Reactant: BrC/C=C/COc1ccc2c(-c3ccc(Br)cc3)coc2c1
Reactant: C=CCNC
Agent: BrC/C=C/CBr
Agent: Oc1ccc2c(-c3ccc(Br)cc3)coc2c1
Product: C=CCN(C)C/C=C/COc1ccc2c(-c3ccc(Br)cc3)coc2c1

Procedure:
Analogously to Example 1, from 3-(4-bromo-phenyl)benzofuran-6-ol and (E)-1,4-dibromo-2-butene via (E)-6-(4-bromo-but-2-enyloxy)-3-(4-bromo-phenyl)-benzofuran and by reaction with N-allyl-methyl-amine there is obtained (E)-allyl-[4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl]-methyl-amine which is converted into the fumarate, MS: m/e 412 (M+H+, 1 Br).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1.[O:13]1[CH2:16][CH:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=3)[CH2:19][CH2:18]2)[CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:12][C:4]1[CH:3]=[C:2]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][N:17]([CH:15]4[CH2:14][O:13][CH2:16]4)[CH2:18][CH2:19]3)=[CH:28][N:27]=2)[C:10]2[N:9]=[CH:8][N:7]([CH3:11])[C:6]=2[CH:5]=1
Reactant: Nc1ccc(N2CCN(C3COC3)CC2)cn1
Reactant: Cn1cnc2c(Br)cc(Cl)cc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cn3)cc(Cl)cc21
Temperature: 120 °C
Yield: 108.1 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 109d (486 mg, 2.0 mmol), 5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-amine (390 mg 1.67 mmol), cesium carbonate (1.09 g, 3.34 mmol), tris(dibenzylideneacetone)dipalladium(0) (152 mg, 0.167 mmol) and Xantphos (193 mg, 0.334 mmol). After bubbling nitrogen through the suspension for 5 minutes, the reaction was heated at 120° C. for overnight. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with a mixture of petroleum ether/ethyl acetate (15 mL, 2:1) to afford 109e as a yellow solid (720 mg, 100%). LCMS: [M+H]+ 399.3. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J=2.0, 1H), 8.04 (d, J=2.5, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 7.28-7.29 (m, 1H), 6.90-6.91 (m, 2H), 4.70-4.71 (m, 4H), 3.77 (s, 3H), 3.70-3.71 (m, 1H), 3.17 (t, J=5.0, 4 H), 2.52 (t, J=5.0, 4H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](N(OC)C)=[O:22])=[CH:19][C:18]=1[O:29][CH3:30].[Cl-].[NH4+]>O1CCCC1>[Cl:16][C:17]1[CH:28]=[CH:27][C:20]([C:21](=[O:22])[CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:19][C:18]=1[O:29][CH3:30]
Reactant: COc1cc(C(=O)N(C)OC)ccc1Cl
Reactant: Cc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)Cc2ccncc2)ccc1Cl
Temperature: 25 °C

Procedure:
4-Picoline (16.9 ml, 0.174 mol) was added dropwise to a stirred solution of lithium di-isopropylamide (110 ml, 0.22 mol, 2M solution in heptane, ethylbenzene, tetrahydrofuran) in dry tetrahydrofuran (150 ml) at −78° C. After stirring at −78° C. for 15 min a solution of the product of Step 1 (40.0 g, 0.174 mol) in tetrahydrofuran (100 ml) was added dropwise. The reaction was allowed to warm to room temperature over 3 hours. The solution was cooled in ice and saturated ammonium chloride solution added. The aqueous mixture was extracted with ethyl acetate, washed with brine, dried (MgSO4), filtered and concentrated at reduced pressure. The resulting gum was triturated with cold diethyl ether/hexane (1:1, 300 ml) and the solid collected to give the title compound, as a pale yellow solid (29 g, 64%); MS(ES+) m/e 262/264 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C@@H:11]([CH3:16])[C:12]([O:14]C)=[O:13].C1COCC1.O[Li].O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C@@H:11]([CH3:16])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)[C@H](C)CSc1ccccc1OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1SC[C@@H](C)C(=O)O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
In a round-bottom flask, 7.11 g (29.6 mmoles) of methyl (2S)-3-[(2-methoxyphenyl)sulfanyl]-2-methylpropanoate (7a-1) and 35.5 mL of THF are introduced. 6.21 g (0.148 mole) of LiOH.H2O dissolved in 35.5 mL of water is added. The mixture is stirred at 50° C. for 12 hours then concentrated under reduced pressure. The residue is taken up with water and the extract is taken up with toluene. The aqueous phase is acidified (pH=2) by adding 36% hydrochloric acid and then extracted with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The title compound is obtained in the form of a white solid, (5 g, 22.1 mmoles) that can be recrystallized in isopropyl ether if desired.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13](=[O:16])[S:14][CH3:15])=[C:5]([NH2:17])[C:4]=1[C:18](=[O:21])SC.C(O)C.[OH-:26].[Na+]>C(OCC)(=O)C>[NH2:17][C:5]1[C:4]([C:18]([OH:21])=[O:26])=[C:3]([CH:2]([F:1])[F:22])[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]=1[C:13]([S:14][CH3:15])=[O:16]
Reactant: CSC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)SC)c1N
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CSC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)O)c1N
Reaction time: 24 h

Procedure:
A solution of 40.8 g (0.113 mol) of product of Example 191, 400 ml of ethanol and 4.5 g (0.113 mol) of 10% aqueous sodium hydroxide was stirred at 25° C. for 5 days. Another 2 g (0.05 mol) of sodium hydroxide was added and stirring continued for 24 hours. The reaction mixture was then diluted with ethyl acetate and washed with three 500 ml portions of 5% HCl, dried (CaSO4), filtered and concentrated to 31.4 g (84%) of product as a yellow solid; mp 219° C. (dec).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:7][C@H:8]1[CH2:15][C:14]2[C:9]1=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH3:6].[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22]>C(OCC)(=O)C.C(O)C>[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[Cl:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:7][C@H:8]1[CH2:15][C:14]2[C:9]1=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:6][CH3:20]
Reactant: COc1cc2c(cc1OC)[C@@H](CN(C)CCCCl)C2
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CCCCl)C[C@H]1Cc2cc(OC)c(OC)cc21
Yield: 116.6 %

Procedure:
To a solution of 3-chloro-N-{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}-N-methyl-1-propanamine (19.8 g, 69.8 mmoles) in 60 mL of ethyl acetate heated at reflux there is added a solution of oxalic acid (6.91 g, 76.7 mmoles) in 60 mL of ethanol. Precipitation from the mixture occurs during contact at reflux. After returning to ambient temperature, the mixture is filtered and washed with 20 mL of ethanol to obtain 17.35 g of a brown powder corresponding to the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Br)c(OCc3ccc(F)cc3)c2s1
Yield: 19 %

Procedure:
A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6, potassium carbonate and p-fluoro-benzyl-bromide in DMF was reacted to give 0.013 g (19%) of the desired compound 13. 1H NMR (DMSO) δ 1.08 (t, 3H, J=8 Hz CH2CH3), 3.18 (m, 2H, CH2), 5.16 (s, 2H, OCH2Ar), 6.73 (br s, 1H, NH), 7.26 (dd, 2H, J=4, 4 Hz, ArH),7.36 (d, 1H, J=8 Hz, ArH), 7.56 (d, 1H, J=4 Hz, ArH), 7.58 (d, 2H, J=4 Hz, ArH), 10.89 (br s, 1H, NH). HPLC retention time 3.61 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH2:27])[C:18]2=[O:28])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C(O)C>CCOCC>[CH:29]1([C:32]([NH:27][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:24]=2[C:25](=[O:26])[N:17]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])[C:18]3=[O:28])=[O:33])[CH2:31][CH2:30]1
Reactant: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)cc1OC
Reactant: O=C(Cl)C1CC1
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C4CC4)c3C2=O)cc1OC
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A stirred mixture of 2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-4-aminoisoindoline-1,3-dione (0.68 g, 1.7 mmol) and cyclopropane carbonyl chloride (1.3 mL) was heated to reflux for 25 min. To the mixture was added ethanol (10 mL) at 0° C. and kept for 30 min. The solvent was removed in vacuo to give a oil. The oil was stirred in ether (20 mL) for 30 min to give a suspension. The suspension was filtered and the solid washed with ether to give a white solid. The solid was purified by column chromatography (Silica Gel, 10% ethyl acetate in methylene chloride) to give cyclopropyl-N-{2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}carboxamide as a white solid (330 mg, 42% yield); mp, 130-132° C.; 1H NMR (CDCl3) δ 0.92-0.98 (m, 2H, 2CHH), 1.09-1.14 (m, 2H, 2CHH), 1.61-1.64 (m, 1H, CH), 2.88 (s, 3H, CH3), 3.73 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 3.90 (s, 3H, CH3), 4.58 (dd, J=10.4, 14.3 Hz, 1H, CHH), 5.90 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.84 (d, J=8 Hz, 1H, Ar), 7.09-7.14 (m, 2H, Ar), 7.47 (d, J=7.2 Hz, 1H, Ar), 7.65 (t, J=7.6 Hz, 1H, Ar), 8.75 (d, J=8.4 Hz, 1H, Ar), 9.68 (s, 1H, NH); 13C NMR (CDCl3) δ 6.75, 16.13, 41.54, 48.43, 54.36, 55.81, 55.94, 110.98, 111.11, 114.78, 117.88, 120.27, 124.93, 129.30, 130.94, 136.00, 137.68, 149.19, 149.35, 167.45, 169.48, 172.79; Anal Calcd for C23H24N2O7S: C, 58.46; H, 5.12; N, 5.93. Found: C, 58.10; H, 5.16; N, 5.78.
Reaction SMILES: B(F)(F)[F:2].CCOCC.N[C:11]1[CH:12]=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2.C(ON=O)(C)(C)C.ClC1C=CC=CC=1Cl>ClCCl.CCCCCC.C(OCC)(=O)C>[F:2][C:11]1[CH:12]=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2
Reactant: COc1ccc2ncc(N)cc2c1
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1Cl
Solvent: CCOCC
Product: COc1ccc2ncc(F)cc2c1
Temperature: 73 °C
Reaction time: 0.25 h

Procedure:
To boron trifluoride etherate (1.29 g) at −12° C. under an atmosphere of nitrogen was added with stirring a solution of 3-amino-6-methoxyquinoline (1.05 g) in dry dichloromethane (15 ml). The yellow suspension was stirred for 15 minutes then a solution of t-butylnitrite (0.74 g) in dichloromethane (5 ml) was added dropwise. The mixture was stirred for 2 hours at 0° C. then 1,2-dichlorobenzene was added and the mixture gradually heated to 73° C., allowing the dichloromethane to distil out from the reaction vessel and then increased to 90° C. to complete the reaction. The mixture was allowed to cool to ambient temperature, diluted with dichloromethane, washed with water, dried over magnesium sulfate, filtered then evaporated under reduced pressure to give a black oil that was fractionated by chromatography (silica; hexane/ethyl acetate) to give an oil, 0.54 g, containing the required product. MH+178
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:37])[CH2:20][NH:21][C:22](=[O:36])[NH:23][C:24]1[CH:34]=[C:28]([C:29]([O:31]CC)=[O:30])[C:27]([OH:35])=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]1[C:19](=[O:37])[CH2:20][NH:21][C:22](=[O:36])[NH:23][C:24]1[CH:34]=[C:28]([C:29]([OH:31])=[O:30])[C:27]([OH:35])=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1ccc(O)c(C(=O)O)c1
Yield: 51.8 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 4.7 g of ethyl (2RS,5SR)-5-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}salicylate in solution in 80 cm3 of methanol and 1.04 g of potassium hydroxide dissolved in 40 cm3 of water and after treatment, 2.3 g of (2RS,5SR)-5-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}salicylic acid, melting at 190° C., are obtained.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].C1(C)C(C)=CC=CC=1>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CC1C=CC(C)=CC=1>[CH2:1]([O:5][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccc(C)cc1
Product: CCCCO[Si](C)(C)C(C)(C)C

Procedure:
0.1 moles of n-butanol, 0.15 moles of t-butyldimethylchlorosilane and 0.0005 moles of triethylbenzyl ammonium chloride were heated under reflux (77°-106° C.) in 50 ml of p-xylene. After termination of the reaction, excess silylating agent and xylene were distilled off at reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:29][CH:30]=3)=[CH:7][N:6]=1)[CH2:10]2
Reactant: Brc1cnc(OC2CN3CCC2CC3)nc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cnc(OC3CN4CCC3CC4)nc2)cc1
Temperature: 60 °C

Procedure:
The product of Example 18A (283 mg, 1 mmol) in tetrahydrofuran (anhydrous, 10 mL) was treated with t-butyl [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamate (Frontier, 319 mg, 1 mmol), Pd2(dba)3 (Strem Chemicals, 24 mg, 0.025 mmol), (tBu3P)2Pd (Strem Chemicals, 26 mg, 0.05 mmol), K2CO3 (Aldrich, 276 mg 2 mmol) and heated at 60° C. under N2 for 15 hours. The resulting mixture was allowed to cool to room temperature, diluted with ethyl acetate (20 mL), and washed with brine (2×5 mL). The organic phase was concentrated and the title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as a solid (340 mg, yield, 86%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.63 (m, 10H), 1.65-1.91 (m, 2H), 2.02-2.16 (m, 1H), 2.22-2.30 (m, 1H), 2.75-3.05 (m, 5H), 3.36-3.48 (m, 1H), 5.13-5.21 (m, 1H), 7.54 (s, 4H), 8.78 (s, 2H) ppm. MS (DCl/NH3) m/z 397 (M+H)+.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:10]2.[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35])[CH3:25]>C(OCC)(=O)C.C(Cl)Cl>[C:20]([O:19][C:17]([N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([NH:6][C:34]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:24][CH3:25])=[O:35])[CH:8]=2)[CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOc1ccccc1N=C=O
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccccc1NC(=O)Nc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2

Procedure:
A tetrahydrofuran (10 mL) solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (981 mg) and 2-ethoxyphenyl isocyanate (0.9 mL) was stirred at room temperature for 4 hours and then concentrated. The residue was purified by chromatography (hexane:ethyl acetate=5:1→1:1 and then methylene chloride:ethyl acetate=1:0→1:1) to obtain the title compound (1.62 g, quantitative yield) as a pale yellow solid.