Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[OH:9]/[N:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][N:19]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:14][CH:13]=1>CN(C)C=O.O>[Cl:1]/[C:11](/[C:12]1[CH:13]=[CH:14][C:15]([CH:18]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:21][CH2:20][N:19]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:16][CH:17]=1)=[N:10]\[OH:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(/C=N/O)cc2)C1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(c2ccc(/C(Cl)=N/O)cc2)C1
Temperature: 55 °C
Yield: 100 %

Procedure:
N-chlorosuccinimide (239.0 mg, 1.790 mmol) was added to a stirred suspension of (E)-di-tert-butyl 2-(4-((hydroxyimino)methyl)phenyl)piperazine-1,4-dicarboxylate (725.8 mg, 1.790 mmol) in N,N-dimethyl formamide (10 mL). The reaction was then heated at 55° C. for 1 hour. The reaction was cooled to ambient temperature and diluted with water. The reaction mixture was extracted with ethyl acetate (×3). Organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo. The sub-titled compound was used directly in the next step without further purification. (787.5 mg, assume 100% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][C@@H:5]([C@@H:7]2[CH2:9][N:8]2[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][O:3]1.[F:18][C:19]1[CH:20]=[C:21]([Mg]Br)[CH:22]=[C:23]([F:25])[CH:24]=1>C1COCC1.CSC.[Cu](Br)Br>[F:18][C:19]1[CH:20]=[C:21]([CH2:9][C@H:7]([NH:8][C:10](=[O:11])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C@H:5]2[CH2:4][O:3][C:2]([CH3:1])([CH3:17])[O:6]2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H]1[C@H]1COC(C)(C)O1
Agent: Br[Cu]Br
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1COC(C)(C)O1
Reaction time: 8 h

Procedure:
BOC-Aziridine (21), copper bromide-dimethyl sulfide (0.15 eq.), and THF were cooled to −20° and (3,5-difluorophenyl)magnesium bromide (1.25 eq.) in THF was added. The reaction was allowed to warm to 200 and stir overnight. The reaction was extracted and the solvent removed to afford the crude product (26) as a syrup.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)=[CH:11][CH:10]=1>CCO.[Pd]>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)=[CH:13][CH:14]=1
Reactant: FC(F)(F)c1ccccc1-c1ccc(C#Cc2ccc3[nH]ccc3c2)cc1
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1ccc(CCc2ccc3[nH]ccc3c2)cc1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A suspension of the product of Step B (0.25 g, 0.7 mmol) and 10% Pd/C (0.1 g) in EtOH (10 ml) was stirred overnight under H2. The mixture was filtered through Celite bead and the filtrate was evaporated to dryness to give the desired product (0.25 g, 98%) as pale paste. 1H-NMR (CDCl3) 2.97-3.1 (m, 4H); 6.5 (m, 1H); 7.04 (dd, 1H, J=1.37, 8.3 Hz), 7.15-7.2 (m, 2H); 7.30-7.34 (m, 2H); 7.37-7.44 (m, 2H); 7.51 (d, 1H, J=7.56 Hz); 8.68 (broad s, 1H).
Reaction SMILES: [Na].[C:2]([S:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=O)[CH3:3].[N+:13](CCOC(=O)C)([O-:15])=[O:14]>C(O)C>[N+:13]([CH2:3][CH2:2][S:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]1)([O-:15])=[O:14]
Reactant: CC(=O)OCC[N+](=O)[O-]
Reactant: CC(=O)SC1CCCCCC1
Agent: [Na]
Solvent: CCO
Product: O=[N+]([O-])CCSC1C=CCCCC1
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To 40 ml of absolute ethanol was added 1.38 g (.060 gram atom) metallic sodium. When the reaction was completed 10.2 g ( b .060 mole) of 3-acetylmercaptocycloheptane in 20 ml of absolute ethanol was added and the reaction mixture was brought up to reflux for 15 minutes. The solution was then cooled to 0° and 7.98 g (.060 mole) of 1-nitro-2-acetoxyethane in 20 ml absolute ethanol was added. The reaction was allowed to proceed for 3.0 hours at 0° and then was partitioned between lN HC1 and methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic phases were pooled, dried over sodium sulfate, and evaporated to afford 12 g (99%) of pure 3-[2-nitroethylthio]cycloheptene as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7](C)=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].[C:18](OC)(=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30].C(SCCCCCCCCCC(NC1C=CC=CC=1SCCCC(OCC)=O)=O)(C)C>>[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:32])([OH:31])=[O:30]
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Reactant: CCOC(=O)CCCSc1cccc(C)c1N
Agent: CCOC(=O)CCCSc1ccccc1NC(=O)CCCCCCCCCSC(C)C
Product: O=C(O)CCCCCCCCCCC(=O)Nc1ccccc1SCCCC(=O)O

Procedure:
When amine (11) is acylated with acid chloride (7) as per procedure Step (E), and the resultant diester (ethyl 4-(2-(11-carbomethoxyundecanoylamino)phenylthio)butyrate 12 is hydrolyzed in Step I as per procedure (F), the title compound, 13 m.p. 113.5-115° C. is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7]C.[C:15](=S)=[S:16]>ClCC(Cl)(Cl)Cl>[OH:7][CH2:6][CH2:5][N:4]1[CH2:3][CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1][C:15]1=[S:16]
Reactant: COCCNCC(N)c1ccccc1
Reactant: S=C=S
Agent: ClCC(Cl)(Cl)Cl
Product: OCCN1CC(c2ccccc2)NC1=S
Temperature: 120 °C

Procedure:
The methoxyethylamine product of Example IV in the amount of 4.5 g is dissolved in 20 ml of tetrachloroethane, and is stirred with 2 ml carbon disulfide at room temperature for one hour. The resulting slurry is then slowly heated to 120° C. and maintained at that temperature for four hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[CH2:13]2)=[CH:6][C:7]=1[Br:24]
Reactant: CN1C(=O)CC(c2ccc(N)cc2)CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN1C(=O)CC(c2ccc(N)c(Br)c2)CC1=O
Yield: 67 %

Procedure:
A solution of 289 mg (1.32 mmol) of 4-(4-amino-phenyl)-1-methyl-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (15 mL) was treated portionwise with 224 mg (1.29 mmol) of solid NBS for 20 min. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (2×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc-hexane afforded 265 mg (67%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C12H13N2O2Br, 297.0/299.0 (M+H). found 297.0/299.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([NH2:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([NH2:21])=[O:20])[CH:16]=[CH:17][CH:18]=3)[N:14]=2)=[CH:8][CH:9]=1
Reactant: NC(=O)c1cccc2oc(-c3ccc([N+](=O)[O-])cc3)nc12
Agent: [Ni]
Solvent: CO
Product: NC(=O)c1cccc2oc(-c3ccc(N)cc3)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.8 %

Procedure:
To a mixture of 2-(4-nitrophenyl)benzo[d]oxazole-4-carboxamide (800 mg, 2.83 mmol) in methanol (30 mL) was added Raney Ni (2 g), the mixture was purged into hydrogen and stirred at room temperature for 5 hr. The mixture was filtered, washed with methanol, the filtrate was evaporated under reduced pressure to obtain a solid, purified by silica gel chromatography to give 2-(4-aminophenyl)benzo[d]oxazole-4-carboxamide as a yellow solid (450 mg, yield 63%). 1H-NMR (400 MHz, DMSO-d6) δ 6.16 (s, 2H), 6.69-6.72 (d, J=9.2 Hz, 2H), 7.38-7.42 (t, J=8 Hz, 1H), 7.85-7.96 (m, 5H), 8.54 (s, 1H); LC-MS (ESI) m/z 254 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([OH:24])[CH2:19][C:20]([O:22]C)=[O:21])[C:13](=[O:25])[C@@H:12]1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([OH:24])[CH2:19][C:20]([OH:22])=[O:21])[C:13](=[O:25])[C@@H:12]1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@H](O)CN1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1=O
Agent: [Li+]
Agent: [OH-]
Product: C[C@H]1C(=O)N(C[C@@H](O)CC(=O)O)CCN1C(=O)OCc1ccccc1
Yield: 81 %

Procedure:
In analogy to the procedure described in Example 23B, (S)-4-((S)-2-hydroxy-3-methoxycarbonyl-propyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester and 1 M aq. lithium hydroxide solution gave after extraction with EtOAc and precipitation (dichloromethane/n-pentane) the titled compound in 81% yield as light yellow waxy solid. MS: 351.15 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]([C:25]4[N:26]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[Cl:40])[N:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=4)=[CH:23][CH:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(CC(O)=O)(F)F>ClCCl>[Cl:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[N:26]1[C:25]([C:22]2[S:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[N:15][CH:16]=3)=[CH:24][CH:23]=2)=[CH:29][C:28]([C:30]([F:33])([F:31])[F:32])=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(-c4cc(C(F)(F)F)nn4-c4ccccc4Cl)s3)cn2)CC1
Agent: O=C(O)CC(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(-c2ccc(-c3ccc(N4CCNCC4)nc3)s2)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
4-(5-{5-[2-(2-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-thiophen-2-yl}-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (196 mg, 0.33 mmol) was mixed with 4 mL 50% trifluoromethylacetic acid in dichloromethane, and stirred at room temperature for 2 hrs. All solvent was removed; the residue was redissolved in dichloromethane and neutralized to pH 7 by saturated NaHCO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a solid that was washed several times with dichloromethane to give yellow solid (75 mg, 47% yield). 1H-NMR (400 MHz, CDCl3): δ 3.32-329 (m, 4H), 3.94-3.91 (m, 4H), 6.67 (d, J=8.8, 1H), 6.79 (d, J=3.8, 1H), 6.87 (s, 1H), 7.02 (d, J=3.8, 1H), 7.57-7.45 (m, 4H), 7.63 (dd, J=8.8, J=2.5, 1H), 8.34 (d, J=2.2, 1H). MS (ES) 490.3, 492.3, [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH2:12][Br:13])=[CH:10][C:5]=2[S:4](=[O:15])[CH2:3]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][Br:13])=[CH:10][C:5]=2[S:4](=[O:15])[CH2:3]1
Reactant: CN1CS(=O)c2cc(C(=O)CBr)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN1CS(=O)c2cc(CCBr)ccc21

Procedure:
In a 500-cm3 ground-necked flask surmounted by a condenser and placed in an oil bath, 42.9 g (0.15 mol) of 3-methyl-6-(bromoacetyl)benzothiazolinone are dissolved in 77 cm3 of trifluoroacetic acid with magnetic stirring and while the temperature is stabilized at 60° C. 52.7 cm3 (0.33 mol) of triethylsilane are introduced dropwise via a dropping funnel. After the addition, the heating is stopped and the mixture is left stirring vigorously for 30 hours. The reaction medium is hydrolyzed by pouring it into ice-cold water, and the precipitate obtained is drained and washed with water until the filtrate is neutral and then with hexane. The product is dried and recrystallized in cyclohexane.
Reaction SMILES: [OH-].[K+].[S:3]([C:7]1[S:15][C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:9]=2[CH:8]=1)(=[O:6])(=[O:5])[NH2:4].Cl.C(=O)([O-])[O-].[Na+].[Na+]>O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[S:3]([C:7]1[S:15][C:10]2=[CH:11][N:12]=[CH:13][CH:14]=[C:9]2[CH:8]=1)(=[O:5])(=[O:6])[NH2:4]
Reactant: NS(=O)(=O)c1cc2c(s1)CNCC2
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Product: NS(=O)(=O)c1cc2ccncc2s1
Temperature: 80 °C
Yield: 34.9 %

Procedure:
To a solution of potassium ferricyanide (76 g, 0.23 mol) in water (400 ml) was added a solution of potassium hydroxide (68 g, 0.113 mol) in water (150 ml), followed by a suspension of 2-sulfamoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (10.8 g, 49.5 mmol) in water (50 ml). This mixture was warmed at 80° C. for 4-6 hours. This solution was acidified with concentrated hydrochloric acid and then made basic with saturated sodium carbonate solution. The product was extracted from this solution with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered through a pad of charcoal and evaporated to give 5.5 g of crude product. This material was chromatographed on silica gel and eluted with ethyl acetate to give 3.7 g (34.9% yield) of pure product; m.p. 191°-193° C.
Reaction SMILES: Cl.[CH:2]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([NH2:19])[C:7]=2[N:6]=1)([CH3:4])[CH3:3].[NH:20]1[CH2:25][CH2:24]N[CH2:22][C@@H:21]1[CH2:26][CH2:27][OH:28]>>[CH:2]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([N:19]3[CH2:24][CH2:25][NH:20][C@@H:21]([CH2:26][CH2:27][OH:28])[CH2:22]3)[C:7]=2[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Reactant: OCC[C@H]1CNCCN1
Agent: Cl
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCO)C1

Procedure:
In a manner such as that described in Example 300, combine 2-isopropyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.558 g, 1.89 mmol) and (S)-2-piperazin-2-yl-ethanol (0.493 g, 3.79 mmol) to obtain the title compound: mass spectrum (APCI): m/z=372.4 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]1[N:12]=[C:11]([CH2:13][O:14][C:15]2[CH:32]=[CH:31][C:18]([CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[CH:17][CH:16]=2)[O:10][N:9]=1.[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[S:42](Cl)(=[O:44])=[O:43]>>[NH:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[S:42]([N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]1[N:12]=[C:11]([CH2:13][O:14][C:15]2[CH:32]=[CH:31][C:18]([CH2:19][N:20]3[C:21](=[O:30])[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]3=[O:29])=[CH:17][CH:16]=2)[O:10][N:9]=1)(=[O:43])=[O:44]
Reactant: O=S(=O)(Cl)c1nc2ccccc2[nH]1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3)no2)cc1
Agent: Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2nc([C@@H]3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1

Procedure:
The title compound was prepared by a similar method to Example 1 from 2-[4-(3-[(2S)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione hydrochloride [see Preparation 15] and 1H-benzo[d]imidazole-2-sulfonyl chloride [see Preparation 8] to afford 2-[4-(3-[(2S)-1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-1,3-isoindolinedione (956 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])=[C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:32]([F:35])([F:33])[F:34])[CH:24]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: COC(=O)c1cccc(CSc2ccc(Cl)cc2N)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 65.3 %

Procedure:
Following General Procedure B, the title compound (1.65 g, 65%) was prepared from methyl 3-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (1.41 g, 4.59 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.28 g, 4.59 mmol) in pyridine (10 ml).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[C:21]([C:29]1[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32])(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br:38][C:36]1[CH:37]=[C:29]2[C:30](=[CH:34][CH:35]=1)[C:31](=[O:32])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:4]([C:3](=[O:2])[CH2:17][CH2:18][CH2:19][CH3:20])=[C:21]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: Cl
Product: CCCCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1

Procedure:
In the same manner as in Example 452, Step 2, the title compound was synthesized from 4-[(2-hydroxyhexylamino)methyl]benzenesulfonamide hydrochloride and 2-benzoyl-4-bromobenzoic acid.
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[CH2:7][O:6][S:5](=[O:9])(=[O:8])[O:4]1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+:28].[K+]>C(#N)C>[K+:28].[Cl:1][CH2:2][C@H:3]([O:4][S:5](=[O:9])(=[O:8])[O-:6])[CH2:7][NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])=[CH:15][CH:16]=1
Reactant: O=S1(=O)OC[C@H](CCl)O1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1COCCN1c1ccc(NC[C@H](CCl)OS(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 126.1 %

Procedure:
Under an atmosphere of nitrogen to a solution of a 7.11 g of (R)-4-chloromethyl-[1,3,2]dioxathiolane 2,2-dioxide (MW=156.59; 1.38 eq.) in 95 mL of acetonitrile were added 6.34 g of 4-(4-aminophenyl)-morpholin-3-one (APMO) (MW=192.22; 1 eq.) and 3.29 g (MW=138.21; 0.72 eq.) of potassium carbonate. The reaction mixture was stirred for 24 h at room temperature. Then the resulting suspension was cooled to 0° C. After stirring for at least 2 h at this temperature, the product was isolated by filtration and the filter cake was washed with 50 mL of acetonitrile. After drying in vacuo at 30° C., 12.09 g of the crystalline title compound (MW=402.90) were isolated. Yield=91.0%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(=O)([O-])[O-].[K+].[K+].[Si:16]([O:23][CH2:24][CH2:25]Br)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C)C=O>[Si:16]([O:23][CH2:24][CH2:25][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: OCc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccccc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-hydroxybenzyl alcohol (0.4 g) and potassium carbonate (0.67 g) in N,N-dimethylformamide (6 mL) was added 2-(tert-butyldimethylsilyloxy)ethyl bromide (1.05 mL), and the mixture was stirred at room temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:59]1([CH3:67])[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][NH2:66])[CH:60]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:66][CH2:65][C:61]3[CH:62]=[CH:63][CH:64]=[C:59]([CH3:67])[CH:60]=3)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: Cc1cccc(CN)c1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(CNC(=O)C2CCN(C(=O)c3cc4ccccc4n3Cc3ccc(Cl)cc3)CC2)c1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (393 mg, 0.990 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (237 mg, 1.23 mmol), and 1-Hydroxybenzotriazole (167 mg, 1.23 mmol) were dissolved in 2.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (216 μL, 1.059 mmol) and m-tolylmethanamine (100 mg, 0.83 mmol) were added as a 1.0 mL DCM solution. The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with 1N HCl followed by saturated sodium bicarbonate then saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was triturated with methanol and filtered under vacuum to obtain pure product as a white solid. Yield: 190 mg (White solid)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:24][CH:25]([CH3:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:24][CH:25]([CH3:31])[CH2:26][S:27]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])(=[O:29])=[O:28]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a white solid in analogy to example 3 from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione, product of example 1 step D), and 2-methyl-propane-1-sulfonyl chloride. MS (ESI): 466.1 (M+NH4)+.
Reaction SMILES: CON(C)[C:4]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.C1COCC1>[F:10][C:9]([F:12])([F:11])[C:6]1([CH:4]=[O:5])[CH2:8][CH2:7]1
Reactant: CON(C)C(=O)C1(C(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=CC1(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 38.6 %

Procedure:
To a solution of N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (0.23 g, 1.162 mmol) in diethyl ether (3 mL, aldrich) at 0° C. under Ar(g) was added lithium aluminium hydride (1.0 M solution in THF; 1.39 mL, 1.39 mmol, aldrich) dropwise. After completed addition the reaction was then stirred at 0° C. for 45 min. The reaction was quenched with a solution of KHSO4 (1M) at −78° C. and gradually warmed to RT and stirred for 30 min. The reaction was extracted with diethyl ether (2×10 mL). The combined organic extracts were dried over MgSO4, concentrated, and dried in vacuo to afford 62 mg of the title compound as a light yellow liquid, which was used in the next step without further purification. 1H NMR (CHLOROFORM-d) δ: 9.69 (s, 1H), 1.43 (m, 2H), 1.21 (t, J=7.0 Hz, 2H)
Reaction SMILES: C(O[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.CO[C:16]([C:18]#CC(OC)=O)=O>[N+](C1C=CC=CC=1)([O-])=O>[CH:16]1[C:8]2[C:9](=[CH:12][CH:13]=[CH:6][CH:7]=2)[CH:10]=[CH:11][CH:18]=1
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc2ccccc2c1
Yield: 142.9 %

Procedure:
p-t-butoxy styrene 35.25 g (0.2 mol) and acetylene dicarboxylic acid dimethyl ester 56.84 g (0.4 mol) were dissolved in nitrobenzene, 200 ml, and then reacted at the temperature of 140° C. for 5 hours. After cooling, nitro benzene was removed under a reduced pressure, silica gel column chromatography (developing solvent n-hexane:acetic acid ethyl=9:1) was performed to the residual, thus 40.78 g crude material was obtained. Further, 36.63 g (yield 57.9%) objective naphthalene compounds were obtained by recrystallizing through diisopropyl ether. Melt points were 82.0-83.0° C. This naphthalene compound's infrared absorption spectrum is indicated in FIG. 4.