Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrN1C(=[O:7])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[C:29]1[O:33][CH:32]=[N:31][CH:30]=1>C(Cl)(Cl)(Cl)Cl>[Br:21][C:22]1[CH:27]=[C:26]([CH:25]=[CH:24][C:23]=1[C:29]1[O:33][CH:32]=[N:31][CH:30]=1)[CH:28]=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2cnco2)c(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2cnco2)c(Br)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 10.9 %

Procedure:
N-Bromosuccinimide (2.36 g) and 2,2′-azobis(2-methylpropionitrile) (164 mg) were added to a solution (100 mL) of 5-(2-bromo-4-methylphenyl)-1,3-oxazole (2.6 g) in carbon tetrachloride, and the mixture was refluxed under heating for 2.5 hours. Insoluble matter was removed through filtration, followed by purification, to thereby yield 5-[2-bromo-4-(bromomethyl)phenyl]-1,3-oxazole (3.2 g). Acetic acid (190 mg) and sodium hydrogencarbonate (336 mg) were added to a solution (50 mL) of the thus-obtained 5-[2-bromo-4-(bromomethyl)phenyl]-1,3-oxazole (500 mg) in anhydrous N,N-dimethylformamide, and the mixture was stirred at room temperature for 23 hours. The solvent was evaporated, and the residue was purified, to thereby yield 3-bromo-4-(1,3-oxazol-5-yl)benzyl acetate (300 mg). This procedure was repeated. 2N Aqueous sodium hydroxide solution (5 mL) was added to a solution (50 mL) of the thus-obtained 3-bromo-4-(1,3-oxazol-5-yl)benzyl acetate (490 mg) in methanol, and the mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was purified, to thereby yield [3-bromo-4-(1,3-oxazol-5-yl)phenyl]methanol (350 mg). Manganese dioxide (672 mg) was added to a solution (50 mL) of the thus-obtained [3-bromo-4-(1,3-oxazol-5-yl)phenyl]methanol (350 mg) in chloroform, and the mixture was refluxed under heating for 20 hours. Insoluble matter was removed through filtration by use of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (dichloromethane), followed by concentration, to thereby yield the title compound (300 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(=O)OC(C)(C)C)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.C(Cl)Cl.Cl.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4([NH2:21])[CH2:18][CH2:19][CH2:20]4)=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: NC1(c2ccc(-c3nc4ccc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 68 %

Procedure:
To a solution of tert-butyl {1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6.2 (0.075 g, 0.15 mmol) in MeOH (0.65 mL) and DCM (1.0 mL) was added hydrogen chloride (4 M in dioxane, 0.8 mL, 3.2 mmol, 20.0 eq), and the resulting mixture was stirred at room temperature for 19 h. The resulting mixture was added to ice water (50 mL), made alkaline with aqueous sodium hydroxide (2 N), and extracted with EtOAc (2×50 mL). The combined organic phases were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting material was recrystallized using diisopropyl ether to give 1-[4-(6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutanamine (0.040 g, 68%):
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>>[Br:19][C:3]1[N:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:6][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1ncc(C)[nH]1
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)c1nc(Br)c(C)[nH]1
Yield: 94 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-methyl-1H-imidazole-2-carboxylate obtained by the method described in Example (5a) (0.30 g, 1.95 mmol) and NBS (0.35 g, 1.96 mmol), to obtain 0.43 g of the title compound as a white solid (94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(N)nn4c3-c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of tert-butyl {1-[4-(6-amino-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-6.3 (0.10 g, 0.22 mmol) in DCM (4 mL) was added pyridine (0.036 mL, 0.44 mmol, 2 equiv) and acetic anhydride (0.027 mL, 0.29 mmol, 1.3 equiv). The reaction mixture was stirred for 24 h at room temperature, additional acetic anhydride (0.042 mL, 0.44 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for an additional 24 h. The resulting mixture was concentrated under reduced pressure to give tert-butyl {1-[4-(6-acetamido-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.11 g, 100%) which was used without further purification:
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][C@@H:44]([OH:46])[CH3:45])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:37]4[CH2:38][CH2:39][N:40]([CH2:43][C@@H:44]([OH:46])[CH3:45])[CH2:41][CH2:42]4)=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: C[C@H](O)CN1CCN(c2ccc(N)cc2)CC1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(C[C@H](C)O)CC4)cc3)nn12
Yield: 55.6 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and (S)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (0.205 g, 0.000870 mol) were dissolved in 2-Methoxyethanol (1.0 mL) and The reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 110.96 mg of (S)-1-(4-{4-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol as a lyophilized powder. (M+H)=459.20. 1H NMR (400 MHz, DMSO, d6) δ 9.22 (s, 1H), 8.92 (s, 1H), 7.82 (dd, 1H, J=1.44, 6.16 Hz), 7.61 (d, 2H, J=8.96 Hz), 7.43 (t, 1H, J=7.36 Hz), 6.90 (m, 4H), 4.11 (m, 2H), 3.80 (s, 3H), 3.60 (m, 3H), 3.18 (m, 3H), 3.03 (m, 3H), 1.14 (d, 3H, J=6.16 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.C(OCC)(=O)C>ClCCl>[N+:28]([C:27]1[CH:22]=[CH:23][C:24]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)=[CH:25][CH:26]=1)([O-:30])=[O:29]
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1ccc([N+](=O)[O-])cc1
Yield: 16 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using p-nitrophenol (18 mg, 0.13 mmol) as the coupling partner. Chromatography (1:1 ethyl aceate:dichloromethane) through SiO2 yielded 11 mg (16%) of the titled compound. ESI-MS m/z 413 (MH+), 411 (M−H−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CS(C)=O.[OH-].[Na+].Cl[CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: Nc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CO[Si](CCCOc1cccc(N)c1)(OC)OC
Yield: 85 %

Procedure:
Using the general procedure described in the preceding Example 1, a reactor was charged with 300 g (2.75 mole) m-aminophenol, 560 cc dimethylsulfoxide, 600 cc toluene and 216 cc of a 50% aqueous solution of sodium hydroxide (2.70 moles NaOH). The water present in the reactor was removed by azeotropic distillation under a nitrogen atmosphere at a temperature of 120° C. The temperature of the reaction mixture was then lowered to 90° C. and maintained at about this value during the gradual addition of 545 g (2.75 mole) of 3-chloropropyl trimethoxysilane. Following completion of the addition, which required 2 hours, the reaction mixture was heated at the boiling point for 16 hours. The product was recovered and fractionally distilled as described in the preceding example. The fraction boiling from 178° to 180° C. at a pressure of 3 mm of mercury was collected and weighed 630 g (85% yield). The infrared and nuclear magnetic resonance spectra of the distillate confirm the proposed structure ##STR16## A vapor phase chromatogram of the product indicated a purity of greater than 98%.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[CH:8]=[CH:9][C:10]=1[Cl:11])C=C.Cl.C(N(CC)[C:29]1[CH:34]=CC=C[CH:30]=1)C>>[CH2:34]([C:6]1[C:5]([OH:4])=[C:10]([Cl:11])[CH:9]=[CH:8][C:7]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]1=[O:24])[CH:29]=[CH2:30]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: Cl
Product: C=CCc1c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc(Cl)c1O
Temperature: 180 °C
Reaction time: 3 h

Procedure:
In 100 ml of N,N-diethylaniline, 8.0 g of 1-(3-allyloxy-4-chlorophenyl)-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione was dissolved, and the solution was stirred at 180° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into diluted hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was purified by silica gel chromatography, which afforded 6.3 g of the desired compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([Cl:18])[CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1cccc(Br)n1
Product: O=C(O)c1cccc(-c2cc(Cl)cc(Cl)c2)n1

Procedure:
6-Bromo-pyridine-2-carboxylic acid (500 mg, 2.47 mmol) was coupled to 3,5-dichloro-phenylboronic acid (473 mg, 2.47 mmol) acid using Method F to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10](=[C:13](OC)[CH3:14])[C:11]#[N:12])=[N:7][C:6]=2[CH:17]=1.O.[NH2:19][NH2:20]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:13]([CH3:14])=[N:20][NH:19][C:11]=3[NH2:12])=[N:7][C:6]=2[CH:17]=1
Reactant: NN
Reactant: COC(C)=C(C#N)c1nc2cc(F)ccc2s1
Solvent: O
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2cc(F)ccc2s1
Temperature: 25 °C

Procedure:
A suspension of 2-(5-fluorobenzothiazol-2-yl)-3-methoxybut-2-enenitrile (330 mg, 1.3 mmol) and hydrazine hydrate (70 μL) in methanol (40 mL) was heated to reflux overnight. The solution was then cooled to room temperature and the resulting solid was isolated by filtration. The crude material was recrystallized from ethanol to yield 260 mg (78%, 10% for five steps) of the title compound. MS (m/z, ES+): 249.0 (M+1,100%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>[Pt]=O.C(O)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:21]3[C:22]4[C:17]([CH2:18][CH2:19][CH2:20]3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)Nc2cccc3cccnc23)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(=O)N1CCC(c2nc3cccc4c3n2CCC4)CC1
Yield: 102.7 %

Procedure:
A mixture of 1-acetyl-N-(quinolin-8-yl)-4-piperidinecarboxamide (51.28 g), glacial acetic acid (800 ml), and platinum oxide (4.00 g) was shaken under hydrogen at ambient temperature until the calculated amount of hydrogen was consumed. The platinum oxide was filtered through a bed of celite and the filter cake was washed with acetic acid. The filtrate was evaporated to ~200 ml, and was then stirred under reflux for four hrs, basified with 10% ammonium hydroxide solution and extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was combined with material from another reaction mixture. The combined residue was purified by high performance liquid chromatography (silica gel; 20:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated. The residue was crystallized from ethyl acetate and then recrystallized from ethyl acetate to give 50.2 g (76%) of product, mp 139°-140° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14](Br)[CH:15]=1.[C:18]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:20][C:18](=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([C:14]2[CH:13]=[N:12][C:11]([NH2:17])=[C:10]([C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH:15]=2)[CH:27]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Nc1ncc(Br)cc1-c1nc2ccccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Temperature: 90 °C

Procedure:
A mixture of 3-benzothiazol-2-yl-5-bromopyridin-2-ylamine (BB7) (1.37 g, 4.5 mmol), 3-(carbomethoxy)phenylboronic acid (0.85 g, 4.7 mmol), Pd(PPh3)4 (5 mol %), and Cs2CO3 (3.5 g, 10.8 mmol) in dioxane/H2O (4:1, 30 mL) were heated under nitrogen at 90° C. for 5 h. Solvents were removed in vacuo, water (10 mL) was added to the residue, and the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material thus obtained was purified by column chromatography on silica gel using mixtures of EtOAc/Hexanes to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=7.28 (brs, 2H), 7.41 (t, J=6.9 Hz, 1H), 7.51 (t, J=6.9 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.77 (d, J=6.3 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 8.01-8.05 (m, 2H), 8.18 (d, J=2.1 Hz, 1H), 8.26 (t, J=1.8 Hz, 1H), 8.47 (d, J=2.1 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][O:10][C:11](=[O:25])[CH2:12][C:13](=[O:24])[CH2:14][O:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O.N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][O:10][C:11](=[O:25])[C:12]([C:13](=[O:24])[CH2:14][O:15][CH2:16][CH2:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:36][C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([Cl:32])[CH:34]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C(COCCC1CCCCC1)CC(=O)OCCC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=C(COCCC1CCCCC1)C(=Cc1cccc(Cl)c1)C(=O)OCCC(c1ccccc1)c1ccccc1

Procedure:
1.23 g (2.90 mmol) of 4-(2-cyclohexylethoxy)-3-oxobutanoic acid 3,3-diphenylpropyl ester, 0.33 ml (2.91 mmol) of 3-chlorobenzaldehyde, 0.05 ml (0.51 mmol) of piperidine and catalytic amount of p-toluenesulfonic acid were refluxed in 20 ml of benzene removing water for 1.5 hours. After adding ethyl acetate, the organic layer was washed with 1 N hydrochloric acid and saturated aqueous sodium hydrogencarbonate solution, and dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:19][CH2:18][CH2:17]2)#[N:13].C([BH3-])#N.[Na+]>>[C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19]([CH:7]1[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH2:6]1)[CH2:18][CH2:17]2)#[N:13]
Reactant: N#Cc1ccc2c(c1)CCNC2
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc2c(c1)CCN(C1CCC3(CC1)OCCO3)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of cyclohexane-1,4-dione monoethylene ketal(5.3 g, 33.9 mmole) and 6-cyano-1,2,3,4-tetrahydro-isoquinoline (5.3 g, 28.5 mmole) was treated with sodium cyanoborohydride (2.13 g, 33.8 mmole)at room temperature and stirred at ambient temperature for 18 hr. The reaction was concentrated to 1/4 volume at reduced pressure and poured into sat. NaHCO3 (500 ml ) and extracted with EtOAc (3×500 ml ). The combined organic layers were dried over anhydrous MgSO4 and evaporated under reduced pressure. The resulting foam was chromatographed on silica gel, eluting with 50% ethyl acetate/hexane to give 7.01 of product as a white solid which was recrystallized from ethanol. MP=127° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:25][C:23]1([CH3:26])[C:22]([CH3:27])([CH3:28])[O:21][B:20]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][C:10]=2[CH2:9][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:24]1
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2c(CNc3ccccc3)ccc3ccccc23)OC1(C)C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 12.0 g (129 mmol) of aniline, 30.0 g (86.5 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 13.1 g (94.9 mmol) of K2CO3 in 500 cm3 of DMF was stirred for 12 h at 80° C. The resulting mixture was poured into 1000 cm3 of water. The product was extracted with 3×200 ml of ethyl acetate. The combined extract was dried over MgSO4 and then evaporated to dryness. An excess of aniline was distilled off using Kugelrohr apparatus. Yield 25.3 g (82%). Anal. calc. for C23H26BNO2: C, 76.89; H, 7.29; N, 3.90. Found: C, 77.02; H, 7.45; N, 3.70. 1H NMR (CDCl3): δ 8.19 (m, 1H, 8-H in naphthalene), 7.83 (d, J=8.8 Hz, 1H, 4-H in naphthalene), 7.80 (m, 1H, 5-H in naphthalene), 7.49 (d, J=8.8 Hz, 1H, 3-H in naphthalene), 7.40-7.51 (m, 2H, 6, 7-H in naphthalene), 7.19 (m, 2H, 2, 6-H in Ph), 6.75 (m, 1H, 4-H in Ph), 6.69 (m, 2H, 3, 5-H in Ph), 4.51 (s, 2H, CH2N), 4.07 (br.s, 1H, NH), 1.38 (s, 12H, Me in tetramethyldioxaborolane).
Reaction SMILES: Br[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]2[C:3]=1[CH2:4][C:5](=[O:23])[NH:6][CH:7]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].C([O-])(=O)C.[Na+].[H][H]>C(O)(=O)C.[Pd]>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:7]1[C:8]2[C:3](=[CH:2][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:9]=2)[CH2:4][C:5](=[O:23])[NH:6]1
Reactant: O=C1Cc2c(cc3ccccc3c2Br)C(c2ccccc2Cl)N1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Cc2cc3ccccc3cc2C(c2ccccc2Cl)N1
Yield: 76.9 %

Procedure:
A mixture of 5-bromo-1-(2'-chlorophenyl)-1,4-dihydrobenz[g]isoquinol-3-one (Description 7) (7.6 g), sodium acetate (3.0 g) and 10% palladium-charcoal (2.0 g) in acetic acid (750 ml) was hydrogenated at atmospheric temperature and pressure until the initial rapid uptake of hydrogen had ceased (2.5 hours). The mixture was filtered (celite) and the filtrate evaporated to dryness in vacuo and recrystallised from ethylacetate to afford the title compound (4.65 g) m.p. 234°-237° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[N:12][N:13]=2)[CH:10]=1)[OH:4].O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:34]=[CH:33][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.[Sn](Cl)(Cl)(Cl)Cl>Cl.CO>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[N:12][N:13]=2)[CH:10]=1)[CH2:2][NH:1][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:34]=[CH:33][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: NC[C@H](O)c1ccc2nnnn2c1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CO
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4ccc5nnnn5c4)CC3)cc2)S1

Procedure:
5-[4-(4-{[(2R)-2-Hydroxy-2-[1,2,3,4]tetraazolo[1,5-a]pyridin-6-ylethyl]amino}-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione was prepared from (1R)-2amino-1-[1,2,3,4]tetraazolo[1,5-a]pyridin-6-yl-1-ethanol (which was obtained in Example 132) and 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione(which was obtained in Example 38) in substantially the same manner, as described in Example 125. The product was obtained as a yellow solid; mp: 130–132° C. This solid was dissolved in concentrated aqueous hydrochloric acid (0.3 mL) and methyl alcohol (2 mL). Tin chloride (0.196 g, 0.87 mmol) was added to the solution at room temperature. The mixture was then stirred at reflux for 2 hours. Evaporation and purification by flash column chromatography (dichloromethane/methyl alcohol 7/3)] gave a yellow solid. This solid was further purified by reverse phase HPLC to give a yellow solid (0.117 g, 61% yield); mp 182° C. (decomposed); 1H NMR (400 MHz, DMSO-d6) δ 1.90 (brs, 2 H), 2.21 (brs, 2 H), 3.03–3.36 (m, 8 H), 3.75–3.79 (m, 1 H), 4.86–4.90 (m, 1 H), 4.98–5.01 (m, 1 H), 7.03–7.05 (m, 1 H), 1.20 (brs, 4 H), 7.95–7.99 (m, 2 H), 8.21 (brs, 1 H), 9.13 (brs, 1 H), 9.45 (brs, 1 H), 12.04 (brs, 1 H), 14.13 (brs, 1 H); MS (ES) m/z: 442 (MH+).