Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:16][CH2:15][C:5]2([CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=O)[CH2:4][O:3]1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C.O>[OH:20][N:19]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13][C:5]21[CH2:15][O:16][C:2]([CH3:17])([CH3:1])[O:3][CH2:4]2
Reactant: CC1(C)OCC2(CO1)Cc1ccccc1C2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OCC2(CO1)Cc1ccccc1C2=NO
Reaction time: 12 h
Yield: 93.9 %

Procedure:
A suspension of 1 g of 2,2-dimethylspiro[1,3-dioxane-5,2′-inden]-1′(3′H)-one, 329 mg of hydroxylamine hydrochloride, and 388 mg of sodium acetate in 5 ml of ethanol was stirred for 12 hours. Then, 1.2 ml of triethylamine was added thereto, followed by stirring at room temperature for 3 days and further stirring at 50° C. for 1 hour. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.0 g of N-hydroxy-2,2-dimethylspiro[1,3-dioxane-5,2′-inden]-1′(3′H)-imine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][S:28][C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([S:28][CH3:27])[CH:30]=2)=[N:3][CH:4]=1
Reactant: CSc1cccc(O)c1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: CSc1cccc(Oc2ncc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC(C)(C)C)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 3-(methylthio)phenol (J. Amer. Chem. Soc. 1957, 79, 717): 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=2.7 Hz), 8.13–8.10 (1H, m), 7.97–7.94 (2H, m), 7.41–7.34 (3H, m), 7.20–7.16 (1H, m), 7.03–7.01 (1H, m), 6.93–6.89 (1H, m), 5.41–5.31 (1H, m), 2.50 (3H, s), 1.60–1.57 (12H, m); MS (ESI) m/z 499 (M+H)+, 497 (M−H)−.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[F:35][C:36]1[CH:41]=[C:40]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1cccc(F)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3-fluoro-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.89-1.00 (m, 6H), 1.58 (dt, J=13.39, 6.63 Hz, 1H), 1.78 (ddd, J=13.76, 7.34, 7.03 Hz, 1H), 2.01-2.13 (m, 1H), 3.82 (t, J=7.83 Hz, 1H), 7.05-7.13 (m, 1H), 7.32 (dd, J=10.03, 1.47 Hz, 1H), 7.36-7.47 (m, 2H), 7.52-7.61 (m, 2H), 7.66-7.76 (m, 5H); Calcd for C25H22F4O2 (M+Na) 453.16, Found 453.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:13][CH2:12][C@@H:11]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:39][Si](C)(C)C)(C)C.[Li+].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOCC>[N:14]1([C@@H:11]2[CH2:12][CH2:13][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([NH2:39])[CH:21]=[CH:20][C:5]=4[N:6]=3)[CH2:10]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Brc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Nc1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)sc2c1
Reaction time: 0.08 h

Procedure:
A solution of (R)-6-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 14, 100 mg, 0.273 mmol), tri-tert-butylphosphine (66.3 mg, 0.033 mmol), tris(dibenxylideneacetone)dipalladium(0) (12.5 mg, 0.014 mmol) and lithium bis(trimethylsilyl)amide (63.9 mg, 0.382 mmol) in toluene (1 ml) was heated in a microwave reactor to 160° C. for 30 minutes. The mixture was treated with HCl (1 N, 1 mL) and stirred for 5 minutes. It was then basified with NaOH (10%), diluted with ether and partitioned. The organic was separated, dried with MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel column eluting with 2% (9:1 methanol:concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.43-1.52 (m, 2H), 1.58-1.68 (m, 4H), 1.91-2.07 (m, 1H), 2.20-2.34 (m, 1H), 2.39-2.56 (m, 4H), 2.90-3.05 (m, 1H), 3.39 (t, J=9.12 Hz, 1H), 3.46-3.58 (m, 3H), 3.66-3.76 (m, 1H), 3.82 (dd, J=9.52, 7.54 Hz, 1H), 6.69 (dd, J=8.33, 2.38 Hz, 1H), 6.96 (d, J=1.98 Hz, 1H), 7.39 (d, J=8.33 Hz, 1H); MS (DCI/NH3) m/z 303 (M+H)+.
Reaction SMILES: CC1C=C(C)N=C(NC23N([C:17]4([N:26]5[N:30]=[CH:29][CH:28]=[N:27]5)[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]4[CH:24]=[O:25])C(CC2)CC3)N=1.FC(F)(F)C1N=CC(N[C@@H]2C[C@@H]3N[C@H]2CC3)=NC=1.[CH3:49][C:50]1[CH:55]=[C:54]([CH3:56])[N:53]=[C:52]([NH:57][CH:58]2[CH2:63][CH:62]3[NH:64][CH:59]2[CH2:60][CH2:61]3)[N:51]=1>>[CH3:56][C:54]1[CH:55]=[C:50]([CH3:49])[N:51]=[C:52]([NH:57][CH:58]2[CH2:63][CH:62]3[N:64]([C:24]([C:18]4[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=4[N:26]4[N:30]=[CH:29][CH:28]=[N:27]4)=[O:25])[CH:59]2[CH2:60][CH2:61]3)[N:53]=1
Reactant: Cc1cc(C)nc(NC2CC3CCC2N3)n1
Reactant: Cc1cc(C)nc(NC23CCC(CC2)N3C2(n3nccn3)C=CC(F)=CC2C=O)n1
Agent: FC(F)(F)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2N3)cn1
Product: Cc1cc(C)nc(NC2CC3CCC2N3C(=O)c2cc(F)ccc2-n2nccn2)n1

Procedure:
(±)-(2-(((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-10 and (1S,2R,4R)—N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine with the title compound of step B. MS (ESI) mass calcd. for C21H22FN7O, 407.2; m/z found 408.2 [M+H]+. 1H NMR (CDCl3): 8.23-7.67 (m, 2.5H), 7.54-6.93 (m, 2.5H), 6.40-6.19 (m, 1H), 4.89-4.65 (m, 1H), 4.41-3.66 (m, 2H), 2.39-1.34 (m, 12H).
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3]([F:20])([F:19])[C:4]([F:18])([F:17])[O:5][C:6]([F:16])([F:15])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[CH2:26]([C:35]1[CH:36]=[N:37][C:38]([C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=2)=[N:39][CH:40]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:26]([C:35]1[CH:36]=[N:37][C:38]([C:41]2[CH:42]=[CH:43][C:44]([O:47][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([O:5][C:4]([F:18])([F:17])[C:3]([F:20])([F:19])[C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])([F:16])[F:15])=[CH:45][CH:46]=2)=[N:39][CH:40]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCCBr)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCCCCc1cnc(-c2ccc(OCCCCCOCC(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-(2-(nonafluorobutoxy)-2,2-difluoroethoxy)-pentyl bromide (6.9 g of 91% purity, 13.5 mmol, Example 33) with 5-nonyl-2-(4-hydroxyphenyl)pyrimidine (4.0 g, 13.5 mmol). The resulting crude product was isolated essentially as described in Example 3 and purified by chromatography on silica gel, eluting with 5 vol. % ethyl acetate in hexane, recrystallization from ethanol followed by Kugelrohr distillation (240° C. at 0.4 torr) to provide a yield of 5.6 g.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[F:35])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3](=[O:17])[N:4]([CH3:16])[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:28][C:27]=1[F:35])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(Br)c1=O
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: [Cl-]
Solvent: C1COCCO1
Product: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(OCc3ccccc3)c(F)c2)c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A suspension of 5-bromo-2-(4-fluorophenylamino)-3-methylpyrimidin-4(3H)-one (0.130 g, 0.436 mmol), 4-(benzyloxy)-3-fluorophenylboronic acid (0.129 g, 0.523 mmol), Pd(PPh3)4 (0.025 g, 0.022 mmol) and lithium chloride (0.092 g, 2.18 mmol) in dioxane (1.5 mL) and 2 M aqueous Na2CO3 (1.5 mL) was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude black solid. The crude product was purified by flash column chromatography, eluting with 10:1 dichloromethane/EtOAc. The desired product (0.139 g, 76%) was obtained as a grey-white solid.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:15][CH:14]=1
Reactant: Clc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution prepared by adding 30 g (0.2 mol.) of phthalic anhydride to 122 ml of dried chlorobenzene, was added 64 g (0.48 mol.) of well-ground anhydrous aluminium chloride with stirring. The reaction temperature rose gradually, and the reaction system reached a refluxing condition. The refluxing was continued for 1 hour as the reaction temperature was controlled so that the reaction system refluxed moderately using the ice bath. Then, the reaction product solidified spontaneously. 300 ml of water was added dropwise to the reaction system while cooling by means of an ice bath. The thus produced white precipitate was thoroughly washed with water and cooled ethanol to obtain 45 g of crude crystals. These crude crystals were recrystallized from benzene to obtain the intended compound. Yield 38 g, Melting Point 146° to 148° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[CH2:12]([NH2:17])[CH2:13][CH2:14][CH2:15][CH3:16].[Cl-].[NH4+]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:5]2[CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: CCCCCN
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCNc1nc(Cl)nc2c1CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (410 mg) and pentylamine (1 ml) were stirred at room temperature for 8 hours. The reaction mixture was poured into an aqueous ammonium chloride solution and the solution was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo to give the object compound (296 mg, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][NH2:25])[O:15][C:14]3=[O:26])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C@H:16]([CH2:24][NH:25][S:36]([CH3:39])(=[O:38])=[O:37])[O:15][C:14]3=[O:26])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC[C@@H]1OC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of (4S,5S)-3-(4-(4-chlorophenoxy)phenyl)-5-(aminomethyl)-4-phenyl-oxazolidin-2-one (14 mg, 0.035 mmol) and triethylamine (0.01 mL, 0.07 mmol) in dichloromethane (0.4 mL) at 0° C. was added mesyl chloride (0.005 mL, 0.05 mmol). The reaction mixture was stirred for 10 min and was then quenched with saturated NaHCO3 aqueous solution. Water and dichloromethane was added and the organic was washed with brine, dried (MgSO4), and concentrated. Purification by prep-LC (10-90% Acetonitrile/water (0.05% ammonium acetate) gave 5 mg (31%). 1H NMR (acetone-d6) δ (ppm) 7.45-7.51 (m, 4H), 7.32-7.42 (m, 5H), 6.94-6.97 (m, 4H), 6.66 (t, 1H, J=6.6 Hz), 5.56 (d, 1H, J=5.6 Hz), 4.51, (dd, 1H, J=10.1, 4.7 Hz), 3.59-3.72 (m, 2H), 3.04 (s, 3H). HPLC-MS calculated C23H21ClN2O5S (M+H+): 473.1, found: 473.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:16][C:17](=[O:19])[CH3:18])C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:16][C:17](=[O:19])[CH3:18])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)C=Cc1cccnc1

Procedure:
Pyridine-3-carboxaldehyde (18.9 ml) and 1-triphenylphosphoranylidene-2-propanone (70 g) were heated at reflux in toluene for 2 hr. The solvent was evaporated and the residue was distilled at reduced pressure to give 1-(3-pyridyl)but-1-en-3-one as an oil. Pmr spectrum (CDCl3 ; δ in ppm): 2.41 (3H, s); 6.79 (1H, d); 7.2-8.77 (4H, m); 7.52 (1H, d).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])=[CH:18][CH:17]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Oc2ccc(C#N)c(C#N)c2)cc1
Yield: 106.2 %

Procedure:
A mixture of 4-nitro-phthalonitrile (4.00 g), 4-methoxy-phenol (3.46 g) and potassium carbonate (6.39 g) in acetone (64 ml) was heated to reflux for 2 h. Reaction mixture was cooled and filtered. Filtrate was concentrated and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with NaOH (1 N, 50 ml), water, and then brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the product (6.14 g). 1H NMR (200 MHz, CDCl3) δ 6.70 (d, J=7.8 Hz, 1H), 7.21 (m, 2H), 6.96 (m, 4H), 3.84 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([N:14]=C=O)[C:4]=1[CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH3:2].O.O.[OH-].[Li+]>O1CCOCC1>[NH2:14][C:5]1[C:4]([CH2:17]/[CH:18]=[C:19](\[CH3:26])/[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:3]([CH2:1][CH3:2])[C:11]([CH3:12])=[C:10]2[C:6]=1[C:7](=[O:13])[O:8][CH2:9]2
Reactant: CCc1c(C)c2c(c(N=C=O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g of methyl (E)-6-(1,3-dihydro-6-ethyl-4-isocyanato-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate is dissolved in 50 ml of 1,4-dioxane and treated with 16 ml of water and 2.0 g of lithium hydroxide monohydrate. The mixture is stirred at room temperature for 2 hours and then partitioned between aqueous 1N sodium hydrogen sulfate and ethyl acetate. The organic phase is washed twice with water, once with brine, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure and the residue purified by chromatography on silica gel, to give (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([CH3:16])=[C:14]([C:17]([NH:19][C:20]3[CH:21]=[N:22][C:23]([CH:26]4[CH2:35][CH2:34][C:29]5(OCC[O:30]5)[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[O:18])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([CH3:16])=[C:14]([C:17]([NH:19][C:20]3[CH:21]=[N:22][C:23]([CH:26]4[CH2:35][CH2:34][C:29](=[O:30])[CH2:28][CH2:27]4)=[CH:24][CH:25]=3)=[O:18])[CH:13]=[N:12]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)Nc2ccc(C3CCC4(CC3)OCCO4)nc2)cnn1-c1ccc(C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C3CCC(=O)CC3)nc2)cnn1-c1ccc(C(C)(C)C)cc1

Procedure:
1-(4-tert-Butylphenyl)-N-[6-(1,4-dioxaspiro[4.5]decan-8-yl)pyridin-3-yl]-5-methyl-1H-pyrazole-4-carboxamide (219 mg) trifluoroacetic acid (3 ml) and water (catalytic amounts) were stirred at room temperature overnight. After the reaction, water was added, the mixture was neutralized by the addition of 1N aqueous solution of sodium hydroxide and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated to give 1-(4-tert-butylphenyl)-5-methyl-N-[6-(4-oxocyclohexyl)pyridin-3-yl]-1H-pyrazole-4-carboxamide as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16].[I-].[Na+].[OH:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[C:25]([NH2:30])[C:24]3[N:31]=[C:32]([CH2:37][O:38][CH3:39])[N:33]([CH2:34][CH2:35][CH3:36])[C:23]=3[C:22]=2[CH:21]=1>CC(C)=O>[CH3:39][O:38][CH2:37][C:32]1[N:33]([CH2:34][CH2:35][CH3:36])[C:23]2[C:22]3[CH:21]=[C:20]([O:19][CH2:9][CH2:10][CH:11]4[CH2:15][CH2:14][CH2:13][N:12]4[CH3:16])[CH:29]=[CH:28][C:27]=3[N:26]=[C:25]([NH2:30])[C:24]=2[N:31]=1
Reactant: CN1CCCC1CCCl
Reactant: CCCn1c(COC)nc2c(N)nc3ccc(O)cc3c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CCCn1c(COC)nc2c(N)nc3ccc(OCCC4CCCN4C)cc3c21
Temperature: 25 °C
Yield: 15.1 %

Procedure:
Potassium carbonate (1.48 g, 10.75 mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (483 mg, 2.62 mmol), sodium iodide (100 mg, 0.66 mmol), and 8-hydroxy-2-methoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.75 mmol) were combined in acetone and heated at reflux overnight. Additional 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride and potassium carbonate were added, and the reaction was heated at reflux overnight. The reaction mixture was then cooled to ambient temperature, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on a HORIZON HPFC system (silica cartridge, eluting with a gradient of CMA:chloroform from 0:100 to 25:75) followed by recrystallization from acetonitrile to afford 105 mg of 2-methoxymethyl-8-[2-(1-methylpyrrolidin-2-yl)ethoxy]-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid, mp 155-157° C. Anal. calcd for C22H31N5O2.0.25H2O: C, 65.66; H, 7.90; N, 17.40. Found: C, 65.66; H, 8.24; N, 17.26.
Reaction SMILES: [C:1]([CH2:5][C:6]1[N:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:8]2[S:9][CH:10]=1)([O:3][CH3:4])=[O:2].CN(C)[CH:22]=[O:23].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O.C(N(CC)CC)C>[C:1]([CH2:5][C:6]1[N:7]2[C:13]([CH:22]=[O:23])=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:8]2[S:9][CH:10]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)Cc1csc2cc(-c3ccccc3)cn12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Cc1csc2cc(-c3ccccc3)c(C=O)n12
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of 200 mg. of 3-carbomethoxymethyl-6-phenylpyrrolo[2,1-b] thiazole in 2 ml. of dimethylformamide is cooled to -40°, and 500 mg of a 1:2 mixture of phosphorous oxychloride:dimethylformamide is added. The temperature of the reaction is maintained at -40° C. for 30 minutes, then 2 ml of triethylamine are added and the mixture allowed to warm to room temperature. After 2 hours, 2 ml of 10% sodium hydroxide solution are added; the reaction mixture is diluted with water and extracted four times with ether. The combined ether extracts are diluted with hexane and washed with water. After drying and evaporation, the residue is chromatographed on 10 g of silica gel. Elution with chloroform initially gives 3-carbomethoxy-5-phenylthiacycl[2.2.2]azine as a brilliant yellow material, intensely fluorescent under long wavelength ultra-violet light, which may be crystallized from hexane, m.p. 118°-120°. Continued elution with chloroform affords 3-carbomethoxymethyl-5-formyl-6-phenylpyrrolo[2,1-b] thiazole, δ 3.70(3H), 4.42(2H), 6.40(1H), 6.61(1H), 0.93(1H) ppm. 150 Mg. of this aldehyde is refluxed in 100 ml of tetrahydrofuran with 0.5 ml. of triethylamine, 5 mg. of p-toluenesulfonic acid, and 20 ml of pentamethylsilazane to give an additional amount of 3-carbomethoxy-5-phenylthiacyl[2.2.2] azine.
Reaction SMILES: C(=O)([O-])O.[Na+].CS(C)=O.Cl.[NH2:11][OH:12].[CH2:13]([O:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]4[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=4[C:38]#[N:39])=[N:34][CH:35]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH:47]([CH3:49])[CH3:48])=[N:20][CH:21]=1)[CH3:14]>C(OCC)(=O)C.O>[CH2:13]([O:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]4[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=4[C:38](=[N:11][OH:12])[NH2:39])=[N:34][CH:35]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]=[C:23]2[CH:47]([CH3:49])[CH3:48])=[N:20][CH:21]=1)[CH3:14]
Reactant: NO
Reactant: CCCc1nc(C(C)C)n(-c2ncc(OCC)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C(C)C)n(-c2ncc(OCC)cn2)c(=O)c1Cc1ccc(-c2ccccc2C(N)=NO)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
Process 5: Sodium hydrogen carbonate (1.19 g, 14.1 mmol) was added to dimethyl sulfoxide (15 mL) mixture of hydroxylamine hydrochloride (838 mg, 12.1 mmol) and stirred for 1 hour at 40° C. The reaction mixture was added dimethyl sulfoxide (15 mL) solution of 2-{5-{[1-(5-ethoxypyrimidin-2-yl)-2-isopropyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}benzonitrile (353 mg, 0.71 mmol) and stirred for 18 hours at 90° C. The reaction mixture was added water (80 mL) and ethyl acetate (20 mL) and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with water and ethyl acetate. It was then dried in vacuo to give 2-{5-{[1-(5-ethoxypyrimidin-2-yl)-2-isopropyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}-N′-hydroxybenzimidamide (214 mg, 57%) as a white solid.