Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16](=O)C)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([N:31]3[CH2:35][CH2:34][CH2:33][C:32]3=[O:36])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:19]3[CH2:20][CH2:21][CH:22]([C:25]4[CH:26]=[C:27]([N:31]5[CH2:35][CH2:34][CH2:33][C:32]5=[O:36])[CH:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: O=C1CCCN1c1cccc(C2CCNCC2)c1
Reactant: CCn1c2ccccc2c2cc(C(C)=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCn1c2ccccc2c2cc(CN3CCC(c4cccc(N5CCCC5=O)c4)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Prepared by Scheme R and Procedure F. A solution of 1-(9-ethyl-9H-carbazol-3-yl)ethanone (22.3 mg, 0.100 mmol) and 1-[3-(4-piperidinyl)phenyl]-2-pyrrolidinone (27.2 mg, 0.100 mmol) in 1,2-dichloroethane (1.00 mL) was treated with sodium triacetoxyborohydride (63.6 mg, 0.300 mmol) and HOAc (5.70 uL, 0.100 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was treated with a saturated aqueous NaHCO3 solution (10 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL) and the combined organic layers were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative TLC using 5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 1-(3-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-pyrrolidinone (4.60 mg, 9.43%): 1H NMR (400 MHz, CDCl3) δ 8.04 (d, 1H, J=7.4 Hz), 7.99 (s, 1H), 7.43–7.28 (m, 5H), 6.96 (d, 1H, J=7.4 Hz), 4.31 (q, 2H, J=6.8 Hz), 3.77 (t, 2H, J=7.3 Hz), 3.70 (s, 2H), 3.06 (d, 2H, J=10.6 Hz), 2.56–2.42 (m, 3H), 2.07 (m, 4H), 1.77 (m, 4H), 1.36 (m, 3H) ESMS m/e: 452.5 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.Cl.[CH3:11]N(C)CCCN=C=NCC.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][CH2:31][N:30]2[C:34](OC(C)(C)C)=[O:35])=[C:25]([F:41])[CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:34]([N:30]1[CH2:31][CH2:32][CH2:33][CH:29]1[C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:24][C:25]=1[F:41])(=[O:35])[CH3:11]
Reactant: O=C(O)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1F
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCCC1c1ccc(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
90 mg of pyridine-2-carboxylic acid and 190 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added in order to a pyridine (2 ml) solution of 181 mg of t-butyl 2-(4-amino-2-fluoro-phenyl)-pyrrolidine-1-carboxylate, and the reaction liquid was stirred at room temperature for 3 hours. The reaction liquid was diluted with chloroform, washed with water and saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and 2 ml of 4 N hydrochloric acid-dioxane solution was added to 300 mg of the resulting residue, and the reaction liquid was stirred at room temperature for 1 hour. The reaction liquid was diluted with chloroform, and made basic with aqueous saturated sodium bicarbonate solution added thereto, and the organic layer was washed with saturated saline and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and 0.020 ml of acetic anhydride was added to a pyridine (1 ml) solution of the resulting residue, and the reaction liquid was stirred at room temperature for 20 minutes. The reaction liquid was diluted with chloroform, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: chloroform/methanol=50/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>O1CCCC1>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(Br)cn1
Reactant: Brc1ccccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccccn2)cn1
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
In a 300 mL inner volume flask replaced by nitrogen, tetrahydrofuran solution containing isopropylmagnesium chloride (19.5% by weight, 30.3 g, 57.5 mmol) was charged, and cooled at 10° C., and then, tetrahydrofuran solution (20 g) containing 5-bromo-2-chloropyridine (9.6 g, 50.0 mmol) was added dropwise in the range of 10 to 20° C. for 1.0 hour. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20° C. for 1.5 hours, and then reaction mixture was added dropwise to the solution of tetrahydrofuran (20 g) containing 2-bromopyridine (7.9 g, 50.0 mmol) and [1,1′-bis(diphenylphosphino)propane]nickel dichloride (0.14 g, 0.25 mmol) in the range of 10 to 20° C. for 2.0 hours. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20° C. for 4.0 hours. However, 6-chloro-3,2′-bipyridine could not be obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20]C#N)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(OCC)(=[O:37])C>C(Cl)Cl.O>[CH3:30][S:31]([O:33][CH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)(=[O:37])=[O:32]
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)Cl
Reactant: N#CC[C@@H]1CCCN1c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CCCN1c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-2-(1-(4-(benzyloxy)phenyl)pyrrolidin-2-yl)acetonitrile: To a clear, yellow homogeneous solution of 91A (14 g, 49.5 mmol) at 0° C. in methylene chloride (150 mL) was added triethylamine (13.3 mL, 98.9 mmol) and methanesulfonyl chloride (8.5 g, 74 mmol). The reaction mixture stirred at 0° C. becoming cloudy and orange in color. After 1 h, the reaction mixture was diluted with ethyl acetate and water. The combined organics were washed with 1N HCl, saturated sodium bicarbonate and brine, then were dried over MgSO4 and concentrated to yield (S)-(1-(4-(benzyloxy)phenyl)pyrrolidin-2-yl)methyl methanesulfonate (thick brown oil, 15 g, 41.5 mmol). To the solution of (S)-(1-(4-(benzyloxy)phenyl)pyrrolidin-2-yl)methyl methanesulfonate (15 g, 41.5 mmol) in DMSO (50 mL) was added sodium cyanide (6.1 g, 49 mmol) and the mixture was heated to 50° C. After 4 h, the reaction mixture was diluted with 1000 mL of ethyl acetate and 350 mL of water. The layers were extracted and the organic layer was washed twice with 200 mL of water, then 200 mL of brine. The organic layer was dried over MgSO4, filtered and evaporated to dryness to yield 15 g of an orange solid. The residue was purified silica gel column (60-120 mesh) with dichloromethane as eluent to yield 91B (off-white solid, 5 g, 34% yield). LC-MS Anal. Calc'd for C19H20N2O 292. found [M+H] 293.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.45 (5H, m), 6.91 (2H, d, J=8.80 Hz), 6.60 (2H, d, J=8.80 Hz), 5.03 (2H, s), 3.97 (1H, m), 3.42 (1H, m), 3.04 (1H, m), 2.71 (2H, m), 2.14 (2H, m), 1.9 (2H, m).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22]>ClCCCl.CC(O)(C)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:3]3[N:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Fc1ccc(-c2nc3c(Cl)ncnc3o2)cc1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: Fc1ccc(-c2nc3c(Nc4ccc(F)c(Cl)c4)ncnc3o2)cc1
Temperature: 90 °C
Yield: 82 %

Procedure:
To a solution of 7-chloro-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine (85 mg, 0.34 mmol) in 1,2-dichloroethane/t-BuOH (1:1, 2 ml) was added 3-chloro-4-fluoroaniline (50 mg, 0.34 mmol). The mixture was heated at 90° C. for 1 day. After cooling down to room temperature, the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography (CH2Cl2/MeOH 50:1) to yield the title compound as a white solid (0.1 g, 82%).
Reaction SMILES: [C:1]([Si:5]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[O:6][CH2:7][CH:8]([CH3:41])[O:9][C:10]1[CH:11]=[C:12]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25](OCC)=[O:26])[CH2:22][N:23]=1)=[CH:15]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.CCCCCC>[C:48]([Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[O:6][CH2:7][CH:8]([CH3:41])[O:9][C:10]1[CH:11]=[C:12]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:35][CH:36]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][CH2:25][OH:26])[CH2:22][N:23]=1)=[CH:15]2)([CH3:51])([CH3:49])[CH3:50]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)CO[Si](c4ccccc4)(C(C)(C)C)C(C)(C)C)c3[nH]2)S1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CCO)S3)[nH]c12
Reaction time: 1 h
Yield: 26.1 %

Procedure:
Ethyl (2-{7-(2-{[di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (500 mg) was dissolved in tetrahydrofuran (20 mL), lithium borohydride (21 mg) was added under ice-cooling, and the mixture was stirred for 1 hr. Lithium borohydride (28 mg) was added again to the reaction solution, and the mixture was further stirred at room temperature for 1 hr, and then at 50° C. for 7 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtrated, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=20:80 to 70:30, volume ratio) to give the title compound (123 mg, yield 55%) as a yellow oil. MS 729 (MH+).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4](O)=O.[C:9]1(C)C(C)=CC=CC=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](CC=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>N1CCCCC1.O.C(OCC)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH:4]=[CH:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: Cc1ccccc1C
Solvent: O
Solvent: C1CCNCC1
Solvent: CCOCC
Product: COC(=O)CC=CC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
3.12 g of maleic acid and one drop of piperidine were added to 50 ml of xylene and the resulting mixture was heated under reflux for 30 minutes. After adding 2.27 g of [1-(tert-butoxycarbonyl)piperidin-4-yl]acetaldehyde, the resulting mixture was heated under reflux for 2 hours and 20 minutes while eliminating water with a Dean Stark trap. Then the reaction mixture was distributed into diethyl ether and water, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 150 ml of diethyl ether and treated with a solution of diazomethane in diethyl ether. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.71 g of the title compound as an oily substance.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C@@H:15]([NH:20][CH3:21])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1.[CH3:30][C:31]([CH3:35])=[CH:32]C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:22])[C@@H:15]([N:20]([CH3:36])[CH2:21][CH:30]=[C:31]([CH3:35])[CH3:32])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:7][CH:8]=1
Reactant: CN[C@@H](CC(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)=CC=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)=CCN(C)[C@@H](CC(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-4-Methyl-2-methylamino-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride (0.25 g, 0.59 mmol, Example 12) and 3-methyl-2-butenal (50 mg, 0.59 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (10 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.19 g, 0.88 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Six milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes. The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (50% EtOAc in hexanes), the mixed fractions were combined, concentrated in vacuo, and purified by preparative plate (50% EtOAc in hexanes). The desired product isolated from flash chromatography and preparative plate were combined and further purified by preparative plate (5% acetonitrile in chloroform, developed twice). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 75 mg (28% over 2 steps) of the pure titled compound as a white foam: mp 55-68° C. APCI-MS m/z 456.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25]([OH:27])=O)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1>CN(C)C=O.O1CCCC1>[OH:49][C:46]1[CH:47]=[CH:48][C:43]([NH:42][C:25](=[O:27])[CH2:24][C@@H:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)=[CH:44][CH:45]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Agent: CC(C)(C)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)Nc1ccc(O)cc1)c1nnc(C)n1-2
Temperature: -10 °C
Reaction time: 7.5 h
Yield: 16.8 %

Procedure:
(S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (3.0 g) and triethylamine (1.2 ml) are added to a mixed solvent of dimethylformamide (30 ml) and tetrahydrofuran (15 ml). The mixture is cooled to -10° C., and pivaloyl chloride (1.0 ml) is dropwise added at said temperature. Thirty minutes later, a solution of 4-aminophenol (0.99 g) in dimethylformamide (20 ml) is dropwise added at said temperature, and the mixture is stirred at room temperature for 7.5 hours. After the completion of the reaction, tetrahydrofuran is distilled away, and saturated brine (200 ml) is added. The mixture is extracted with ethyl acetate, and the organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate: methanol=10:1) and crystallized from isopropyl alcohol to give 620 mg of (S)-N-(4-hydroxyphenyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide as pale-pink powdery crystals, melting point 215°-220° C.
Reaction SMILES: Cl[C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[O:17]1CCOCC1.CO>[OH-].[K+].Cl.O>[N+:11]([C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([OH:17])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-:13])=[O:12]
Reactant: NC(=O)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1COCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=O)c1cc(O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 98 %

Procedure:
2 4-Dinitro-5-hydroxybenzamide. A solution of 5-chloro-2,4-dinitrobenzamide (5.50 g, 0.022 mmol) in p-dioxane/methanol (1:1, 120 mL) and 6N aqueous KOH (20 mL) is stirred at room temperature for 2 h. After acidification with concentrated HCl, the mixture is diluted with water and extracted into EtOAc. Workup gives 2,4-dinitro-5-hydroxybenzamide (4.91g, 98%) as yellow cubes. 1H NMR (DMSO) δ8.64 (1H, s), 8.16 (1H, brs), 7.81 (1H, brs), 7.13 (1H, s), 5.80 (1H, brs).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[CH:36]([OH:40])[CH2:37][NH:38][CH3:39].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:38]([CH2:37][CH:36]([C:29]4[C:30]([O:34][CH3:35])=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH3:26])[OH:40])[CH3:39])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1c(OC)cccc1OC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cccc(OC)c1C(O)CN(C)Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1C
Temperature: 60 °C
Reaction time: 7 h
Yield: 52.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (50 mg, 0.13 mmol), 1-(2,6-dimethoxyphenyl)-2-(methylamino)ethanol (PNU-149291, Arch. Intern. Pharmacodyn. 1965, 154, 26-39) (42 mg, 0.20 mmol) and diisopropylethylamine (34 μL, 0.20 mmol) in dry DMF (2.7 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (7 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (39 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:36])[CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3N=CN(C)[CH:22]=3)[S:17][C:10]=12.FC1C=C(NC(=O)CC(NC2C=CC=CC=2OC)=O)C=CC=1OC1C=CN=C2C=[C:52]([C:54]3[N:58]([CH3:59])[CH:57]=NC=3)SC=12.[CH3:75]CCCCCCCCCCCN.FC1C=C(C=CC=1OC1C=CN=C2C=C(C3CCN(C)CC=3)SC=12)N>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:36])[CH2:26][C:27]([N:29]([CH3:75])[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH2:22][CH2:57][N:58]([CH3:59])[CH2:54][CH:52]=3)[S:17][C:10]=12
Reactant: CCCCCCCCCCCCN
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cncn4C)sc23)c(F)c1
Agent: CN1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Product: CN1CC=C(c2cc3nccc(Oc4ccc(NC(=O)CC(=O)N(C)c5ccccc5)cc4F)c3s2)CC1
Yield: 44 %

Procedure:
Following the procedure described above for the compound 5c (scheme 3) but replacing acid 1 with the acid 31 and amine 12 with amine 260; the title compound 256 was obtained in 44% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.31 (s, 1H), 8.44 (d, J=5.48 Hz, 1H), 7.79 (d, 12.72 Hz, 1H), 7.5-7.3 (m, 8H), 6.59 (d, J=5.48 Hz, 1H), 6.38 (t, J=3.52 Hz, 1H), 3.22 (s, 2H), 3.21 (s, 3H), 3.08 (m, 2H), 2.61 (m, 4H), 2.30 (s, 3H). MS (m/z): (M+1) 531.0 (100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[N+]=[N-])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1

Procedure:
To a stirred solution of (±)-trans-4-azido-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10 mmol, 2.42 g) in methanol (25 mL) was added 10% palladium on carbon (0.5 g, wet), and the resultant reaction mixture was subjected to hydrogenation using a balloon full of hydrogen for 8 h. The catalyst was filtered through a pad of celite, and the pad was with methanol (25 mL). The combined filtrate was concentrated under reduced pressure to provide (±)-trans-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccc(F)cc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 39.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.067 g, 0.61 mmol), the title compound (0.023 g, 39%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([N:12]3[CH:16]=[CH:15][C:14]([CH3:17])=[N:13]3)[C:8]=2[CH:18]=1)([O-])=O.C(=O)(O)[O-].[Na+].C(#N)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([N:12]3[CH:16]=[CH:15][C:14]([CH3:17])=[N:13]3)[C:8]=2[CH:18]=1
Reactant: Cc1ccn(-c2nsc3ccc([N+](=O)[O-])cc23)n1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccn(-c2nsc3ccc(N)cc23)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 5-nitro-3-(3-methylpyrazol-1-yl)-1,2-benzisothiazole (3.12 g, 12.0 mmol), sodium bicarbonate (2.00 g, 23.8 mmol), acetonitrile and water is stirred one hour at 70° C. and treated with sodium hydrosulfite (8.70 g, 50.0 mmol) in portions. The resultant mixture is stirred overnight at reflux, cooled to room temperature and diluted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is washed with a mixture of methylene chloride and ethyl acetate. The organic layer is decanted to afford the title compound as a viscous brown oil which is identified by NMR spectral analysis.