Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:13])([CH3:12])[CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:12][C:3]([NH2:2])([CH3:13])[CH2:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(N)Cc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(N)Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.6 %

Procedure:
A solution of 4-(2-amino-2-methylpropyl)aniline hydrochloride salt (1.0 g, 4.98 mmol) in anhydrous DMF (30 mL) was treated with benzenesulfonyl chloride (880 mg, 4.98 mmol). The solution was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue was washed twice with hexane. The insoluble material was dissolved in water and extracted twice with ethyl ether to remove any remaining neutral impurities. The aqueous layer was separated and basified with excess 1N sodium hydroxide. Upon standing, a crystalline solid soon precipitated. The solid was collected, and dried under vacuum at 60° C. to provide 570 mg (38%) of the desired product as a white crystalline solid. Mp 180-181° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>O1CCCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][CH:29]=[C:20]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=2)[CH:21]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
4-Methoxy-3-nitrobenzoic acid (5.0 g, 25 mmol) was added to thionyl chloride (20 mL) under an inert atmosphere and stirred and heated to reflux. After 2 hours the mixture was stripped to dryness by rotary evaporator, and 2 portions of benzene were successively mixed with then stripped from the residue to leave a solid. This residue was dissolved in tetrahydrofuran (20 mL) and added dropwise to a stirred solution of methyl 3-aminobenzoate (3.83 g, 25 mmol) and pyridine (2 mL) cooled in an icebath. The mixture was allowed to warm to room temperature following the addition, then the solvent was removed under reduced pressure. The residue was suspended in 1N HCl, stirred, filtered off, and washed successively with 1N HCl, 1N NaHCO3 (2×), and water (2×). The resulting solid was boiled briefly in methanol (500 mL) then allowed to cool. Filtration afforded the product (8.0 g); m.p. 233-235° C., in sufficient purity for the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>[Pd]>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:7]=[N:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)Oc1ccc(-c2cncc(Cl)n2)cc1
Agent: [Pd]
Product: O=Cc1ccc(-c2cncc(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of the product of step 1 with 4-formylphenyl boronic acid: 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 9.07 (s, 1H), 9.03 (s, 1H), 8.33 (d, J=8.1 Hz, 2H), 8.21 (d, J=8.7 Hz, 2H), 8.07 (d, J=7.6 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H); EIMS m/z 344 (M+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si](OCCO[C:40]1[N:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[N:46]=[C:45](CC)[CH:44]=[C:43]2OCC1C=CC(C2C=CC=CC=2C2N=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)N=2)=CC=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[N:41]1[C:42]2[C:47](=[N:46][CH:45]=[CH:44][CH:43]=2)[CH:48]=[CH:49][CH:40]=1
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: c1cnc2cccnc2c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 550.3 %

Procedure:
A 1M solution of tetrabutylammonium fluoride in THF (14 ml) was added to a solution of compound E (1.1 g) in THF (10 ml) and the mixture was stirred for 2 hours. The solution was then warmed to 40° C. for 10 minutes. Volatile material was removed by evaporation and the residual oil was dissolved in ethyl acetate (75 ml) and washed with water (75 ml and 30 ml). The precipitated solid was collected by filtration to give 2-ethyl-6-hydroxy-4-[(2'-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)-methoxy]-1,5-naphthyridine (F) (0.83 g) as a white solid, m.p. 148°-149° C.; NMR (d6 -DMSO): 1.2(t,3H), 2.7(q,2H), 5.3(s,2H), 6.65-7.9(m,26H), 11.1(s,1H).
Reaction SMILES: [CH3:1][N:2]([C@H:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])[C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][C:6]([OH:8])=O.Cl.CN.C[CH2:42][N:43](C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([C@H:32]([CH3:37])[C:33]([O:35][CH3:36])=[O:34])[C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][C:6]([NH:43][CH3:42])=[O:8]
Reactant: COC(=O)[C@@H](C)N(C)C(=O)C(CC(=O)O)c1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)CC(C(=O)N(C)[C@H](C)C(=O)OC)c1ccc(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
A solution of methyl 2-{N-methyl-N-[(R/S)-α-hydroxycarbonylmethyl-4-(3,5-bistrifluoromethylbenzyloxy)phenylacetyl]amino}-(R)-propionate 48f (0.3 g, 0.56 mmol), methylamine hydrochloride (68 mg, 1 mmol) and DIEA (0.35 mL, 2 mmol) in DMF (5 mL) was cooled in an ice bath and to it was added BOP (265 mg, 0.6 mmol). After stirring at room temperature for 1 hour, EtOAc was added and the solution was washed with NaHCO3 and brine, dried over MgSO4, and concentrated to give the amide (312 mg, 100%) as a solid. MS (ESI): (M+Na)+=571.8.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:29]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc3oc(-c4ccc(OC)c([N+](=O)[O-])c4)nc3c2)c1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-methoxyphenylboronic acid (131 mg, 0.86 mmol) the subtitle compound was obtained, (98 mg, 45%). 1H NMR (DMSO) δ 8.71(d, 1H), 8.52(dd, 1H), 8.35(t, 1H), 8.17(d, 1H), 7.93(d, 1H), 7.82(dd, 1H), 7.69(d, 1H), 7.48(t, 1H), 7.36(m, 2H), 7.03(dd, 1H), 4.12(s, 3H), 3.90(s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:11][O:10]2)=[CH:4][CH:3]=1.C(O)(=O)C(O)=[O:14].O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:14])[CH2:11][OH:10])=[CH:6][CH:7]=1
Reactant: Brc1ccc(CC2CO2)cc1
Reactant: O=C(O)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: OCC(O)Cc1ccc(Br)cc1

Procedure:
A mixture of 90 parts of 2-(4-bromophenylmethyl)oxirane, 8 parts of ethanedioic acid, 100 parts of water and 300 parts of 1,4-dioxane is stirred and refluxed overnight. The reaction mixture is evaporated. The residue is dissolved in trichloromethane. The solution is washed with 110 parts of a sodium hydroxide solution 10%, dried, filtered and evaporated. The residue is distilled (bp. 165° C. at 0.6 mm. pressure). The distillate is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 25 parts of 3-(4-bromophenyl)-1,2-propanediol; mp. 60.6° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][C:11]#[N:12])[CH2:3][CH2:2]1.[CH2:13](N)[CH2:14][NH2:15]>>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][C:11]2[NH:12][CH2:13][CH2:14][N:15]=2)[CH2:3][CH2:2]1
Reactant: NCCN
Reactant: N#CCc1ccccc1C1CC1
Product: c1ccc(C2CC2)c(CC2=NCCN2)c1

Procedure:
2-(2-Cyclopropyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-cyclopropyl-phenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): light brown powder; MS (ISP): 201.4 ((M+H)+.).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH2:20][C:21]([N:23]2[CH2:28][C@H:27]([CH3:29])[N:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:25][C@H:24]2[CH3:38])=[O:22])=[N:6][CH:5]=1.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([O:19][CH2:20][C:21]([N:23]2[CH2:28][C@H:27]([CH3:29])[N:26]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:25][C@H:24]2[CH3:38])=[O:22])=[C:12]([CH:17]=1)[O:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(COc2cc(Cl)ccc2OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.3 %

Procedure:
To a solution of 6-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenoxymethyl)-nicotinic acid methyl ester (0.13 g, 0.23 mmol) in 2:2:1 tetrahydrofuran:methanol:H2O (2 mL) was added lithium hydroxide hydrate (0.020 g, 0.48 mmol). The reaction was stirred at ambient temperature for 3 hours, the pH was then adjusted to 4 with 0.2 M hydrochloric acid. The solution was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration in diethyl ether provided the title compound (0.034 g, LRMS: 542.4, 544.5).
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][C:5]([NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:6].O.Cl>CO>[Cl:3][CH2:4][C:5]([NH:7][C@@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[OH:18])=[O:6]
Reactant: O=C(CCl)NC1CCc2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(CCl)N[C@@H]1CCc2ccccc2[C@H]1O
Yield: 100 %

Procedure:
Sodium borohydride (0.93 g, 24.6 mmol) was added to a solution of 2-chloro-N-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (2.9 μg, 12.2 mmol) in methanol (30 ml). When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and pH was adjusted to 5-6 with 3N aqueous hydrochloric acid. The solution was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-((1RS,2RS)-trans-1-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-acetamide (2.92 g, 12.2 mmol, 100%) as white crystals.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[C:10]3[NH:14][C:13](=O)[NH:12][C:11]=3[CH:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:32]>>[Cl:32][C:13]1[NH:14][C:10]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:16][C:11]=2[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(N2CCOCC2)cc2[nH]c(=O)[nH]c12
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1cc(N2CCOCC2)cc2nc(Cl)[nH]c12
Temperature: 103 °C
Yield: 23 %

Procedure:
To a solution of combined batches of methyl 6-(4-morpholinyl)-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (6.8 g, 24.5 mmol) in POCl3 (25 mL) was added N,N-Dimethylaniline (8.8 g, 73.5 mmol) and the mixture was heated to 103° C. for 12 h. When TLC analysis showed no starting material remaining, the mixture was cooled to room temperature, purified by chromatography (eluted with petroleum ether/EtOAc=1/1) on silica to afford the desired product as a off-white solid (1.6 g, 23%). 1H NMR (300 MHz, DMSO-d6): δ ppm 3.11 (t, 4H, J=4.5 Hz), 3.77 (t, 4H, J=4.5 Hz), 3.93 (s, 3H), 7.43 (d, 1H, J=1.8 Hz), 7.50 (d, 1H, J=1.8 Hz), 12.97 (s, 1H). LC-MS: m/e=296 [M+1]+.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][CH:49]=1>CN(C=O)C.O>[N:1]([C:4]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH:52][C:51]1[CH:53]=[CH:54][C:48]([F:47])=[CH:49][CH:50]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)O
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=Nc1cc(Br)ccc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
To a stirred solution of compound (xi) (15 g, 61.98 mmol) in DMF (150 mL) was added HATU (28.28 g, 74.34 mmol) at 0° C. The reaction mixture was stirred for 15 min and DIPEA (16.01 mL, 92.26 mmol) was added followed by 4-fluoroaniline (7.57 g, 68.68 mmol) at the same temperature. The reaction mixture was allowed to warm to RT and stirring was continued for 16 h. The reaction was then poured into cold water (500 mL) and stirred for 15 min. The solid was filtered and washed with water (3×100 mL) and dried (Na2SO4) to give 2-azido-4-bromo-N-(4-fluorophenyl)-benzamide (xii) (19 g, 91%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C1COCC1.CCCCCC>[OH:17][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([F:11])([F:10])[F:9])[CH2:22][CH2:21][CH2:20][N:19]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1(O)c1ccccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromo-2-(trifluoromethyl)benzene (0.27 mL, 2.0 mmol) in THF (5 mL) at −78° C. was added nBuLi (0.72 mL of a 2.8 M solution in Hexane, 2.0 mmol). The reaction was stirred at −78° C. for 15 minutes then added to a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (0.33 mL, 2.0 mmol) in THF (5 mL) at −78° C. The reaction was stirred to room temperature over 1 hour, quenched with saturated aqueous ammonium chloride and diluted with EtOAc. The organic layer was separated, dried over magnesium sulfate, filtered and reduced to dryness to afford tert-butyl 2-hydroxy-2-(2-(trifluoromethyl)phenyl)pyrrolidine-1-carboxylate (I-27) as a clear oil. MS m/z 276.1 (M−55)+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[N+:19]([O-:21])=[O:20])[CH:14]=[C:13]([F:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl.C(O)(C)C>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([CH2:17][CH2:18][N+:19]([O-:21])=[O:20])[CH:14]=[C:13]([F:22])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])/C=C/c1cc(F)cc(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])CCc1cc(F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.3 %

Procedure:
Add sodium borohydride (1.69 g, 44.64 mmol) to 1-benzyloxy-3-fluoro-5-((E)-2-nitro-vinyl)-benzene (3.05 g, 11.16 mmol) and silica gel (22 g) in chloroform (112 mL) and isopropanol (33 mL) at room temperature in portions over 5 minutes. Stir at room temperature 90 minutes and filter. Concentrate and dissolve in ethyl acetate. Wash (10% potassium carbonate and saturated aqueous sodium chloride), dry over magnesium sulfate, filter and concentrate. Purify on 120 g silica gel eluting with 100:0 to 80:20 hexanes:ethyl acetate to afford 1.33 g (43.3%) of the desired compound as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH3:20][O:21][C:22]([NH:24][C:25](=NC(OC)=O)SC)=[O:23].CC(O)=O>CO.[Pd]>[CH3:1][N:2]1[C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=3)[CH:14]=[CH:15][C:16]=2[N:17]=[C:25]1[NH:24][C:22](=[O:23])[O:21][CH3:20]
Reactant: CNc1cc(Oc2ccc(N)cc2)ccc1[N+](=O)[O-]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc(Oc3ccc(N)cc3)cc2n1C
Temperature: 85 °C
Reaction time: 5.5 h
Yield: 84.7 %

Procedure:
After hydrogenation of 4-(3-methylamino-4-nitrophenoxy)aniline (Intermediate 8G-519.2 mg, 2.0 mmol) with 5% Pd—C in MeOH (20 mL), 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.03 g, 5.0 mmol) and AcOH (2.0 mL) was added then stirred at 85° C. for 5.5 hrs. After cooling, the mixture was added 2N HClaq. (25 mL) then stirred at 65° C. for 2 hrs. The mixture was passed through celite pad to remove catalyst and the solvent was removed by evaporation. The residue was extracted with ethyl acetate. The organic layer was washed with NH4OH(aq). and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (529.1 mg, 85%): MS m/e 313 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13](=O)[CH2:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[NH2:24][C:25]1[C:29]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:28][NH:27][N:26]=1>>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[N:26]3[N:27]=[CH:28][C:29]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)=[C:25]3[N:24]=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1n[nH]cc1-c1ccncc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1C(F)(F)F
Yield: 34.9 %

Procedure:
Reaction of 1-(3,4-bis-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (176 mg, 0.5 mmol), prepared from commercially available 3,4-bis-trifluoromethyl-acetophenone [CAS No. 129604-25-7] according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (83 mg, 35%). Yellow solid. MS (ISP) 477.2 [(M+H)+]; mp 209° C.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C1(=O)O[CH2:16][CH2:15][O:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:16][CH2:15][OH:14])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(O)cc1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCCO)cc1
Temperature: 0 °C

Procedure:
4-(1-Methylpropoxy)phenol (6.92 g, 41.6 mmol), ethylene carbonate (7.34 g, 83.2 mmol) and DMF (456 ml) are mixed under N2. With stirring, the mixture is degassed (3X) by alternate application of vacuum and N2. Potassium carbonate (11.51 g, 83. 2 mmol) is then added, under N2, and the mixture is heated at 90° for 27 hours. The reaction mixture is then poured into ice water and 10 ml of 40% potassium carbonate solution is added to increase the pH to 13. The aqueous phase is extracted with ether (3X) and the organic layers are washed with 40% KOH, the water until neutral and with brine, dried, filtered and the solvent evaporated to give 2-[4-(1-methylpropoxy)phenoxy]ethanol.
Reaction SMILES: Cl.C(=[N:15][C:16]1[CH:17]=[C:18]([C:22]2([CH3:32])[N:27]=[C:26]([NH2:28])[CH2:25][N:24]3[N:29]=[CH:30][CH:31]=[C:23]23)[CH:19]=[CH:20][CH:21]=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>O.C(O)(C)C>[NH2:15][C:16]1[CH:17]=[C:18]([C:22]2([CH3:32])[N:27]=[C:26]([NH2:28])[CH2:25][N:24]3[N:29]=[CH:30][CH:31]=[C:23]23)[CH:19]=[CH:20][CH:21]=1
Reactant: CC1(c2cccc(N=C(c3ccccc3)c3ccccc3)c2)N=C(N)Cn2nccc21
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: O
Product: CC1(c2cccc(N)c2)N=C(N)Cn2nccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
Hydrochloric acid 37% in H2O (0.14 mL) was added to a solution of rac-4-[3-(benzhydrylidene-amino)-phenyl]-4-methyl-4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-ylamine (0.37 g, 0.9 mmol) in isopropanol (10 mL). The mixture was stirred at room temperature for 3 hours. Et2O was added and the mixture was stirred for 15 minutes. The solid precipitated was filtered, washed with Et2O and dried in vacuo. The residue was suspended in DCM and washed with NaHCO3 (aq. sat. solution). The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield (0.21 g, 97% yield) as a white solid which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+:15]>C1COCC1>[N+:1]([C:4]1[C:5]([N+:11]([O-:13])=[O:12])=[C:6]([O-:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Na+:15]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc([O-])c1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
The anhydrous dinitrophenol (10.0 g, 54.3 mmol) was dissolved in anhydrous THF (300 mL) and then NaH(1.30 g, 54.3 mmol) was added slowly. After the solution was stirred for 3 hrs, solvent was removed under the reduced pressure to obtain 100 mol % sodium dinitrophenolate.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[N:6]=[C:5]([C:12]([O:14]CC)=O)[CH:4]=1)[CH3:2].CO.[OH-].[NH4+:20]>>[CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[N:6]=[C:5]([C:12]([NH2:20])=[O:14])[CH:4]=1)[CH3:2]
Reactant: CCCCn1nc(C(=O)OCC)cc1CC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1nc(C(N)=O)cc1CC
Temperature: 25 °C

Procedure:
Ethyl 5-ethyl-1-butyl-1H-pyrazole-3-carboxylate (13.27 g, 59.2 mmol) in concentrated ammonium hydroxide (50 mL) was heated at 125° C. for 14 hours in a pressure vessel. After the vessel was allowed to cool to ambient temperature, methanol (40 mL) was added and the vessel was heated at 125° C. for 1 day. After cooling to ambient temperature, the vessel was cooled in an ice bath and the product began to crystallize from the reaction mixture. Two crops of crystals were isolated to provide 5.50 g of 5-ethyl-1-butyl-1H-pyrazole-3-carboxamide as off-white crystals, mp 60-61° C. MS (APCI) m/z 196.1 (M+H)+; Anal. calcd for C10H17N3O: C, 61.51; H, 8.78; N, 21.52.