Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20].C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:25]([C:24]2[CH:28]=[CH:29][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)=[O:26])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.0 g), 4-cyanobenzoyl chloride (662 mg), triethylamine (1.67 mL), and tetrahydrofuran (30 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (NH-silica gel, ethyl acetate) to provide the title compound (1200 mg, quant.) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][OH:19])=[O:12])[S:10][C:3]=12.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])=[O:12])[S:10][C:3]=12
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC[C@H]1CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reaction time: 16 h
Yield: 126.5 %

Procedure:
To a stirred solution of 7-chloro-2-[(S)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 3a (4.50 g, 15 mmole) were added t-butyldimethylchlorosilane (3.18 g, 21 mmole) and triethylamine (3.4 ml, 2.47 g, 24 mmole). The resultant reaction mixture was stirred at ambient temperaure for 16 hours. The crude reaction mixture was poured into water (150 ml) and extracted with CH2Cl2 (150 ml). The combined organic extracts were washed with brine (150 ml), dried over Na2SO4 and concentrated, in vacuo, to give 7.8 g of an orange syrup, which was purified by silica gel chromatography. Elution with Et2O:hexane (67:33) and evaporation of the appropriate fractions gave 5.73 g (92%) of an off-white solid. 1H NMR (DMSO-d6): δ8.72 (1H, d, J=5.0 Hz), 8.07 (1H, s), 7.68 (1 H, d, J=5.0 Hz), 4.30-4.15 (1H, m), 3.94-3.67 (4H, m), 2.12-1.81 (4H, m), 0.85 (9H, s), 0.03 (3H, s), 0.00 (3H, s). Anal. Calcd. for C19H27N2O2SClSi: C, 55.52; H, 6.62; N, 6.82; S, 7.80; Cl, 8.63. Found: C, 55.49; H, 6.46; N, 6.92; S, 7.80; Cl, 8.88.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC.O>CN(C=O)C>[Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(O)c1Br
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cccc([N+](=O)[O-])c1Br
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 2-bromo-3-nitro-phenol synthesized above (11.5 mmol, 1.0 eq.) in DMF at room temperature was added cesium carbonate (13.8 mmol, 1.2 eq.), followed by iodomethane (33.7 mmol, 2.9 eq.), and the resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water, stirred for 2 hours, filtered, the cake washed with two portions of water, and the resultant solid dried to afford 2-bromo-3-nitro-anisole (I-9, X═Br, R1═CH3) as a pale orange solid. Yield: 97%; 1H NMR (400 MHz; CDCl3): 3.97 (s, 3H), 7.07 (dd, J=8.4, 1.2 Hz, 1H), 7.32 (dd, J=8.0, 1.6 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H) ppm.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:34])[CH3:33])[NH:27][C:26](=[O:35])[CH2:25]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[CH:29][C:30]([NH:31][C:32](=[O:34])[CH3:33])=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:35])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: CC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(NC(C)=O)c(F)cc43)c(C)c2C1=O
Yield: 32 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-acetamide as starting materials to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-acetamide (38 mg, 32%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:16]#[C:17][C:18]2[CH:19]=[C:20]([C:24]([N:26]=[S@:27]([CH2:35][C:36](OCC)=[O:37])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8].[NH:41]1[CH2:51][CH2:50][CH2:49][CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42]1>>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:16]#[C:17][C:18]2[CH:19]=[C:20]([C:24]([N:26]=[S:27]([CH2:35][C:36]([N:41]3[CH2:51][CH2:50][CH2:49][C@H:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42]3)=[O:37])([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: CCOC(=O)C1CCCNC1
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Product: CCOC(=O)[C@H]1CCCN(C(=O)CS(=O)(=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4occc4C)c3)c2)c2ccccc2)C1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl (N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and ethyl nipecotate were reacted to give the title compound
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:33]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(O)C.O1CCOCC1>[N:13]1([C@H:11]2[CH2:12][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:29]5[CH:30]=[N:31][N:32]([C:34]([C:41]6[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=6)([C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)[CH:33]=5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:10]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Brc1ccc2nc([C@H]3C[C@H](N4CCCCC4)C3)sc2c1
Reactant: CC1(C)OB(c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc4nc([C@H]5C[C@H](N6CCCCC6)C5)sc4c3)cn2)cc1

Procedure:
The product of Example 44A (120 mg, 0.34 mmole), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-trityl-1H-pyrazole (224 mg, 0.51 mmole), dichlorobis-(triphenylphosphine)palladium(II) (14.0 mg, 0.020 mmole), 2-(dicyclohexyl-phosphino)biphenyl (7.0 mg, 0.020 mmole), sodium carbonate (1 M solution, 0.51 ml, 0.51 mmole) and 1.5 ml of ethanol/dioxane (1:1) were combined under N2 in a capped, sealed vial. The vial was sealed and was placed a commercial (i.e. Emrys Creator) microwave for 10 minutes at 140° C. The reaction mixture was quenched with water and extracted with dichloromethane (4×5 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the crude product which was purified by column chromatography (1% ammonium hydroxide and 10% methanol in dichloromethane) to give 138.1 mg (70% yield) of title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.99 (s, 1H), 7.89 (d, J=8.31 Hz, 1H), 7.88 (d, J=2.03 Hz, 1H), 7.68 (s, 1H), 7.53 (dd, J=8.31, 1.87 Hz, 1H), 7.52-7.35 (m, 9H), 7.19-7.23 (m, 6H), 3.93 (m, 1H) 3.42 (m, 1H) 2.61-2.73 (m, 2H) 2.26-2.52 (m, 4H) 1.73-1.90 (m, 4H) 1.43-1.58 (m, 4H). MS: (M+H)+=581.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32].O>O1CCCC1>[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:25](=[O:27])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
Solid carbonyldiimidazole (79.10 g, 0.488 mol) was added to a room temperature solution of N-benzyloxycarbonyl-glycine (117.11 g, 0.560 mol) in anhydrous tetrahydrofuran (THF, 600 mL). The resulting solution was stirred for 45 minutes until C02 evolution had ceased. A solution of L-phenylalanine methyl ester (79.65 g, 0.444 mol) in anhydrous THF (~200 mL) was then added. The reaction temperature was maintained below 40° C. by application of a water bath to the exterior of the reaction vessel. After two hours, a small portion of water (1.5 mL, ~0.08 mol) was added to the reaction mixture to hydrolyze any remaining acylimidazolides and the resulting solution was left to stir overnight. The reaction mixture was concentrated in vacuo and the residual oil was dissolved in ethyl acetate (~1 L). This ethyl acetate solution was extracted with 1 N HCI (2×300 mL--the first aqueous extract was acidified to a pH of 1 by addition of 6 N HCl), water (300 mL), saturated aqueous sodium carbonate (300 mL), half-saturated aqueous sodium carbonate (250 mL), and brine (250 mL). The organic phase was dried by filtration through magnesium sulfate and sodium sulfate and concentrated in vacuo to constant weight. Field desorption mass spectrometry (FDMS) of the resulting oil (160.88 g, ~0.434 mol, 98%) indicated the presence of a single component (M+=370). This material was not further purified, but was instead converted directly into cyclo-glycyl-L-phenylalanine (8) by catalytic hydrogenation (vide infra).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:12][CH2:13][NH2:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][C:19](Cl)=O.CCN(CC)CC.O=P(Cl)(Cl)Cl.[BH4-].[Na+]>C(Cl)Cl.C1C=CC=CC=1.CCO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[CH2:12][CH2:13][N:14]4[CH:16]([CH2:17][CH2:18][CH2:19]4)[C:7]=3[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCBr
Reactant: Cn1cc(CCN)c2ccc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c2c(c3ccc(Br)cc31)CCN1CCCC21
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
To a solution of 2-(6-bromo-1-methyl-1H-indol-3-yl)ethanamine (6.50 g, 25.7 mmol) in CH2Cl2 (50 mL) were added 4-bromobutyryl chloride (4.50 mL, 38.6 mmol) and NEt3 (7.20 mL, 51.4 mmol). After 2 h, the reaction mixture was diluted with CH2Cl2 and filtered through a layer of Celite. The filtrate was concentrated to give a brown oil. The oil was diluted with benzene (120 mL) and treated with POCl3 (12 mL, 0.13 mol). The reaction mixture was heated at reflux for 1 h. After the mixture was concentrated, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give the crude product (6.1 g) as a brown oil. The oil was diluted with EtOH and cooled to 0° C. NaBH4 (0.60 g, 16 mmol) was added, and the reaction was stirred from 0° C. to room temperature for 1 h. After the solution was concentrated, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give the title compound (1.66 g, 34% in three steps) as a yellow foam: 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J=1.5 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.23 (dd, J=8.4, 1.5 Hz, 1H), 4.79 (t, J=6.6 Hz, 1H), 3.63 (s, 3H), 3.44-3.25 (m, 3H), 3.16-3.10 (m, 1H), 2.99-2.96 (m, 2H), 2.70-2.61 (m, 1H), 2.26-1.96 (m, 3H); ESI MS m/z 305 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][CH2:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.S(Cl)([Cl:38])=O.O>C(Cl)(Cl)Cl>[Cl:38][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][CH2:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CCC3)cc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.2 %

Procedure:
To a solution of N-(4-hydroxymethylphenyl)-2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (10.0 g, 26.1 mmol) and pyridine (0.1 ml) in chloroform (150 ml) was dropwise added a solution of thionyl chloride (3.4 ml, 39.2 mmol)in chloroform (90 ml), and the mixture was stirred under nitrogen atmosphere at room temperature for 17 hours. After the reaction completed, water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the resulting powder was washed with hexane to give N-(4-chloromethylphenyl)-2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (10.2 g, 97%) as colorless powder.
Reaction SMILES: [CH:1]1([C:7]([N:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=3[O:27][CH3:28])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.O.NN>[Ni+2].CO>[CH:1]1([C:7]([N:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[O:27][CH3:28])[CH2:14][CH2:13]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccn2)CC1
Agent: [Ni+2]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture consisting of 1.70 g of compound of Example 5, 18 mL of tetrahydrofurane, 18 mL of methanol, 50 mg of Nichel-Raney and 1 mL of hydrazine hydrate was stirred for 2 h, at room temperature, followed by the addition of 1 mL of hydrazine hydrate, and stirred for 1 h, at a temperature of 50° C. The catalyst was then filtered out, and the recovered solution was evaporated to dryness, affording the crude product, which was then purified by flash chromatography (ethyl acetate—3 N solution of ammonia, in methanol; 95:5). Subsequent evaporation of the solvents afforded 1.33 g of the title compound (yield 84%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C@@H:12]([NH:16][C:17](=[O:41])[CH:18]([CH2:30][S:31]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:33])=[O:32])[CH2:19][S:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:22])=[O:21])[CH2:13][CH2:14][CH3:15])[OH:11].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C@@H:12]([NH:16][C:17](=[O:41])[CH:18]([CH2:30][S:31]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)(=[O:32])=[O:33])[CH2:19][S:20]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:21])[CH2:13][CH2:14][CH3:15])=[O:11]
Reactant: CCC[C@H](NC(=O)C(CS(=O)(=O)Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)C(O)c1nc2ccccc2o1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC[C@H](NC(=O)C(CS(=O)(=O)Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)C(=O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A solution of N-[(S)-1-(1-Benzooxazol-2-yl-1-hydroxy-methyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide (0.140 g, 0.234 mmol) in methylene chloride (5 mL) was treated with 1,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (0.127 g, 0.30 mmol.) and the resulting solution was stirred at room temperature for 30 minutes. Aqueous sodium thiosulfate and sodium bicarbonate (15 mL, 0.25 M) were added and the reaction mixture was stirred for 20 minutes. The product was extracted with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was crystallized from t-butylmethyl ether to give N-[(S)-1-(1-benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide (0.103 g, 74%); NMR (DMSO): 9.15 (d, J=6 Hz, 1H); 8.01 (d, J=7 Hz, 1H); 7.89 (d, J=8 Hz, 1H); 7.65 (t, J=7 Hz, 1H); 7.54 (t, J=8 Hz, 1H); 7.37 (m, 10H); 5.36 (m, 1H); 4.5 (m, 4H); 3.68 (m, 1H); 3.45–3.25 (m, 4H); 1.95 (m, 1H); 1.73 (m, 1H); 1.47 (m, 2H); 0.91 (t, J=7 Hz, 3H); MS: M(H+) 597.0 (596.17);
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].CO.[CH3:11][C:12]1[C:16]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)[N:20]=[C:19]([CH3:30])[C:18]=2[C:31]#[N:32])=[C:15]([CH3:33])[O:14][N:13]=1>O.[Cl-].[Na+].O.CCOC(C)=O>[NH2:13][OH:14].[CH3:11][C:12]1[C:16]([C:17]2[N:21]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)[N:20]=[C:19]([CH3:30])[C:18]=2[C:31](=[N:2][OH:3])[NH2:32])=[C:15]([CH3:33])[O:14][N:13]=1
Reactant: COc1ccc(-n2nc(C)c(C#N)c2-c2c(C)noc2C)cc1
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn(-c2ccc(O)cc2)c(-c2c(C)noc2C)c1C(N)=NO
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A hydroxylamine solution was prepared. Hydroxylamine-HCl (26 mg, 0.37 mmol) and NaHCO3 (32 mg, 0.37 mmol) dissolved in water (0.2 mL), methanol (0.4 mL) was stirred 2 min until gas ceased to evolve, the mixture was filtered and degassed (N2). This was added to the 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (11 mg, 0.037 mmol) and stirred at 130° C. for 30 min in the microwave. EtOAc and brine were added and the phases were separated. Purification using preparative HPLC gave E1 5-(3,5-dimethylisoxazol-4-yl)-N′-hydroxy-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carboximidamide (2.52 mg, 7.71 μmol, 21%) ES/MS m/z: 328.19 (M+H), 326.22 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.10 m 2H, 6.84 m 2H, 2.36 s 3H, 2.10 s 3H, 1.89 s 3H. Starting material 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile was recovered (0.99 mg, 3.36 μmol) as well as E2 5-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carboxamide (3.22 mg, 0.01 mmol) ES/MS m/z: 313.17 (M+H), 311.22 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.10 m 2H, 6.85 m 2H, 2.47 s 3H, 2.12 s 3H, 1.95 s 3H. Identification of Example 6 by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH:28]=1>>[C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:15])=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCOc2ccccc2C(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCOc2ccccc2C(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O
Yield: 77 %

Procedure:
The reaction of 0.83 g of 2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]benzoic acid with 0.38 g (0.0026 mol) of 3-pyridine butanamine according to Example 40 gave 0.88 g, mp 77°-80°, (77% yield) of 2-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10]C)[CH:3]=1.C[S-].[Na+].Cl>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(O)cc(Br)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
Commercially available 1-bromo-3,5-dimethoxybenzene (18.74 g, 86.3 mmol) was dissolved in 1-methyl-2-pyrrolidone (100 mL), and sodium thiomethoxide (6.74 g, 96.2 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, 1N hydrochloric acid (200 mL) was added, and extraction was carried out with diethyl ether (500 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-25%) to afford the desired compound (15.03 g, yield 86%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([Br:12])[CH:6]=2.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[CH2:31]([O:30][C:28]([NH:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([Br:12])[CH:6]=2)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1nc2cc(Br)ncc2cc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2cc(Br)ncc2cc1NC(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 59.6 %

Procedure:
To a solution of ethyl 3-amino-7-bromo-1,6-naphthyridine-2-carboxylate (47 mg, 0.16 mmol) and DIPEA (83 μL, 0.48 mmol) in DCM (1.5 mL), a solution of benzyl chloroformate (68 μL, 0.48 mmol) was added and the resulting mixture was heated at 60° C. in a sealed vial for 14 h. The crude reaction mixture was then concentrated under reduced pressure and the residue was purified by flash chromatography (24 g silica gel column, eluting with 0-60% EtOAc/hexanes) to afford the sub-title compound (41 mg, 60%). LCMS (ESI) calc. for C19H17BrN3O4[M+H]+: m/z=430.0. found: 429.9.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:17]([F:20])([F:19])[F:18])=[C:7]([NH:9]C(=O)OC(C)(C)C)[CH:8]=1.[F:21][C:22]([F:30])([F:29])[C:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C=O)C>[NH2:9][C:7]1[CH:8]=[C:3]([CH:4]=[CH:5][C:6]=1[C:17]([F:18])([F:19])[F:20])[CH2:2][NH:1][C:26]([C:23]1([C:22]([F:30])([F:29])[F:21])[CH2:25][CH2:24]1)=[O:27]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(CN)ccc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1C(F)(F)F

Procedure:
The compound was prepared in analogy to the procedures in Example 94, step (c) and Example 94, step (b) using tert-butyl 5-aminomethyl-2-trifluoromethyl-phenylcarbamate (2.09 g; 7.20 mmol), 1-trifluoromethyl-cyclopropanecarboxylic acid (1.11 g; 7.20 mmol), HBTU (2.73 g; 7.20 mmol), TEA (2.19 g; 21.6 mmol), DMF (25 mL), TFA (10 mL) and DCM (50 mL). Yield: 1.8 g (77%).