Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH2:12][CH2:13][NH2:14])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[CH:17]1([C:20](Cl)=O)[CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([CH2:20][NH:14][CH2:13][CH2:12][C:10]2[O:9][C:8]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:11]=2)[CH2:19][CH2:18]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc2cc(CCN)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cccc2cc(CCNCC3CC3)oc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a mixture of 10.27 g of 7-methoxy-3-benzofuranethylamine, 60 ml of methylene chloride, and 60 ml of 15% aqueous sodium hydroxide solution was added, with cooling, 8 ml of cyclopropanecarbonyl chloride. The mixture was stirred at room temperature overnight; an additional 2 ml of cyclopropanecarbonyl chloride added after two hours. The solvent was removed from the dried organic layer and the residue heated under reflux with 3.5 g of lithium aluminum hydride in tetrahydrofuran for 6 hours. Water (3.5 ml), 15% aqueous sodium hydroxide solution (3.5 ml) and finally water (10.5 ml) were added with cooling, and the mixture filtered. Removal of the solvent and short-path distillation of the residue (bath to 170°, 1 micron pressure) gave 11.74 g (90% yield) of N-cyclopropylmethyl-7-methoxy-3-benzofuranethylamine; nmr spectrum (in CDCl3): τ2.6 (s, 1); 2.8-3.4 (m, 3); 6.1 (s, 3); 7.1-7.4 (m, 4 ); 7.6 (d, J=6.5 Hz, 2) and 8.1-10.2 (m, 6).
Reaction SMILES: C([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7](N)=[N:8][C:9]=2[Cl:13])(=O)C.[Br:15][Si](C)(C)C.N(OCCC(C)C)=O>O1CCCC1>[Br:15][C:7]1[N:6]=[C:5]2[C:10]([NH:11][CH:12]=[N:4]2)=[C:9]([Cl:13])[N:8]=1
Reactant: C[Si](C)(C)Br
Reactant: CC(=O)n1cnc2c(Cl)nc(N)nc21
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: Clc1nc(Br)nc2nc[nH]c12
Temperature: 22.5 °C
Reaction time: 19 h

Procedure:
9-Acetyl-2-amino-6-chloropurine (1.00 g, 4.72 mmol), bromotrimethylsilane (2.17 g, 14.2 mmol) and isoamyl nitrite (0.83 g, 5.67 mmol) were added to tetrahydrofuran (5 ml), and the mixture was stirred at 20-25° C. for 19 hr to give 2-bromo-6-chloropurine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:48])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:48])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([N:43]3[CH2:44][CH2:45][CH2:46][CH2:47]3)[CH:38]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(N4CCCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K63) (275 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow amorphous substance (379 mg, 82%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:26][C:27]3[C:30](=O)[C:29](=[O:32])[C:28]=3[O:33]C(C)C)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[N:7][CH:6]=2.[CH3:37][C@H:38]1[CH2:42][CH2:41][C@@H:40]([CH3:43])[NH:39]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][C@H:20]([NH:26][C:27]3[C:28](=[O:33])[C:29](=[O:32])[C:30]=3[N:39]3[C@H:40]([CH3:43])[CH2:41][CH2:42][C@@H:38]3[CH3:37])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:18]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[N:7][CH:6]=2
Reactant: CCOC(=O)[C@H](Cc1ccc(Nc2nc(C)cc3ccncc23)cc1)Nc1c(OC(C)C)c(=O)c1=O
Reactant: C[C@@H]1CC[C@H](C)N1
Product: CCOC(=O)[C@H](Cc1ccc(Nc2nc(C)cc3ccncc23)cc1)Nc1c(N2[C@H](C)CC[C@@H]2C)c(=O)c1=O

Procedure:
Prepared in a similar manner to the compound of Example 33, from the compound of Example 30 and cis 2,5-dimethylpyrrolidine. δH (DMSO-d6), 9.75 (1H, s), 9.45 (1H, s), 8.56 (1H, d, J 5.6 Hz), 7.84 (2H, m), 7.65 (1H, d, J 9.1 Hz), 7.55 (1H, d, J 5.6 Hz), 7.23 (2H, d, J 8.5 Hz), 6.96 (1H, s), 5.13 (1H, m), 4.22-4.13 (4H, m), 3.22 (1H, dd, J 13.9, 4.6 Hz), 3.04 (1H, dd, J 13.8, 10.6 (Hz), 2.43 (3H, s), 2.12-2.05 (2H, m), 1.70-1.64 (2H, m), 1.24-1.15 (9H, m); m/z (ES+, 70V) 528 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]2OCC[O:12]2)[S:9][CH:10]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[O:12])[S:9][CH:10]=1
Reactant: Fc1cccc(Oc2csc(C3OCCO3)c2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=Cc1cc(Oc2cccc(F)c2)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2-(4-(3-fluoro-phenoxy)-thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 33 (280 mg, 1.05 mmol) in methanol (10 mL) was added citric acid aqueous solution (10 mL), and the solution was stirred at room temperature for 30 minutes. The reaction solution was neutralized with an aqueous solution of sodium bicarbonate, the solution was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo, and the title compound (210 mg, 0.95 mmol, 90%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]=2[N+:23]([O-:25])=[O:24])=[C:5]([CH3:26])[CH:4]=1.Cl.[CH:28]1([CH:31]([NH2:35])[CH2:32][CH2:33][CH3:34])[CH2:30][CH2:29]1>>[CH:28]1([CH:31]([NH:35][C:11]2[C:10]([N+:23]([O-:25])=[O:24])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:26])[CH:14]=[CH:13][N:12]=2)[CH2:32][CH2:33][CH3:34])[CH2:30][CH2:29]1
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(C)c1
Reactant: CCCC(N)C1CC1
Agent: Cl
Product: CCCC(Nc1nccc(-c2ccc(OC)cc2C)c1[N+](=O)[O-])C1CC1
Yield: 33.2 %

Procedure:
Trifluoro-methanesulfonic acid 4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.764 g, 1.95 mmol), prepared substantially as described in Part C of Example 67a, and 1-cylcopropyl-butyl amine HCl (0.580 g, 3.9 mmol) were treated substantially as described in Part C of Example 67a to produce 0.230 g (50%) of (1-cyclopropyl-butyl)-[4-(4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]amine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[C:25]([CH2:33][CH3:34])=[N:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>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>[CH2:33]([C:25]1[C:24]([O:23][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:20]=2)=[CH:29][CH:28]=[C:27]([N+:30]([O-:32])=[O:31])[N:26]=1)[CH3:34]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (863 mg, 4.15 mmol), 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (892 mg, 3.19 mmol), K2CO3 (1.322 mg, 9.57 mmol) and Pd(PPh3)4 (184 mg, 0.159 mmol) in dioxane (6 mL) and water (1.5 mL) was sparged with Ar, heated at 80° C. for 24 h, then cooled to RT and stirred for 24 h. The mixture was treated with EtOAc, washed with satd. NaHCO3 (1×), then brine (1×), dried over Na2SO4 and concentrated to dryness to afford 2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (100% yield assumed) as a thick oil. Material carried on to the next step without purification. MS (ESI) m/z: 326.1 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][N:7]1[C:15]([OH:16])=[N:14][C:13]2[C:8]1=[N:9][C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[N:11][C:12]=2[NH2:17].[CH2:26]([O:28][P:29]([CH3:33])[O:30]CC)[CH3:27]>O1CCOCC1>[NH2:17][C:12]1[N:11]=[C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])[N:9]=[C:8]2[C:13]=1[N:14]=[C:15]([OH:16])[N:7]2[CH2:6][C:5]1[CH:4]=[C:3]([CH2:2][P:29]([CH3:33])(=[O:30])[O:28][CH2:26][CH3:27])[CH:25]=[CH:24][CH:23]=1
Reactant: CCOP(C)OCC
Reactant: COCCOc1nc(N)c2nc(O)n(Cc3cccc(CBr)c3)c2n1
Solvent: C1COCCO1
Product: CCOP(C)(=O)Cc1cccc(Cn2c(O)nc3c(N)nc(OCCOC)nc32)c1
Reaction time: 0.5 h
Yield: 14 %

Procedure:
A solution of Compound (9) (0.148 mmol) and diethylmethylphosphonite (1 mL) in dioxane (2.5 mL) was placed in an oil bath preheated to 100° C. for 30 minutes. The progress of the reaction was monitored by LCMS at 10 minute intervals. Once the reaction was observed to be complete, all of the solvent and phosphonite reagent were evaporated under high vacuum, and the remaining product was purified by HPLC. Lyophylization of the crude product gave Compound (10) (8.9 mg, 14%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.22 (t, J=6.9, 14.1 Hz, 2H), 1.36 (d, J=14.1 Hz, 3H), 3.20 (d, J=17.7 Hz, 2H), 3.38 (s, 3H), 3.69 (t, J=4.8, 9.6 Hz, 2H), 3.95 (m, 3H), 4.39 (t, J=4.8, 9.6 Hz, 2H), 4.97 (s, 2H), 7.24 (s, 1H), 7.31 (m, 3H). LCMS: m/z for C19H26N5O5P++H observed 436.1 at 1.29 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O (C18 column).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:24]3[CH:25]=[C:26]([CH:32]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=4)[OH:33])[C:27]([NH:30][CH3:31])=[N:28][CH:29]=3)[O:23][CH2:22][CH2:21][O:20]2)=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:24]3[CH:25]=[C:26]([C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=4)=[O:33])[C:27]([NH:30][CH3:31])=[N:28][CH:29]=3)[O:20][CH2:21][CH2:22][O:23]2)=[CH:15][CH:14]=1
Reactant: CNc1ncc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(OC)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CNc1ncc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
PCC (21.19 g, 98.58 mmol) was added to a solution of compound F (28 g, 65.72 mmol) in DCM (550 mL). The mixture was stirred at RT overnight and filtered through a pad of celite. The filtrate was concentrated and purified by column chromatography to obtain 16 g (46%, 2 steps) of compound G.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[CH2:23][N:22]([CH2:24][CH2:25][S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])[C@H:21]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:20]=1.I[CH3:38]>C1COCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[CH2:23][N:22]([CH2:24][CH:25]([S:26]([CH2:29][CH3:30])(=[O:27])=[O:28])[CH3:38])[C@H:21]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:20]=1
Reactant: CI
Reactant: CCS(=O)(=O)CCN1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)C(C)CN1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide in THF (1.0 M, 0.74 mL, 0.74 mmol, 4.0 equiv) was added to a solution of (2S)-4-(2,5-difluorophenyl)-1-[2-(ethylsulfonyl)ethyl]-2-phenyl-2,5-dihydro-1H-pyrrole (70 mg, 0.185 mmol, 1 equiv) in THF (5 mL) at −78° C., then stirred for 1 h. Iodomethane (0.035 mL, 0.56 mmol, 3.0 equiv) was added and the resulting mixture was warmed to 0° C. and stirred for 30 minutes. The mixture was then partitioned between saturated potassium bisulfate solution and ethyl acetate (2×40 mL). The combined organic layers were dried over magnesium sulfate and were concentrated. The residue was purified by flash column chromatography (CH2Cl2 initially, grading to 4% EtOAc in CH2Cl2) to give (2S)4 (2,5-difluorophenyl)-1-[2-(ethylsulfonyl)propyl]-2-phenyl-2,5-dihydro-1H-pyrrole (38-1) as a single diastereomer (colorless oil). 1H NMR (500 M, CDCl3) δ 7.38-7.28 (m, 5H), 7.08-6.92 (m, 3H), 6.29 (br s, 1H), 4.66 (br s), 4.37 (dd, 1H, J=12.5, 4.9 Hz), 3.84 (br d, 1H, J=13.0 Hz), 3.36 (dd, 1H, J=13.7, 7.1 Hz), 2.99 (m, 1H), 2.84 (m, 2H), 2.77 (dd, 1H, J=13.9, 7.3 Hz), 1.31 (d, 3H, J=7.1 Hz), 1.19 (t, 3H, J=7.6 Hz). LRMS m/z (M+H) 392.4 found, 392.1 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[CH2:7][CH2:6]2.CO.[BH4-].[Na+]>C1COCC1.Cl[Ni]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[CH2:7][CH2:6]2
Reactant: COCC(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCC(=O)N1CCc2cc(OC)c(N)cc21
Yield: 25.2 %

Procedure:
A slurry of 5-(methyloxy)-1-[(methyloxy)acetyl]-6-nitro-2,3-dihydro-1H-indole (3.96 g, 14.87 mmol) and NiCl2 6H2O (1.061 g, 4.46 mmol) in THF (50 mL) and MeOH (100 mL) was treated with NaBH4 (1.69 g, 44.6 mmol) in small portions. After 5 minutes the reaction mixture was concentrated onto Celite and purified by silica gel chromatography using THF. The crude product was triturated using CH2Cl2 and Et2O to obtain 5-(methyloxy)-1-[(methyloxy)acetyl]-2,3-dihydro-1H-indol-6-amine as a white solid (884 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.98 (t, J=8.24 Hz, 2H), 3.34 (s, 3H), 3.71 (s, 3H), 3.93 (t, J=8.,33 Hz 2H), 4.12 (s, 2H), 4.67 s, 2H), 6.71 (s, 1H), 7.54 (s, 1H); ESIMS (M+H)+=237.4.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]2[N:15]([C:16]=1[C:17]#[N:18])[CH:14]=[CH:13][CH:12]=[CH:11]2>CCOCC>[F:7][C:8]1[CH:9]=[C:10]2[N:15]([C:16]=1[CH2:17][NH2:18])[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: N#Cc1c(F)cc2ccccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCc1c(F)cc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
LiAlH4 (0.175 g, 4.6 mmol) is added in portions under stirring in argon to a solution of 2-fluoroindolizine-3-carbonitrile x262 [X. Fang, Y.-M. Wu, J. Deng, S.-W. Wang, Tetrahedron 2004, 60, 5487-5493] (0.46 g, 2.9 mmol) in absolute ether (15 ml) for 3 min. The reaction mixture is stirred at room temperature for 30 min, cooled to 0-5° C., and quenched by the addition of a 10% NaOH solution (4 ml). The organic layer is separated, and the aqueous layer is subjected to extraction with ether (3×10 ml). The combined organic extracts are dried over anhydrous Na2SO4. The solvents are removed reduced pressure to give 1-(2-fluoroindolizin-3-yl)methanamine x263 (0.38 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=CC1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)/C=C/C2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 24 h

Procedure:
1.27 g of 4-[3-(1-benzylpiperidin-4-yl)propenoyl]-nitrobenzene was added to a mixed solution of 10 ml of acetic acid and 2 ml of hydrochloric acid, and then 1.38 g of stannous chloride was added thereto under ice cooling. The mixture was stirred for 24 hours while further adding 0.69 g of stannous chloride twice during the reaction. The solvent was removed under reduced pressure to obtain a crude product of (E)-4-[3-(1-benzylpiperidin-4-yl)propenoyl]aniline. Then, this was dissolved in 15 ml of ethanol, and to the solution was added 0.67 g of 4-chloro-5,6-dimethylpyrimidine. Subsequently, the mixture was reacted by heating at 60° C. for 30 minutes. The reaction mixture was neutralized by adding a 28% sodium methylate-methanol solution under cooling, solids were removed by filtration, and then the filtrate was consensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 1.02 g of the title compound as pale yellow powder.
Reaction SMILES: [CH:1]12[CH2:10][CH2:9][CH:5]([NH:6][C:7]1=[O:8])[CH2:4][NH:3][CH2:2]2.Cl[C:12]1[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=1>>[O:8]=[C:7]1[CH:1]2[CH2:10][CH2:9][CH:5]([CH2:4][N:3]([C:12]3[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=3)[CH2:2]2)[NH:6]1
Reactant: O=C1NC2CCC1CNC2
Reactant: OB(O)c1cnc(Cl)nc1
Product: O=C1NC2CCC1CN(c1ncc(B(O)O)cn1)C2

Procedure:
The title compound was prepared from 3,6-diazabicyclo[3.2.2]nonan-7-one and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14]>C1COCC1>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
2-Amino-5-nitropyridine (19) (4.0 g, 28.8 mmol) was dissolved in THF (300 mL). TEA (12.0 mL, 86.1 mmol) was added and the stirred mixture cooled to 0° C. Chloroacetyl chloride (7.0 mL, 87.9 mmol) was added dropwise. The stirred solution was allowed to warm to rt then stirred at this temperature for 1 hour. The mixture was heated at reflux for 1 hour. The solvent was evaporated in vacuo and the residue partitioned between DCM (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The layers were separated and the organic phase washed with saturated brine solution (50 mL), then separated, dried over MgSO4, filtered and concentrated in vacuo. Approximately half the crude product was purified by column chromatography (Biotage SP1) eluting with isohexane→30% EtOAc-isohexane, combining the crude material with this purified product. The combined material was triturated with EtOAc-isohexane to provide the title compound as a brown solid (3.6 g, 58%); Rf: 0.45 (3:1 isohexane-EtOAc).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([O:33][C:34]([F:37])([F:36])[F:35])[CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:27][C:28]=2[O:33][C:34]([F:37])([F:35])[F:36])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CP(C)(=O)c1ccc(N)c(OC(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2OC(F)(F)F)nnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[C:24]([F:27])([F:26])[F:25]>>[F:25][C:24]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:14]=1[CH2:13][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-Indazole-5-carbaldehyde and 1-bromomethyl-2,4-bis-trifluoromethyl-benzene following General Procedure A.
Reaction SMILES: [CH:1]1([Na])[CH:5]=[CH:4][CH:3]=[CH:2]1.S(C1C=CC(C)=CC=1)(O[CH2:11][CH2:12][CH:13]=[CH2:14])(=O)=O>O1CCCC1>[CH2:14]([C:2]1[CH2:1][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: [Na]C1C=CC=C1
Solvent: C1CCOC1
Product: C=CCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
68.9 ml of a 2.0M solution of cyclopentadienyl sodium in tetrahydrofuran (THF) are added to a solution of 100 millimoles of the γ-butenyl 1-tosylate prepared in the preceding stage (a), in 200 ml of THF cooled to 0° C. The mixture is heated to ambient temperature (20° C.) and is stirred for 16 hours. 100 ml of an aqueous saline solution are added to the mixture and the product is extracted with ether (3′ 75 ml). The organic fractions are dried over magnesium sulphate for 2 hours, filtered and the solvents are removed at reduced pressure to give a dark brown oily crude product. The crude product is distilled at reduced pressure to give γ-butenylcyclopentadiene in the form of a colourless oil.
Reaction SMILES: [NH2:1][C:2](SC)=[C:3]([C:6]#[N:7])[C:4]#[N:5].[CH3:10][NH:11][CH3:12]>CN(C)C=O>[NH2:1][C:2]([N:11]([CH3:12])[CH3:10])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: CNC
Reactant: CSC(N)=C(C#N)C#N
Solvent: CN(C)C=O
Product: CN(C)C(N)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.1 %

Procedure:
Into a pressure bottle were placed 5.6 g of 3-amino-2-cyano-3-(methylthio)propenenitrile and 3 ml of dimethylformamide, and the mixture was cooled to 0°. A volume of 5.4 ml (3.6 g) of dimethylamine was condensed in a dry-ice trap and added to the pressure bottle. The bottle was sealed and the reaction mixture was heated, with stirring, at 100° for 3-4 hours (in subsequent runs, the heating time was reduced to 80 minutes without reducing the yield). After this time, the mixture was allowed to cool to ambient temperature, where it stood for two days. The pressure bottle was cooled to 0° and opened. The mixture was allowed to attain ambient temperature, then was poured into 300 ml of ice-water, causing a white solid to precipitate. The slurry was stirred for 30 minutes. The solid product was collected by filtration and washed with cold water to give 5.1 g of 3-amino-2-cyano-3-(dimethylamino)propenenitrile, m.p. 228°-229°. The nmr was consistent with the assigned structure.
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])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: COc1cccc(CBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Product: COc1cccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)c1
Yield: 30 %

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(bromomethyl)-3-methoxybenzene. Yield 30%, white solid. 1H NMR (DMSO-d6, 400 MHz): 1s, 6H), 2.16 (s, 3H), 2.42 (s, 3H), 3.74 (s, 3H), 4.53 (s, 2H), 5.20 (s, 2H), 6.83 (m, 1H) 6.96 (m, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.83 (d, J=0.8 Hz, 1H), 8.21 (d, J=0.8 Hz, 1H). mp 107-108° C. MS 424 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.08 μM.