Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH:13]1([NH:12][C:8]2[C:6]3[N:7]=[C:2]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]4)[C:5]=3[N:11]=[CH:10][N:9]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NC4CCCCC4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NC4CCCCC4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 123 from 2-chloro-8-cyclohexylamino-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 207°-209° C.) and piperazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH:13]=1)[C:8](O)=[O:9])=[O:4].N.O1CCOCC1.C(Cl)CCl.C1C=CC2N(O)N=[N:38][C:36]=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:36][NH:38][C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:9]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CNC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a solution of 3-(methoxycarbonyl)-5-(5-methylpyridin-2-yl)benzoic acid (1.85 g, 6.82 mmol) in N,N-dimethylformamide (20 mL) was added 2 M ammonia in dioxane (10.2 mL, 20.4 mmol), EDC (2.61 g, 13.6 mmol), HOBT (2.09 g, 13.6 mmol) and N,N-diisopropylethylamine (4.76 mL, 27.3 mmol). After 16 h, the reaction was concentrated and the residue was dissolved in 200 ml of dichloromethane. The mixture was washed with 100 mL of saturated aqueous sodium bicarbonate solution (2×) and brine (100 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1% ethyl acetate/hexane→60% ethyl acetate/hexane) to give the title compound (1.82 g). MS 285.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:17][C:16](=O)[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1.P(Cl)(Cl)([Cl:29])=O.C(=O)(O)[O-].[Na+]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([Cl:29])[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]=2[CH:25]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CCCCCOc1ccc2[nH]c(=O)n(-c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CCCCCOc1ccc2nc(Cl)n(-c3ccccc3)c2c1

Procedure:
3 g of 6-[[1-phenyl-2-oxo-2,3-dihydro-1H-benzoimidazol-6-yl]oxy]hexanoic acid methyl ester was mixed with 12 ml of phosphorus oxychloride, and the mixture was refluxed for 4 hours. After cooling, it was stirred into saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the combined organic phases were dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 1.28 g was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].[CH:25]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26]1>ClCCl.N1C=CC=CC=1>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:29]([CH:25]3[CH2:28][CH2:27][CH2:26]3)=[O:30])[CH:10]=[CH:9][CH:8]=2)[C:4]2([C:24]3[C:15](=[CH:16][C:17]4[O:22][CH2:21][CH2:20][O:19][C:18]=4[CH:23]=3)[O:14][CH2:13]2)[C:5]1=[O:12]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(N)cccc21
Reactant: O=C(Cl)C1CCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(NC(=O)C3CCC3)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
To a solution of 4′-amino-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (700 mg, 1.72 mmol) in dichloromethane (50 mL) and pyridine (5 mL) was added cyclobutanecarbonyl chloride (0.17 mL, 1.48 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 18 h, diluted with dichloromethane (150 mL), washed sequentially with water, 10% w/v hydrochloric acid, water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/3) to afford N-(1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-4′-yl)cyclobutanecarboxamide (0.50 g, 71%): mp 234-236° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.32-7.26 (m, 1H), 7.11-7.08 (m, 1H), 6.94-6.91 (m, 1H), 6.43 (s, 1H), 6.17 (s, 1H), 4.68 (ABq, 2H), 4.13-4.05 (m, 4H), 3.15 (s, 3H), 2.96-2.90 (m, 1H), 2.05-1.64 (m, 6H); 13C NMR (75 MHz, DMSO-d6) δ 176.6, 173.5, 155.1, 144.6, 144.3, 138.3, 134.6, 129.5, 125.3, 120.8, 119.4, 112.0, 106.8, 98.8, 78.2, 64.6, 64.0, 57.1, 27.1, 25.0, 24.9, 17.9; MS (ES+) m/z 406.9 (M+1).
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:23])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.CCOCC>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:23])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1(c2cn(C)c3c(N)cccc23)CCc2cc(F)ccc21
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC1(c2cn(C)c3c(NS(C)(=O)=O)cccc23)CCc2cc(F)ccc21
Yield: 84.8 %

Procedure:
Dissolve 3-(1-ethyl-5-fluoro-indan-1-yl)-1-methyl-1H-indol-7-ylamine (0.18 g, 0.58 mmol) in pyridine (3 ml). Add methanesulfonyl chloride (0.05 ml, 0.70 mmol, 1.20 equivalents) and stir at room temperature under nitrogen overnight. Dilute with ether, wash with 1N aqueous hydrochloric acid (2×), dry over anhydrous sodium sulfate, filter, and concentrate solution in vacuo. Purify the residue on silica eluting with 0 to 100% ethyl acetate/hexanes over 25 minutes to provide the title compound as a white solid (0.19 g, 86%). LC-MS m/z 387.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCO
Product: COc1ccc(CS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
A butanol (5 ml) suspension of sodium 4-chlorobenzenesulfinate (264 mg, 1.33 mmol), 4-methoxybenzyl chloride (181 μl, 1.33 mmol) and tetrabutylammonium bromide (24 mg) was stirred at 70° C. for 3 days. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed successively with water and brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=5:1) eluate was concentrated under reduced pressure, whereby the title compound (90 mg, 23%) was obtained as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:16]2[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[CH:11][CH:10]=[N:9]3)[N:6]=[C:5]([CH:17]=O)[CH:4]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>C(O)C.O>[CH3:1][S:2][C:3]1[C:16]2[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[CH:11][CH:10]=[N:9]3)[N:6]=[C:5]([CH:17]=[N:20][OH:21])[CH:4]=1
Reactant: NO
Reactant: CSc1cc(C=O)nc2c1ccc1cccnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1cc(C=NO)nc2c1ccc1cccnc12
Temperature: 25 °C
Yield: 81 %

Procedure:
To a 25 mL round-bottomed flask containing a solution of 4-methylsulfanyl-[1,10]phenanthroline-2-carbaldehyde (228.0 mg, 1.1 mmol) in ethanol (3.2 mL), a solution of hydroxylamine hydrochloride (707.0 mg, 10.2 mmol) in water (5.0 mL) was added followed by the addition of 10% NaOH until a precipitate was formed. The reaction mixture was heated to 90° for about 30 minutes, cooled to room temperature and the white precipitate was filtered, washed with cold water and dried. White solid (240.0 mg, 100%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[NH:5].C(=O)(O)[O-].[Na+].[CH2:24]([O:26][C:27](=[O:32])[C:28](=[O:31])[CH2:29]Br)[CH3:25]>CC(O)C>[CH2:24]([O:26][C:27]([C:28]1([OH:31])[CH2:29][N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[C:4]([C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Cl:1])=[N:5]1)=[O:32])[CH3:25]
Reactant: N=C(Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)C1(O)CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Temperature: 85 °C

Procedure:
A mixture of 2,4-dichloro-N-(4-chloro-phenyl)-benzamidine I-7a (34 g, 113.5 mmol) and sodium bicarbonate (19.1 g, 227 mmol) in 2-propanol (600 ml) was treated with 3-bromo-2-oxo-propionic acid ethyl ester (20 ml, 158.9 mmol). The reaction mixture was heated to 85° C. overnight, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and water, and the layers were separated. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was triturated with ether/hexanes (1:3), and the yellow solid, 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester I-7b (45 g, 96%), was collected by filtration.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13](=[O:24])[N:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=1)=O)C1C=CC=CC=1>CO.[Pd].O>[NH2:11][C:12]1[C:13](=[O:24])[N:14]([CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([CH3:19])=[C:16]([CH3:18])[CH:17]=1
Reactant: CCCCn1c(C)c(C)cc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCCn1c(C)c(C)cc(N)c1=O
Reaction time: 4 h
Yield: 97.7 %

Procedure:
3-Benzyloxycarbonylamino-1-butyl-5,6-dimethyl-2-pyridone (5-017) (2.487 g) was dissolved in methanol (25 mL), and to the reaction mixture was added a suspension of 10% palladium on carbon (373 mg) in water (2.5 mL), and the reaction mixture was reacted in catalytic reduction under atmospheric pressure. After 4 h, the reaction mixture filtered off on Celite, washed with methanol, and evaporated under reduced pressure to give 3-amino-1-butyl-5,6-dimethyl-2-pyridone (5-004-02) (1.438 g, 97.8%, m.p. 94 to 97° C.) as a brown crystal.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[CH:6]=[C:5]([CH3:11])[C:3]=1[OH:4].OO.C(N(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O)CN(CC([O-])=O)CC([O-])=O.[Na+].[Na+].[Na+].[Na+].[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:9][C:8]1[C:7](=[O:10])[CH:6]=[C:5]([CH3:11])[C:3](=[O:4])[C:2]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CCN(CC(=O)[O-])CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Yield: 85.9 %

Procedure:
A solution of 15.2 g (100 mmol) of 2,3,6-trimethylhydroquinone in 150 ml of acetic acid and a 28.4 g (250 mmol) of 30% by weight aqueous hydrogen peroxide were simultaneously added dropwise to a stirred solution of 0.68 g (2.0 mmol) of iron 5,14-dihydrodibenzo[b,i][5,9,14,18]tetraaza[14]annulene, 2.52 g (2.0 mmol) of a 40% by weight aqueous solution of pentasodium diethylenetriaminepentaacetate and 0.5 ml of concentrated sulfuric acid in 50 ml of acetic acid at 40° C. with cooling. The reaction mixture was then subjected to steam distillation. The distillate was extracted by shaking with methylene chloride. The organic phase was shaken with aqueous sodium bicarbonate solution and then with water, separated from the aqueous phase, dried over magnesium sulfate, filtered and concentrated to a yellow oil, which slowly solidifed. 12.9 g (86%) of 2,3,5-trimethyl-p-benzoquinone were obtained in the form of yellow oily crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.NCC([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=2)[CH2:57][CH2:56]1)=O>CN(C=O)C.O>[O:27]=[C:25]([N:65]1[CH2:66][CH2:67][CH:62]([O:61][C:58]2[CH:59]=[CH:60][N:55]=[CH:56][CH:57]=2)[CH2:63][CH2:64]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: NCC(=O)N1CCC(Oc2ccncc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccncc2)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 34.9 %

Procedure:
DIPEA (540 mg, 4.2 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (344 mg, 1.4 mmol) in DMF (3 mL) followed by HOBt (229 mg, 1.7 mmol) and EDCI.HCl (321 mg, 1.7 mmol). After 2 minutes 2-amino-1-[4-(pyridin-4-yloxy)-piperidin-1-yl]-ethanone hydrochloride (250 mg, 1.4 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using 60-120 silica gel and 5% MeOH in CHCl3 as eluent) afforded 198 mg (% 34.9 Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(pyridin-4-yloxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 406.18, 95.8%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (m, 1H), 8.4 (m, 2H), 8.1 (m, 1H), 7.8 (m, 2H), 7.1 (m, 1H), 7.0 (s, 2H), 4.8 (m, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.8 (m, 1H), 3.4 (m, 1H), 3.3 (m, 1H), 2.0 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([OH:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([OH:45])[CH2:40][CH2:41][N:42]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:30])([F:29])[F:31])[C:9]=5[CH:17]=4)=[CH:19][CH:20]=3)=[O:23])[CH2:43][CH2:44]2)=[CH:35][CH:34]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=640.96 (M+H+); retention time=0.94 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=O.C1COCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:46]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(CCCCS(C)(=O)=O)CCCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Temperature: 62.5 °C
Reaction time: 48 h
Yield: 44.2 %

Procedure:
To a solution of N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]carbonyl]-4-nitro-L-phenylalanine methyl ester (33 mmol, 15 g) in toluene (100 mL, stored over 4 Å molecular sieves) and freshly distilled THF (50 mL) was added Lawesson's reagent (33 mmol, 13.35 g, 1.0 equiv.) at room temperature. The solution was heated to 60-65° C. and was stirred for 48 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and was poured into saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3×150 mL). An oil formed in the aqueous layer, which was separated, diluted with water and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extracts were washed with saturated sodium bicarbonate solution (200 mL), with brine (300 mL), dried (MgSO4), filtered and the solution was concentrated in vacuo. The residual light brown syrup was purified by silica gel column chromatography (hexane:ethyl acetate, 1:1) to obtain 6.87 g (44%) of N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxo-methyl]-4-nitro-L-phenylalanine methyl ester as a fluffy yellow solid. HRMS: Obs. mass, 493.1438. Calcd. mass, 493.1443 (M+Na).
Reaction SMILES: BrCCCC1CCCCCCCCCCC1=O.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[OH:29][CH2:30][CH2:31][CH2:32][CH:33]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=[O:45].Cl>N1C=CC=CC=1>[C:24]1([CH3:25])[CH:26]=[CH:27][C:21]([S:18]([O:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:34]2=[O:45])(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCCCCCCCCC1CCCO
Agent: Cl
Agent: O=C1CCCCCCCCCCC1CCCBr
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC2CCCCCCCCCCC2=O)cc1
Reaction time: 8 h
Yield: 80.5 %

Procedure:
2-(3-Bromo-prop-1-yl)-cyclododecanone used hereinabove as starting material was prepared as follows: (a) 171.5 g (0.90 mole) of tosyl chloride were added under good stirring to a solution of 206.7 g (0.86 mole) of 2-(3-hydroxy-prop-1-yl)-cyclododecanone in 280 ml of pyridine cooled to 0°. After stirring at 0° to 10° for 3 further hours, the reaction mixture was kept overnight at 4°, then poured onto crushed ice and finally acidified with 600 ml of 36% aqueous HCl. After extraction with ether, drying of the organic layer over CaCl2 and evaporation, there were isolated 273 g (81% yield) of 2-(3-p-toluene-sulfonyloxy-prop-1-yl)-cyclododecanone.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([NH:33][C:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:35])=[N:25]1.C(N(CC)CC)C.O>CN(C)C=O>[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([NH:33][C:34]([N:36]2[CH2:41][CH2:40][N:39]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=4)[N:3]=3)[CH2:38][CH2:37]2)=[O:35])=[N:25]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: FC(F)(F)c1ccc(-c2nsc(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccc(C(F)(F)F)cc3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
To a solution of 5-chloro-3-(4-trifluoromethylphenyl)-1,2,4-thiadiazole (147 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 97.0 mg (36.9%) of the desired product.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:14][C:13]=1[CH3:19]
Reactant: N#Cc1cc(F)ccc1F
Reactant: Cc1cc(O)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Temperature: 25 °C
Yield: 99.1 %

Procedure:
In a 5 L flask that had been evacuated and back-filled with Argon, 2,5-difluorobenzonitrile (1092 mL, 3057 mmol) and 4-amino-3-methylphenol (376.5 g, 3057 mmol) were dissolved in dry DMSO (2.75 M) with rapid stirring at ambient temperature. The solution was evacuated/backfilled with Argon. Potassium carbonate (697.2 g, 5044 mmol) was added. The reaction was evacuated/backfilled with Argon and warmed to 81° C. for 14 hours. After cooling to ambient temperature, the reaction was poured slowly into 3 separate beakers, each containing 2.5 L of rapidly stirring ice water to prevent clumping. The residue in the round bottom flask was taken up in water repeatedly and poured into the beakers until a total volume of 3.5 L was realized in each of the three beakers. The suspension was stirred rapidly for 2 hours as it came to ambient temperature. The brown solids were collected by filtration, washed with water (15 L), air dried, dried with latex dam, and dried under high vacuum at 45° C. for 72 hours to provide 734 g (99%) of desired product as a tan solid. MS M+1 (243).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:12][C@@H:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.CCOC(C)=O>CS(C)=O.O>[Br:1][C:2]1[CH:9]=[C:8]([NH:12][C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:18]([NH2:20])=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)C[C@@H](N)C(N)=O
Reactant: N#Cc1ccc(F)cc1Br
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@@H](Nc1ccc(C#N)c(Br)c1)C(N)=O
Yield: 60.3 %

Procedure:
A solution of 2-bromo-4-fluorobenzonitrile (200 mg, 1.00 mmol), D-leucine amide hydrochloride (200 mg, 1.20 mmol) and DIEA (0.620 mL, 3.56 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. EtOAc and water were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silicsa gel column, eluted first with 30% EtOAc in hexane, then with 80% EtOAc to give (R)-2-(3-bromo-4-cyanophenylamino)-4-methylpentanamide (187 mg).