Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]=1[OH:18])([O-])=O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]=1[OH:18]
Reactant: O=[N+]([O-])c1cccc(OCc2ccccc2)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(OCc2ccccc2)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 153 %

Procedure:
A mixture of 2-nitro-6-benzyloxy phenol (1.00 g, 4.10 mmol) and tin (II) chloride (2.75 g, 12.2 mmol) in ethanol(150 mL) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.35 g, 88%). 1H NMR (CD3OD): d7.46 (d, 2H), 7.40-7.35 (m, 5H), 6.55 (d, 1H), 6.40 (d, 1H), 5.10 (s, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@:13]([C:16]#[CH:17])([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:27][C:28](OC(C)=O)=[O:29]>N1C=CC=CC=1>[C:28]([O:15][CH2:14][C@@:13]1([C:16]#[CH:17])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:10][C@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])(=[O:29])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: C#C[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Product: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 11 h
Yield: 94.9 %

Procedure:
To a pyridine (4 mL) solution of 10a (161 mg, 0.423 mmol) was added Ac2O (120 mL, 1.269 mmol) at 0° C., and the mixture was stirred at room temperature for 11 h. The reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (60 mL×3/20 mL). Silica gel column chromatography (hexane/EtOAc=3/1) of the organic layer gave 11 (169.7 mg, 95%) as a foam: UV (MeOH):λmax 266 nm (ε9200),λmin 234 nm (E2000); 1H NMR(CDCl3)δ0.10 and 0.14 (6H, each as s, SiMe), 0.90 (9H, s, SiBu-t), 1.90-1.94 (4H, m, H-2′a and Me), 2.14 (3H, s, Ac), 2.58 (1H, s, ethynyl), 3.01 (1H, ddd, Jgem=14.8 Hz, J1′,2′b=8.3 Hz and J2′b,3′=5.0 Hz, H-2′b), 4.37 (1H, d, Jgem=11.1 Hz, H-5′a), 4.45 (1H, d, J2′b,3!=5.0 Hz, H-3′), 4.53 (1H, d, Jgem=11.1 Hz, H-5′b), 6.40 (1H, dd, J1′,2′a=2.8 Hz and J1′,2′b=8.3 Hz, H-1′), 7.53 (1H, d, J6,Me=1.3 Hz, H-6), 8.04 (1H, br, NH); FAB-MS m/z 461 (M++K). Anal. Calcd for C20H30N2O6Si: C, 56.85; H, 7.16; N, 6.63. Found: C, 56.84; H, 7.35; N, 6.26.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=2[CH:14]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1nc2cc(OC(=O)c3ccccc3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (7.0 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (200 mg., catalyst) in dimethylformamide (25 ml.) is added benzoyl chloride (1.4 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 11/2 hours and then poured into ice water (150 ml.) containing excess hydrochloric acid to give 2-sulfamoyl-5-benzothiazolyl benzoate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][CH:3]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[Cl:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C=Cc2ccc(O)cc2)c1
Reactant: ClCCCBr
Product: COc1cccc(/C=C/c2ccc(OCCCCl)cc2)c1
Yield: 91.6 %

Procedure:
The procedures of Example 1 were followed using 4-hydroxy-3'-methoxystilbene (5.0 g, 22 mmol) and 1-bromo-3-chloropropane (4.5 mL, 44 mmol) to give 6.1 g (92%) of (E)-4-chloropropoxy-3'-methoxystilbene as an amber oil. 1NMR (CDCl3): δ7.51-6.74 (m,10H), 4.11 (t,2H), 3.81 (s,3H), 3.72 (t,2H), 2.22 (m,2H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:17]O>>[O:1]([CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCOc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCOc1ccccc1
Temperature: 0 °C
Yield: 95 %

Procedure:
3-Phenoxypropionic acid (10.0 g, 60 mmol) was dissolved in methanol (100 mL) . The reaction mixture was allowed to cool to 0° C. and SOCl2 was slowly added over a 15 min period. The reaction mixture was slowly allowed to warm to room temperature over a 2 h period. The reaction mixture was concentrated in vacuo, then redissolved in ethyl acetate (100 mL). The organic layer was washed with water (2×150 mL), dried (MgSO4), concentrated in vacuo to provide crude product in 95% yield. 1H NMR (CDCl3) δ2.84 (t, J=6.4 Hz, 2H), 3.76 (s, 3H), 4.28 (t, J=6.4 Hz, 2H), 6.95 (m, 3H), 7.31 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:25]([NH:28][CH2:29][CH2:30][NH2:31])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:31][CH2:30][CH2:29][NH:28][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)NCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(NCCNC(C)C)cc3)cc2s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-acetylaminobenzothiazol-6-yl ester (intermediate 64) (66 mg, 0.180 mmol), N-isopropylethylenediamine (55.2 mg, 0.540 mmol) and cesium carbonate (58.6 mg, 0.180 mmol) in 2 ml of dimethyl sulfoxide in a test tube, equipped with a magnetic bar, is stirred overnight at 80° C. 100 ml of water are added and the reaction medium is extracted with ethyl acetate. The organic phase is then washed with water, dried over magnesium sulfate and evaporated. The residue, purified by LC/MS, gives 43 mg of 4-(2-isopropylaminoethylamino)benzenesulfonic acid 2-acetylaminobenzothiazol-6-yl ester (white powder) in a yield of 53%.
Reaction SMILES: [Na].Cl.N[OH:4].[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH2:18])=[O:17]>CO>[Cl:5][C:6]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH:18][OH:4])=[O:17]
Reactant: NO
Reactant: NC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)NO

Procedure:
To a solution of 1.84 g of sodium in 80 ml of methanol is added, at 50°, a solution of 1.82 g of hydroxylamine hydrochloride in 30 ml of methanol. To the suspension is added, with stirring, a solution of 5.8 g of [o-(2,6-dichloroanilino)-phenyl]-acetamide (M.P. 188° - 189°) in 80 ml of methanol, and the whole subsequently refluxed for 18 hours. After cooling, the red suspension is concentrated at 40° under 11 Torr to dryness. The residue is shaken with 600 ml of water and 100 ml of ether. The aqueous phase is separated and acidified with 2 N hydrochloric acid. The suspension is extracted with 200 ml of ether, the ether solution separated, washed with water, dried over magnesium sulphate, and concentrated at 40° under 11 Torr. The residue is crystallised from ether, whereby [o-(2,6-dichloroanilino)-phenyl]-acetohydroxamic acid is obtained, M.P. 164° - 165°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[NH:16][CH:17]=[C:18]([C:20](O)=[O:21])[N:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([CH2:37][NH2:38])[OH:36].O>CN(C=O)C>[OH:36][CH2:35][CH2:37][NH:38][C:20]([C:18]1[N:19]=[C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[NH:16][CH:17]=1)=[O:21]
Reactant: COc1ccc(-c2nc(C(=O)O)c[nH]2)cc1OC1CCCC1
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(C(=O)NCCO)c[nH]2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
To a solution of 2-(3-Cyclopentyloxy-4-methoxyphenyl)-imidazole-4-carboxylic acid (500 mg, 1.65 mmol) in DMF (15 ml) at room temperature was added carbonyldiimidazole (295 mg, 1.8 mmol). The resultant solution was stirred for 30 minutes and then ethanolamine (180 μl, 1.8 mmol) was added and the reaction mixture stirred at room temperature overnight. Water (75 ml) was added and the mixture extracted with ethyl acetate (2×75 ml). The combined organics were washed with brine (40 ml), dried over Na2SO4 and the volatiles removed in vacuo. Flash chromatography (SiO2; CH2Cl2:EtOH (95:5) (1% NH3)) afforded 2-(3-cyclopentyloxy-4-methoxyphenyl)-imidazole-4-carboxylic acid, N-(2-hydroxyethyl) amide (247 mg, 43%) as a white solid, mp 206-208° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:5]([C:6]([O:8]C)=[O:7])[C:4]=1[C:13]([O:15]C)=[O:14].[OH-].[K+].CO>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1cccc(OC)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(C(=O)O)c1C(=O)O
Yield: 83.9 %

Procedure:
A suspension of dimethyl 3-methoxyphthalate (69.45 g, 0.31 mol) [prepared as per J. Chem. Soc., Perkin Trans. 1, 1989, 391] in water (300 ml) was treated with potassium hydroxide (43.7 g, 0.78 mol) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the methanol liberated during the course of the reaction was removed in vacuo, the mixture acidified to pH 2 or below by the addition of 5M hydrochloric acid and evaporated gently in vacuo to induce crystallization. The solid material was filtered off, washed with a little ice cooled water, sucked dry under reduced pressure and dried in a vacuum oven at 50° C. overnight to afford 3-methoxyphthalic acid (51.0 g, 84%) as a colourless solid. 1H NMR (DMSO-d6) 13.05 (2H, br s), 7.48 (2H, m), 7.33 (1H, m), 3.82 (3H, s). MS: [M+H]+ 197.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[NH2:13][CH2:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CC(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([NH:9][CH:10]=[O:11])=[C:6]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[N:20]=2)[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: NCc1cccc(N2CCCC2=O)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(NC=O)c(NCc2cccc(N3CCCC3=O)n2)n1
Yield: 54.1 %

Procedure:
A mixture of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (3.61 g, 17.43 mmol) and 1-(6-aminomethylpyridin-2-yl)pyrrolidin-2-one (containing triphenylphosphine oxide) (10.00 g, ca. 50 mmol) and triethylamine (4.86 mL, 34.86 mmol) in propan-2-ol (100 mL) was heated at reflux for 18 h, cooled and the resulting precipitate filtered to give the title compound (3.41 g) as an off-white solid; NMR δH (400 MHz, d6-DMSO) 9.21 (1H, s), 8.20 (1H, d, J 1 Hz), 8.12 (1H, d, J 8.5 Hz), 7.73 (1H, t, J 7.5 Hz), 7.38 (1H, t, J 6 Hz), 7.02 (1H, d, J 7.5 Hz), 6.45 (2H, br s), 4.53 (2H, d, J 6.0 Hz), 4.00-3.95 (2H, m), 2.57 (2H, t, 18.0 Hz) and 2.08-2.00 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([F:12])[CH:3]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:12])[C:9]([NH2:11])=[O:10]
Reactant: NC(=O)Cc1ccc(Br)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: NC(=O)C(Br)c1ccc(Br)cc1F
Temperature: 85 °C
Yield: 39 %

Procedure:
To a suspension of 2-(4-bromo-2-fluorophenyl)acetamide (29.7 mmol) and N-bromosuccinimide (37.2 mmol) in anhydrous carbon tetrachloride (85 ml) was added 2,2′-azobis(2-methylpropionitrile) (1.487 mmol). The reaction mixture was heated at 85° C. for 4 days. The resulting suspension was concentrated in vacuo and the residue was taken into brine and then extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and decolorizing charcoal, filtered through a short pad of celite, and evaporated to a crude residue. Purification of the residue by flash chromatography (30% ethyl acetate in hexanes) afforded the title product (3.60 g, 38% yield) as a cream-colored solid. MS(ES)+m/e 310.1, 312.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.79 (s, 1 H) 7.48 (dd, J=8.59, 1.77 Hz, 1 H) 7.59 (br. s., 1 H) 7.61 (dd, J=9.85, 2.02 Hz, 1 H) 7.70 (t, J=8.21 Hz, 1 H) 7.91 (br. s., 1 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][N:6]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:14][S:15]([NH:1][C:2]1[S:3][C:4]([S:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][N:6]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncc(Sc2ncccn2)s1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ncc(Sc2ncccn2)s1
Yield: 43.8 %

Procedure:
To a solution of 2-amino-5-(2-pyrimidinylthio)thiazole (1.0 g) in a pyridine (20 ml) was dropwise added methanesulfonyl chloride (0.8 ml) at 5° C. with stirring. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and water was added to this residue. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give solid. The solid was recrystallized from 50% ethanol to give 2-methanesulfonylamino-5-(2-pyrimidinylthio)thiazole (0.60 g, yield: 43.8%). mp: 200° C. (dec.) IR (Nujol): 3120, 1585, 1545, 1440, 1305, 1140 cm-1
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[C:8]([C:12]1[CH:13]=[C:14]([OH:18])C=[CH:16][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].C1N2CN3CN(C2)CN1C3>O>[C:8]([C:12]1[CH:13]=[C:14]([OH:18])[C:2](=[CH:16][CH:17]=1)[CH:3]=[O:5])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 80 °C
Yield: 56 %

Procedure:
A five liter three-neck round bottom flask equipped with overhead mechanical stirrer and condenser was charged with trifluoroacetic acid (2.4 L). A mixture of 3-tert-butylphenol (412 g, 2.8 mole) and HMTA (424 g, 3.0 mole) was added portion-wise causing an exotherm. With cooling, the temperature was maintained under 80° C. The reaction was heated at 80° C. for one-hour, then cooled, and water (2 L) added. After 0.5 hour additional water (4 L) was added and the mixture was extracted with ethyl acetate (6 L). The organic extract was washed with water and brine. The resulting organic phase was divided into 2 L volumes and each diluted with water (1 L), and solid NaHCO3 added until the mixture was neutralized. The organic phases were isolated and combined, dried over MgSO4, filtered and concentrated in vacuo yielding an oil. This oil was distilled at 95° C. (0.8 mm) yielding the desired salicylaldehyde as an oil (272.9 g, 56%) which was of sufficient purity to be used without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]2[C:19]=1[C:20](=[O:29])[C:21](=[O:28])[NH:22]2.Cl>C1COCC1.CCCCCC>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]2[C:19]=1[C:20]([OH:29])([C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=1)[C:21](=[O:28])[NH:22]2
Reactant: Brc1ccc2ccccc2c1
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)cc(Cl)c2C1(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
To a solution of 2-bromonaphthalene (2.952 g) in anhydrous THF (25 mL) was added portion wise a solution of n-butyl lithium in n-hexane (1.55 N, 10.12 mL) at −78° C. The reaction solution was stirred for 30 minutes. To the mixture was then added portion wise a solution of 4,6-dichloroisatin (1.54 g) in anhydrous THF (25 ml) for 50 minutes. The reaction mixture was stirred for 2 hours. Then the mixture was allowed to warm to room temperature. To the mixture was added 1N HCl and extracted by ethyl acetate. The organic phase was separated, washed with 1N HCl and brine and dried over MgSO4 and concentrated . Purification was carried out by silica gel chromatography (hexane:ethyl acetate, 2:1 to 1:1 gradient) to give the title compound (0.652 g, yield: 27%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[O:14][CH3:15])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:50][C:51]([C:53]1[C:54]2[CH:55]=[CH:56][N:57]=[CH:58][C:59]=2[CH:60]=[CH:61][CH:62]=1)=[NH:52]>CN(C)C=O>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:52]=[C:51]([C:53]3[CH:62]=[CH:61][CH:60]=[C:59]4[C:54]=3[CH:55]=[CH:56][N:57]=[CH:58]4)[N:50]=2)=[CH:7][C:6]=1[O:14][CH3:15])[CH3:1]
Reactant: COc1cc(C(=O)O)ccc1OC(C)C
Reactant: N=C(NO)c1cccc2cnccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc(-c3cccc4cnccc34)no2)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 4-[(1-methylethyl)oxy]-3-(methyloxy)benzoic acid (Journal of the American Chemical Society (1955), 77 757-8; 135 mg, 0.641 mmol), HATU (244 mg, 0.641 mmol), Hunig's base (0.3 ml, 1.718 mmol) in N,N-dimethylformamide (DMF) (1 ml) was stirred at room temperature for 1 hr before the addition of N-hydroxy-5-isoquinolinecarboximidamide (D1; 100 mg, 0.534 mmol) in N,N-dimethylformamide (DMF) (1 ml). The reaction mixture was stirred at room temperature for 2-3 hrs and then heated in a microwave at 140° C. for 1.5 hr. The reaction mixture was concentrated in vacuo, dissolved in 1-2 ml of N-methylpyrrolidinone and purified by Preparative HPLC (Waters Sunfire C18 column, eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN+0.1% Formic acid)). The solvent was evaporated in vacuo to give the title compound (5 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])[CH2:25][CH2:24]2)=[CH:21][CH:22]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CC1(C)Oc2ccc(C#N)cc2C(N2CCN(c3ccc(Cl)cc3)CC2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 1-(4-chloro-phenyl)-piperazine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][C:8]1[C:9]([CH3:28])=[N:10][C:11]2[N:12]([C:15]([CH3:27])=[N:16][C:17]=2[C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:13]=1[OH:14]>C1(C)C=CC=CC=1>[Cl:3][CH2:6][CH2:7][C:8]1[C:9]([CH3:28])=[N:10][C:11]2[N:12]([C:15]([CH3:27])=[N:16][C:17]=2[C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:13]=1[OH:14]
Reactant: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCO)c(C)nc23)c(C)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(-c2nc(C)n3c(O)c(CCCl)c(C)nc23)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Thionyl chloride (112 mL, 1.54 mmol) was added to a solution of 3-(2-hydroxyethyl)-8-mesityl-2,6-dimethylimidazo[1,5-a]pyrimidin-4-ol (500 mg, 1.54 mmol) in toluene (5 mL) at 80° C., followed by stirring for one hour. After cooling to room temperature, the resulting crystals were washed with diethyl ether, to give the title compound (360 mg) as pale brown crystals.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21][N:20]([C:23]3[CH:38]=[CH:37][C:26]([C:27]([O:29]CC4C=CC=CC=4)=[O:28])=[CH:25][CH:24]=3)[CH2:19]2)[CH2:14]1)=[O:11])=[O:7].[H][H]>CO.[Pd]>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:22][CH2:21][N:20]([C:23]3[CH:38]=[CH:37][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH2:19]2)[CH2:14]1)=[O:11])=[O:7]
Reactant: [H][H]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc(C(=O)OCc4ccccc4)cc3)C2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3ccc(C(=O)O)cc3)C2)C1
Yield: 90.8 %

Procedure:
In a round-bottom flask, a solution of benzyl 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoate (258 mg, 0.43 mmol) in methanol (400 μL) and Palladium (10%) on Carbon (50 mg) was purged with hydrogen gas for two minutes; the reaction was then subjected to 1 atmosphere of hydrogen gas for two hours. The flask was purged with Argon, then the mixture was filtered and concentrated to afford 4-{(3R)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]-1,3′-bipyrrolidin-1′-yl}benzoic acid (197 mg, 91%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)[CH2:8][N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6][CH2:5]2.Cl[C:29]1[CH:34]=[C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:32]=[C:31]([NH2:42])[N:30]=1>>[NH2:42][C:31]1[N:30]=[C:29]([C:11]2[CH:10]=[C:9]3[C:4]([CH2:5][CH2:6][N:7]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:8]3)=[CH:3][C:2]=2[CH3:1])[CH:34]=[C:33]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:32]=1
Reactant: Cc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)CN(C(=O)OC(C)(C)C)CC2
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Product: Cc1cc2c(cc1-c1cc(N3CCN(C)CC3)nc(N)n1)CN(C(=O)OC(C)(C)C)CC2

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 75, Step 4 starting from tert-butyl 6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine Analytic LCMS (M+H)+: m/z=439.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25]>C1COCC1>[CH2:28]([O:27][C:23](=[O:26])[CH2:24][CH2:25][N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([S:10](=[O:12])(=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)=[CH:14][CH:15]=2)[CH2:20]1)[CH3:29]
Reactant: C=CC(=O)OCC
Reactant: O=S(=O)(Nc1cccc(Cl)c1)c1ccc2c(c1)CNCC2
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Yield: 107.5 %

Procedure:
A mixture of 7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.25 g, 9 mmol) (EP No. 0038177-A) and ethyl acrylate (0.91 g, 9 mmol) in THF (8 ml) was heated under reflux for 18 hr. Concentration and chromatography (silica gel, ether) gave ethyl-3-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]propionate as a viscous oil (4.09 g, 98.7%).