Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C@H:7]([CH3:17])[NH:6]1)[OH:4].[C:27](OC(=O)C)(=[O:29])[CH3:28].[ClH:34]>C(OCC)C.C1C=CC=CC=1>[ClH:34].[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([F:25])[CH:22]=1)[CH2:18][C@H:2]([NH:1][C:27](=[O:29])[CH3:28])[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH3:15])([CH3:16])[CH3:14])[C@H:7]([CH3:17])[NH:6]1)[OH:4]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1N[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO[C@H]1OCC(C)(C)C
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1
Reaction time: 1 h
Yield: 45 %

Procedure:
Dissolve (1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-[(3R,5S,6R)-6-(2,2-dimethylpropoxy)-5-methylmorpholin-3-yl]-propan-1-ol (70 mg, 0.188 mmol) in dry dichloromnethane (1.8 mL) under nitrogen. Add dropwise acetic anhydride (22 μL, 0.233 mmol) and stir for 1 hour. Add 1 M hydrogen chloride in diethyl ether (1 mL) and dilute with benzene. Concentrate and purify (HPLC, eluting with 30% to 70% acetonitrile with 0.1% hydrochloric acid in water) to give the title compound as a white solid (38 mg, 45%)
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH3:23].O>CS(C)=O>[NH2:23][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: N
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N
Temperature: 90 °C
Yield: 79.3 %

Procedure:
A mixture of 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (126) (0.30 g, 1.01 mmol) and ammonia (4.05 mL, 8.10 mmol) in DMSO (5 mL) was heated at 90° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, treated with water, and extracted with DCM (3×). The extracts were dried over Na2SO4, concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/DCM) to give 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 235 mg, 79%). m/z (ESI, +ve) 294 (M+H)+. A mixture of 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (445a, 50 mg, 0.17 mmol) and Ac2O (0.016 mL, 0.17 mmol) in pyridine (2 mL) was heated at 50° C. for 16 h. It was concentrated under reduced pressure. The residue was purified by reverse phase HPLC. The pure fractions were combined and concentrated to dryness. The solid was dissolved in MeOH and neutralized by pass through Stratosphere SPE (PL-HCO3 MP-Resin) to give N-(3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)acetamide as a tan solid (445) (10 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.21 (1H, br. s.), 10.22 (1H, s), 8.07-8.20 (1H, m), 7.71 (1H, dd, J=8.2, 1.2 Hz), 7.63 (1H, t, J=7.8 Hz), 7.09 (1H, d, J=2.3 Hz), 6.99 (1H, br. s.), 3.41-3.51 (2H, t, J=6.8 Hz), 2.94 (2H, t, J=6.8 Hz), 2.75 (3H, s), 2.36 (3H, s). m/z (ESI, +ve) 336 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:9][CH:8]([CH2:10][OH:11])[CH2:7]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CS(C)=O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:7][CH:8]([CH:10]=[O:11])[CH2:9]1
Reactant: OCC1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of {1-[2,4-bis(trifluoromethyl)benzyl]azetidin-3-yl}methanol (313 mg) and triethylamine (607 mg) in DMSO (5 mL) was added sulfur trioxide pyridine complex (477 mg) at room temperature. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (202 mg).
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[CH:8]=[N:9][C:10]([S:15][CH3:16])=[N:11][C:12]=2[CH2:13][CH2:14]/1)[CH3:3].[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2C(N)=[CH:28][CH:27]=[N:26]2)=[CH:22][CH:21]=1.FC(F)(F)C(O)=O>CO.C(O)(C)C>[CH3:18][O:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[C:3]3[N:2]=[CH:4][C:5]4[CH2:14][CH2:13][C:12]5[N:11]=[C:10]([S:15][CH3:16])[N:9]=[CH:8][C:7]=5[C:6]=4[C:28]=3[CH:27]=[N:26]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: CSc1ncc2c(n1)CC/C(=C\N(C)C)C2=O
Solvent: CO
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2ncc3c4c(cnc32)CCc2nc(SC)ncc2-4)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 24.1 %

Procedure:
To a mixture of (E)-6-((dimethylamino)methylene)-2-(methylthio)-7,8-dihydroquinazolin-5(6H)-one (8 g, 32 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (7.2 g, 35 mmol) was added trifluoroacetic acid (3 mL). The reaction mixture was heated at 100° C. for 16 hours. The reaction was cooled to room temperature and diluted with a 1:1 mixture of methanol and isopropanol (40 mL). The mixture was stirred for 30 minutes and filtered. The solid obtained was then further purified using flash column chromatography (SiO2, gradient from 100% chloroform to 2% EtOAc in chloroform) to give the desired product (3.0 g, 24%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 9.52 (s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 5.64 (s, 2H), 3.78 (s, 3H), 3.16 (t, J=6.0 Hz, 2H), 3.10 (t, J=6.2 Hz, 2H), 2.65 (s, 3H); LCMS [M+H]: 390.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:21][C:22]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH:1]1([O:4][C:5]2[CH:6]=[CH:7][C:8]([C:9]([NH:21][C:22]3([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23]3)=[O:11])=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1(N)CC1
Reactant: O=C(O)c1ccc(OC2CC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2ccc(OC3CC3)cc2)CC1
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a 0° C. suspension of 4-cyclopropoxybenzoic acid (24.5 g, 137.3 mmol) in dichloromethane (350 mL) containing 2 drops of DMF, slowly add oxalyl chloride (23.8 mL, 274.7 mmol). After addition, remove the cooling bath and stir for 2 hours. Concentrate the material to dryness under reduced pressure. Dissolve the residue in dichloromethane (500 mL), and then add ethyl 1-aminocyclopropanecarboxylate hydrochloride (Indofine #04-265, 24.9 g, 150.5 mmol) and triethylamine (57.2 mL, 410.4 mmol). Stir the mixture at ambient temperature for approximately 16 hours. Wash the mixture once with 10% NaHSO4 (250 mL). Separate the organic portion and extract the aqueous portion 2× with dichloromethane (200 mL). Combine the organic, dry over sodium sulfate, filter, and concentrate under reduced pressure. Purify the crude mixture by flash chromatography (0% to 45% EtOAc/Hex) to give the title compound (33.7 g, 85%): MS (m/z): 290 (M+1).
Reaction SMILES: [CH2:1]([C:4]1([CH3:28])[C:9]2[N:10]([CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=C)[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:27])[CH2:5]1)[CH:2]=C>C(Cl)Cl>[CH3:27][N:6]1[CH2:5][C:4]2([CH3:28])[CH2:1][CH:2]=[C:19]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[CH2:18][N:10]3[C:9]2=[C:8]([C:16]2[CH:15]=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=23)[CH2:7]1
Reactant: C=CCC1(C)CN(C)Cc2c1n(CC(=C)c1ccncc1)c1ccc(C)cc21
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c3n2CC(c2ccncc2)=CCC3(C)CN(C)C1
Temperature: 100 °C
Yield: 1.4 %

Procedure:
4-Allyl-2,4,8-trimethyl-5-(2-pyridin-4-yl-allyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (300 mg, 0.808 mmol) was dissolved in DCM and the solution was purged with nitrogen for 5 min. Hoveyda-Grubbs 2nd generation catalyst (40 mg, 8 mol %) was added, the solution was re-purged with nitrogen and heated at 100° C. for 16 h. The reaction mixture was cooled to RT, filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatography to obtain 4 mg of 2,3a,10-trimethyl-6-pyridin-4-yl-1,2,3,3a,4,7-hexahydro-2,7a-diaza-cyclohepta[jk]fluorene. 1H NMR (Freebase, CDCl3) δ (ppm): 8.61 (d, 2H), 7.37 (m, 2H), 7.21 (s, 1H), 7.19 (d, 1H), 7.0 (d, 1H), 6.21 (m, 1H), 5.18 (d, 1H), 5.0 (d, 1H), 3.80 (d, 2H), 3.56 (d, 2H), 2.59 (s, 2H), 2.41 (s, 3H), 2.12 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.O[CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=2)[O:9][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: Cn1nccc1C(O)c1ccc(Cl)cc1
Reactant: OC1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nccc1C(OC1CCNCC1)c1ccc(Cl)cc1
Yield: 87.3 %

Procedure:
A mixture of 2.074 g of (±)-(4-chlorophenyl)(2-methyl-2H-pyrazol-3-yl)methanol synthesized in Production Example 174, 942 mg of 4-hydroxypiperidine, 1.949 g of p-toluenesulfonic acid monohydrate, and 100 mL of toluene was heated under reflux for 40 minutes while removing water using a Dean-Stark. To the mixture, 1.949 g of p-toluenesulfonic acid monohydrate was added, and the resulting mixture was further heated under reflux for 4.3 hours while removing water. After the mixture was allowed to cool down, toluene and 22 mL of a 1-N sodium hydroxide aqueous solution were added thereto, and the organic layer was collected by separation. The organic layer was washed with 22 mL of a 1-N sodium hydroxide aqueous solution and with a saturated saline solution in this order. The organic layer was dried over sodium sulfate, and then the solvent was distilled off. Thus, the title compound (2.487 g (87%)) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][C@H:6]([NH:20]C(C1C=C(C)N=C(N(CCC)CCC)N=1)=O)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1.[CH2:41]([N:45]([CH3:57])[C:46]1[CH:47]=[C:48]([CH:52]=[C:53]([C:55]#[N:56])[N:54]=1)[C:49]([OH:51])=O)[CH2:42][CH2:43][CH3:44]>>[CH2:41]([N:45]([CH3:57])[C:46]1[CH:47]=[C:48]([CH:52]=[C:53]([C:55]#[N:56])[N:54]=1)[C:49]([NH:20][C@@H:6]([CH2:5][C:4]1[CH:37]=[C:38]([F:40])[CH:39]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1)=[O:51])[CH2:42][CH2:43][CH3:44]
Reactant: CCCCN(C)c1cc(C(=O)O)cc(C#N)n1
Reactant: CCCN(CCC)c1nc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)n1
Product: CCCCN(C)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(C#N)n1

Procedure:
In the same manner as for N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(dipropylamino)-6-methylpyrimidine-4-carboxamide {EXAMPLE S-2435}, Step 3, 2-[butyl(methyl)amino]-6-cyanoisonicotinic acid (0.135 g) was converted to the title compound (0.223 g).
Reaction SMILES: O[CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>CN(C)C=O.O>[Cl:42][CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(CO)cc32)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CCl)cc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
A solution of 6-hydroxymethyl-1-(4-methylphenylsulfonyl)indole (21.0 g) and triphenylphospine (21 g) in a mixture of N,N-dimethylformamide (200 ml) and carbon tetrachloride (27 ml) was stirred at room temperature for 18 hr under a nitrogen atmosphere. The solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried (MgSO4), and evaporated to give 6-chloromethyl-1-(4-methylphenylsulfonyl)indole (21.4 g, 96%) as an ivory solid partial NMR (80 MHz, CDCl3): 2.34 (s, 3H, ArCH3), 4.71(s, 2H, ClCH2), 6.62(dd, 1H, H3 -indole), 8.02(m, 1H, H7 -indole). f. 1-(4-Methylphenylsulfonyl)indole-6-acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.Cl.[NH:33]1[CH2:36][CH2:35][CH2:34]1>>[N:33]1([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:21]3[N:20]=[C:19]([C:11]4[N:10]=[N:9][N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[C:12]=4[C:13]4[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=4)[O:23][N:22]=3)=[CH:25][CH:26]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: C1CNC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Agent: Cl
Product: Fc1ccccc1-n1nnc(-c2nc(-c3ccc(CN4CCC4)cc3)no2)c1-c1ccncc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and azetidine hydrochloride (45.4 mg; 0.48 mmol) to give Example 138 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.6, 1.6 Hz), 7.96-7.87 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.6, 1.6 Hz), 7.51 (4H, t, J=8.1 Hz), 3.67 (2H, s), 3.22 (4H, t, J=6.9 Hz), 2.04 (2H, m). LC/MS (Method C): 454 (M+H)+. HPLC (Method E) Rt 2.19 min (Purity: 96.2%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.C(=O)(O)[O-].[Na+]>ClCCl>[S:23]1[CH:24]=[CH:25][N:26]=[C:22]1[C:11]([C@H:8]1[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]1)=[O:13]
Reactant: C[Si](C)(C)c1nccs1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](C(=O)c2nccs2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (500 mg, 2.69 mmol) in dichloromethane (3 mL) at 0° C. was added oxalyl chloride (0.26 mL, 2.95 mmol) dropwise. The solution was stirred at 0° C. for 30 min and then allowed to warm to room temperature and stirred for one hour. The solution was then cooled back to 0° C. and 2-(trimethylsilyl)-1,3-thiazole (0.63 mL, 4.03 mmol) was added. The solution was allowed to warm to room temperature and then stirred for one hour. The solution was then poured into cold saturated sodium bicarbonate and then diluted with dichlormethane. The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-30% ethyl acetate/hexanes) to provide methyl trans-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate. MS ESI calc'd. for C12H16NO3S [M+H]+ 254. found 254. 1H NMR (500 MHz, CDCl3) δ 8.01 (dd, J=1.6, 2.9 Hz, 1H), 7.67 (dd, J=1.7, 2.9 Hz, 1H), 3.77-3.67 (m, 3H), 3.62 (t, J=11.1 Hz, 1H), 2.35 (t, J=10.4 Hz, 1H), 2.18-2.06 (m, 4H), 1.68-1.48 (m, 4H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10](=[O:20])[NH:9][C:8](=[O:21])[CH:7]=1>C(O)(=O)C>[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10](=[O:20])[NH:9][C:8](=[O:21])[C:7]=1[N:1]=[O:3]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1Cc1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
157.6 ml of 4N sodium nitrite was added over 45 minutes to a suspension of 165 g of 6-amino-1-(4-chlorobenzyl)-uracil in 825 ml of acetic acid at 65-70° C. After a further 15 minutes at 70° C. the reaction mixture was cooled to room temperature, the pink solid collected and washed with 80% acetic acid and water to give the title compound (150.9 g) mp >320° C.
Reaction SMILES: [NH3:1].C([O:4][C:5]([C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:19][N:18]4[CH2:27][CH2:28][CH2:29][C:17]=34)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)=O)C.ClCCl.CO>CO>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]3[N:11]([C:7]([C:5]([NH2:1])=[O:4])=[CH:8][N:9]=3)[CH:12]=2)=[C:17]2[CH2:29][CH2:28][CH2:27][N:18]2[N:19]=1
Reactant: CCOC(=O)c1cnc2ccc(-c3c(-c4ccccn4)nn4c3CCC4)cn12
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1cnc2ccc(-c3c(-c4ccccn4)nn4c3CCC4)cn12
Temperature: 110 °C
Yield: 82 %

Procedure:
Add 7N ammonia in methanol (10 mL) to a sealed tube containing 6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (Example 35; 0.105 g, 0.28 mmol). Heat at 110° C. for 48 h. Flash chromatograph using dichloromethane/methanol mixtures to give the title compound (0.08 g, 82%) as a white solid. MS ES+ m/e 344.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.4-8.37 (m, 1H), 8.28 (s, 1H), 7.82-7.77 (m, 3H), 7.59 (d, J=9 Hz, 1H), 7.4 (dd, J=9.0, 2.0 Hz, 1H), 7.25 (m, 1H), 4.21 (t, J=7 Hz, 2H), 2.99 (t, J=7, 2H), 2.62 (quintet, 2H, 8 Hz).
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:20][CH:21]=2)=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1c2ccccc2c(-c2ccc(-c3nc4ccccc4o3)cc2)c2ccccc12
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc2cc(-c3c4ccccc4c(-c4ccc(-c5nc6ccccc6o5)cc4)c4ccccc34)ccc2c1
Yield: 92.4 %

Procedure:
In a 50 mL three-neck flask, 0.90 g (2.0 mmol) of 2-[4-(10-bromo-9-anthryl)phenyl]benzoxazole, 0.37 g (2.2 mmol) of 2-naphthaleneboronic acid, 0.45 g (4.2 mmol) of sodium carbonate, 10 mL of toluene, 3 mL of ethanol, and 2 mL of water were placed. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture, 31 mg (0.027 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred under nitrogen stream at 80° C. for 7 hours. After a certain period, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extracted solution and the organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a solid. The solid was purified by silica gel column chromatograghy (toluene:hexane=2:1) and recrystallized with toluene/hexane, giving 0.92 g of the target yellow powder in a yield of 92%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].CO>C(#N)C>[Si:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
4-hydroxybenzaldehyde (8.21 g, 67.2 mmol) was dissolved in acetonitrile (164 ml) in nitrogen atmosphere, and imidazole (6.87 g, 100.8 mmol) was added at room temperature. Tert-butyldimethylsilyl chloride was added under cooling with ice, followed by stirring for 30 minutes. Methanol was added to terminate the reaction, the reaction solution was subjected to filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 4-(tert-butyldimethylsilyloxy)benzaldehyde (15.23 g, 96%) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC(C)([O-])C.[K+].[F:16][CH:17]([F:29])[O:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F>CS(C)=O.ClCCl>[F:16][CH:17]([F:29])[O:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]1=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(OC(F)F)c1
Reactant: COc1ccc[nH]c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cccn(-c2ccc([N+](=O)[O-])cc2OC(F)F)c1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
302 mg (2.41 mmol) of 3-methoxypyridone are dissolved in 8.2 ml of anhydrous dimethyl sulfoxide and admixed with 325 mg (2.89 mmol) of potassium tert-butoxide. After 30 min, 500 mg (2.41 mmol) of 2-(difluoromethoxy)-1-fluoro-4-nitrobenzene are added and the mixture is heated to 80° C. for 20 h. The reaction solution is diluted with dichloromethane and washed with water and 1N hydrochloric acid. After the organic phase has been dried over sodium sulfate, it is filtered and concentrated to dryness under reduced pressure. The residue is dissolved in dimethyl sulfoxide and purified by preparative HPLC with a water/acetonitrile gradient. The product fractions are combined and concentrated to dryness under reduced pressure. This affords 207 mg (28% of theory) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8](O)[CH2:9][N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=1.C(OC(=O)C)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:7](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:14]([F:15])([F:16])[F:17])[N:3]=1
Reactant: O=[N+]([O-])CC(O)c1ccc(C(F)(F)F)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])/C=C/c1ccc(C(F)(F)F)nc1Cl
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-nitroethanol (Int-18) (27 g, 1.0 eq.) in dichloromethane (270 mL) was added 4-dimethylamino pyridine (13.5 g, 1.1 eq.) followed by drop wise addition of acetic anhydride (13.5 g, 1.3 eq) at 0° C. and stirred for 15 min. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched with ice water and extracted with dichloromethane (2×200 mL). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to get crude 2-chloro-3-[(E)-2-nitrovinyl]-6-(trifluoromethyl)pyridine (Int-19) (22.0 g, 87.6%).