Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl>[C:40]([NH:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=1)[C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(-c2c(F)cccc2[C@H](OCCN)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a round-bottom flask were added (R)-tert-butyl 2-((S)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (280 mg, 0.63 mmol), triethylamine (0.19 mL, 1.89 mmol) and anhydrous CH2Cl2 (15 mL). The mixture was cooled in an ice bath and a solution of acetyl chloride (49.2 mg, 0.045 mL, 0.63 mmol) was added. The reaction mixture was allowed to warm slowly to rt and stirred until the reaction was complete (ca 1˜2 h). The solvent was removed by evaporation, and the residue was purified by preparative tlc to give (R)-tert-butyl 2-((S)-(2-acetamidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (202 mg, 66%). 1H NMR (300 MHz, CDCl3): δ=1.45 (s, 9 H), 1.93 (s, 3 H), 2.38 (s, 3 H), 2.87˜3.2 (m, 6 H), 3.32˜3.92 (m, 5 H), 4.28 (d, 1 H), 7.01˜7.25 (m, 3 H), 7.28˜7.37 (m, 4 H), 9.41-9.54 (s, 1 H). MS (E/Z): 487 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[I-].[CH2:18]([N:25]([CH3:34])[C:26](N1C=C[N+](C)=C1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:26](=[O:27])[N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:34])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)n1cc[n+](C)c1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Agent: [I-]
Product: CN(Cc1ccccc1)C(=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared from 4-(3,5-dichloro pyridin-2-yloxy)-phenol and 3-(benzyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:11]=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[C:14]([CH:17]=1)[C:15]#[N:16].O.[OH-].[Na+]>CN(C)C=O>[N+:18]([C:13]1[CH:12]=[CH:11][C:10]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][C:14]=1[C:15]#[N:16])([O-:20])=[O:19]
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Oc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 52.6 %

Procedure:
Sodium hydride (60% in mineral oil), 1.5 grams (0.038 mole) was washed in petroleum ether. The petroleum ether was decanted , and the sodium hydride was suspended in about 20 mL of N,N-dimethylformamide. The suspension was stirred, and solutions of 4.5 grams (0.035 mole) of 4-chlorophenol in 20 mL of N,N-dimethylformamide and 5.0 grams (0.027 mole) of 5-chloro-2-nitrobenzonitrile in 20 mL of N,N-dimethylformamide were added, respectively. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for about 18 hours. The reaction mixture was then cooled and poured into a mixture of 500 mL of water and 50 mL of aqueous 2N sodium hydroxide. The mixture was stirred for about 15 minutes, then it was allowed to stand for about 18 hours. The resultant solid was collected by filtration and recrystallized from ethanol, yielding 3.9 grams of 2-nitro-5-(4-chlorophenoxy)benzonitrile, mp 120°-122° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH3:6][O:5][C:1](=[O:4])[NH:2][NH:3][C:14](=[O:15])[NH:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)NN
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: COC(=O)NNC(=O)Nc1ccccc1
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
A solution of methyl carbazate (91.9 g, 1.02 moles) in 450 ml of benzene was added dropwise with stirring during 45 min. to phenyl isocyanate (122 g, 1.02 moles); a temperature rise to near 80° C was observed. After addition of the ester solution the mixture was heated under reflux, with stirring, for 45 min. Stirring was continued at ambient temperature for 15 hr. Removal of volatiles under reduced pressure gave 210.6 g (99%) of product ester, as long prisms, m.p. 154°-155°. Recrystallization from isopropyl alcohol/ethanol (4/1) gave a polymorph as chunky crystals, m.p. 166°-168°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1ccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-4-methylbenzene. Yields 25%. MS M+H calculated 380.1. Found 380.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 uM.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:17][C:18]1[CH:19]=[C:20]([O:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:21]=[CH:22][CH:23]=1.Cl>C(OCC)(=O)C>[C:8]1([NH:14][C:15]([N:27]2[C:28]([CH3:30])=[CH:29][C:25]([O:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[N:26]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(Oc2cccc(Cl)c2)n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2cccc(Cl)c2)nn1C(=O)Nc1ccccc1
Reaction time: 6 h
Yield: 86.4 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and phenyl isocyanate (0.15 g, 1.3 mmol) were added to a solution of 3-(3-chlorophenyloxy)-5-methylpyrazole (0.25 g, 1.2 mmol) in ethyl acetate (5 ml) at 0° C., and while the mixture was allowed to have room temperature gradually, it was stirred for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow viscous substance of N-phenyl-3-(3-chlorophenyloxy)-5-methylpyrazole-1-carboxamide (0.34 g, yield: 84.5%). 1H-NMR (CDCl3, TMS, ppm): δ 2.66 (d, J=0.8 Hz, 3H), 5.78 (q, J=0.8 Hz, 1H), 7.05-7.11 (m, 1H), 7.14-7.21 (m, 3H), 7.28-7.39 (m, 3H), 7.52-7.56 (m, 2H), 8.91 (br s, 1H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]6[S:24][C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=6)=[O:22])=[CH:16][CH:15]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)s1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)cc2)s1
Temperature: 65 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A small screw cap test tube was charged with 5-Acetyl-thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 34, 40 mg, 0.093 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (22 mg, 0.1150 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜2 mL of i-prOH affording the title compound in 57% yield (0.032 g, 0.0528 mmol).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:11](Cl)=[N:12][OH:13])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23])[CH:19]=[C:18]([Cl:28])[CH:17]=1.C(=O)([O-])O.[Na+]>CC(O)C>[Br:1][C:2]1[C:10]2=[N:9][S:8][N:7]=[C:6]2[C:5]([C:11]2[CH2:23][C:22]([C:20]3[CH:19]=[C:18]([Cl:28])[CH:17]=[C:16]([Cl:15])[CH:21]=3)([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=C(Cl)c1ccc(Br)c2nsnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3nsnc23)=NO1
Temperature: 65 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a solution of 7-bromo-N-hydroxybenzo[1,2,5]thiadiazole-4-carbimidoyl chloride (10.01 g) (Example I5) in 2-propanol (140 ml) was added 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (6.87 g) (prepared according to WO 2005/085216) and sodium hydrogen carbonate (5.99 g). The reaction mixture was stirred at 65° C. for 3 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (heptane/ethyl acetate 9:1) to give 4-bromo-7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzo[1,2,5]thiadiazole (7.4 g). 1H-NMR (DMSO-d6, 400 MHz): 8.17-7.53 (m, 5H), 4.70 (d, 1H), 4.49 (d, 1H) ppm.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=[O:37])[CH2:31]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=[O:37])[CH2:31]1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: O=C(O)C1CCCNC1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCCC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and piperidine-3-carboxylic acid (25.6 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 18 mg 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (2H, dd, J=8.35, 1.98 Hz), 7.83 (2H, dd, J=7.91, 1.54 Hz), 7.56-7.75 (5H, m), 5.13-5.39 (1H, m), 4.11-4.31 (2H, m), 3.21-3.41 (3H, m), 2.96-3.05 (2H, m), 2.70-2.85 (1H, m), 1.75-2.14 (4H, m), 1.62-1.77 (2H, m), 1.36-1.56 (1H, m), 0.98 (3H, t, J=7.36 Hz). MS (m+1)=503. HPLC Peak RT=3.35 minutes (Analytical Method A). Purity=90%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[C:35]([CH2:36][O:37]C3CCCCO3)=[N:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[C:35]([CH2:36][OH:37])=[N:34][CH:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:45])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ncnc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(isobutyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M115) (0.61 g, 0.93 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (290 mg, 69%).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[CH2:16][CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1cc(C(=O)O)ccc1C1=CCCCC1
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C(=O)O)ccc1C1CCCCC1
Yield: 97.7 %

Procedure:
4-(1-cyclohexen-1-yl)-3-ethylbenzoic acid (D18) (803 mg, 3.49 mmol) was dissolved in methanol (70 mL) and hydrogenated on an H-Cube using a palladium on carbon cartridge. The product solution was concentrated in vacuo to give the title compound as a white solid (792 mg, 3.41 mmol). δH (methanol-d4, 400 MHz): 7.82-7.68 (2H, m), 7.33 (1H, d), 2.83 (1H, m), 2.73 (2H, q), 1.87 (2H, m), 1.85-1.70 (3H, m), 1.58-1.30 (5H, m), 1.22 (3H, t). LCMS (ES): no mass ion observed.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH2:18][C:19]4[CH:20]=[C:21]([S:25]([CH2:33][CH3:34])(=[N:27]C(OCC)=O)=[O:26])[CH:22]=[CH:23][CH:24]=4)=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.ClCCl.CO>CO>[CH:1]1([NH:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH2:18][C:19]4[CH:20]=[C:21]([S:25]([CH2:33][CH3:34])(=[NH:27])=[O:26])[CH:22]=[CH:23][CH:24]=4)=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)N=S(=O)(CC)c1cccc(COc2cc3ncnc(NC4CC4)c3cc2OC)c1
Solvent: ClCCl
Solvent: CO
Product: CCS(=N)(=O)c1cccc(COc2cc3ncnc(NC4CC4)c3cc2OC)c1
Yield: 92 %

Procedure:
According to GWP 6, the conversion of (RS)-S-[3-({[4-(cyclopropylamino)-6-methoxy-quinazolin-7-yl]oxy}methyl)phenyl]-N-(ethoxycarbonyl)-S-ethylsulphoximide (47 mg, 0.097 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 92% yield (37 mg).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][NH:6][CH:7]1[CH:12]2[CH2:13][CH2:14][CH:8]1[CH2:9][CH:10]([C:15]1[NH:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH2:30][CH3:31])[C:17]=3[N:16]=1)[CH2:11]2)C.[OH-].[K+]>CO.C1COCC1>[O:28]=[C:19]1[N:18]([CH2:29][CH2:30][CH3:31])[C:17]2[N:16]=[C:15]([CH:10]3[CH2:11][CH:12]4[CH:7]([NH:6][CH2:5][C:4]([OH:32])=[O:3])[CH:8]([CH2:14][CH2:13]4)[CH2:9]3)[NH:23][C:22]=2[C:21](=[O:24])[N:20]1[CH2:25][CH2:26][CH3:27]
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4NCC(=O)OCC)nc2n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4NCC(=O)O)nc2n(CCC)c1=O

Procedure:
[3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]oct-8-ylamino]-acetic acid ethyl ester (Example 40a) was hydrolyzed using 1N KOH in MeOH/THF. Mass (ES+418)
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:32][CH:31]([N:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:32][CH:31]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1CCN(C2CNC2)CC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCCCC4)C3)n(C)c2n1

Procedure:
Following General Procedure E for amine alkylation, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 1-(azetidin-3-yl)piperidine were reacted to give 386. LCMS m/z: 502.3 (MH+)
Reaction SMILES: O1C=CC[CH:2]1C(O)=O.[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[C:19]([OH:21])=[O:20].CC(C)([O-])C.[K+].C[Si](C)(C)[N-][Si](C)(C)C.[K+]>O1CCCC1>[CH3:2][C:10]1([C:19]([OH:21])=[O:20])[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9]1
Reactant: O=C(O)C1CC=CO1
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: CC(C)(C)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCc2ccccc2O1

Procedure:
The title compound was prepared following the procedures described for Reference Example 5 substituting 2,3-dihydrofuran-2-carboxylic acid with chromane-2-carboxylic acid at Step A and potassium tert-butoxide in tetrahydrofuran with potassium hexamethyldisilazide (0.5 M in toluene) at Step B. 1H NMR (500 MHz, CD3OD): δ 7.07 (t, 1H), 7.03 (d, 1H), 6.82 (m, 2H), 2.75 (m, 2H), 2.40 (m, 1H), 1.80 (m, 1H), 1.60 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([S:23][CH2:24][C:25]5[CH:32]=[CH:31][CH:30]=[C:27]([CH3:28])[CH:26]=5)=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: Cc1cccc(CBr)c1
Reactant: COc1ccc(-c2coc3ccc(-c4nnc(S)o4)cc23)cc1
Product: COc1ccc(-c2coc3ccc(-c4nnc(SCc5cccc(C)c5)o4)cc23)cc1
Yield: 80 %

Procedure:
In the same manner as in Example 1 and using 5-[3-(4-methoxyphenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-methylbenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[CH:32]1([CH2:38][C@H:39]([NH:51][C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[C@@H:40]([OH:50])[CH2:41][C:42]([NH:44][C@H:45]2[CH2:49][CH2:48][NH:47][CH2:46]2)=[O:43])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1>[CH:32]1([CH2:38][C@H:39]([NH:51][C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=2)=[O:53])[C@@H:40]([OH:50])[CH2:41][C:42]([NH:44][C@H:45]2[CH2:49][CH2:48][N:47]([C:27]([C@@H:11]3[CH2:10][C@H:9]([S:8][CH2:7][C:6]4[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:13][N:12]3[C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)=[O:15])=[O:28])[CH2:46]2)=[O:43])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Solvent: C1CCOC1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)C[C@H](O)[C@H](CC4CCCCC4)NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.47 g) in anhydrous tetrahydrofuran (30 ml), N,N'-carbonyldiimidazole (0.59 g) was added, followed by stirring at 30° C. for one hour. To the reaction mixture, a solution of (3S)-3-[(3S,4S)-5-cyclohexyl-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)aminopentanoylamino]pyrrolidine (1.38 g) in anhydrous tetrahydrofuran (30 ml) was added. The reaction mixture was treated in a similar manner to that described in Referential Example 18-(1), whereby 2.43 g of the title target compound were obtained as an amorphous substance.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>O.C(#N)C>[OH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([NH:20][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:22][CH2:23]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
Potassium carbonate (304 mg, 2.2 mmol) was dissolved in a minimum amount of water. Next, 4-fluoro-2-trifluoromethylbenzonitrile (378 mg, 2.0 mmol) and trans-4-aminocyclohexanol (460 mg, 4.0 mmol) dissolved in acetonitrile (10 mL) were added. The resulting mixture was then heated at 80° C. for 3 days. After cooling at room temperature, the mixture was concentrated under vacuum, taken up in ethyl acetate (15 mL), washed with saturated aqueous ammonium chloride (2×10 mL), and washed with water (10 mL). The organic phase was collected and dried over sodium sulfate, filtered, and concentrated under vacuum. The desired product was isolated as a colorless solid (456 mg, 80% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([CH:10]=1)C(O)=O.[I:12]I.[I-]>>[Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([I:12])[CH:10]=1
Reactant: II
Reactant: O=C(O)c1cnc(O)c(Cl)c1
Agent: [I-]
Product: Oc1ncc(I)cc1Cl

Procedure:
Alternatively, the present compound is prepared by reacting 5-chloro-6-hydroxynicotinic acid with I2 in an aqueous alkaline iodide solution to form 3-chloro-5-iodo-2-pyridinol. This reaction is conveniently conducted at an elevated temperature of between 40° C. and 150° C. and preferably at about 100° C. Lowering the pH of the reaction mixture to ≤1 such as, for example, by addition to the reaction mixture of SO2, will precipitate the 3-chloro-5-iodo-2-pyridinol from the reaction mixture.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([O:15]CC)=[O:14])=[CH:6]2)[CH3:2]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2)[CH3:2]
Reactant: CCOC(=O)c1cc2cc(CC)ccc2nn1
Solvent: CCO
Product: CCc1ccc2nnc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Sodium hydroxide (10 ml.) was added to a stirred solution of ethyl 6-ethylcinnolin-3-yl carboxylate (2.3 g.) in ethanol (10 ml.). The mixture was stirred at room temperature overnight. It was then evaporated under reduced pressure to approximately half-volume, diluted with water (20 ml.), and the mixture filtered. The filtrate was cooled to 0°-5° C., and acidified to pH 2 with concentrated hydrochloric acid. The resulting precipitate was filtered off, washed with water, and dried in vacuo. The solid was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 40°-60° C.) to give 6-ethylcinnolin-3-yl carboxylic acid, m.p. 176°-8° C. (decomposition).