Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Cl:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].FC(Br)C1C=CC=CC=1.C1(C(Cl)=O)CCC1>>[Cl:10][CH2:11][CH2:12][CH2:13][C:14](=[O:15])[CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: Clc1ccccc1CBr
Reactant: O=C(Cl)CCCCl
Agent: FC(Br)c1ccccc1
Agent: O=C(Cl)C1CCC1
Product: O=C(CCCCl)Cc1ccccc1Cl
Yield: 79 %

Procedure:
Following a procedure similar to that described in Preparation 13, except that equivalent amounts of 2-chlorobenzyl bromide and 4-chlorobutyryl chloride were used in place of the 2 fluorobenzyl bromide and cyclobutanecarbonyl chloride, the title compound was obtained as a yellow oil in a yield of 79%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[S:31][CH2:30][CH2:29][NH:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:28]1[CH2:29][CH2:30][S:31][CH:26]([CH3:25])[CH2:27]1)=[O:24])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: CC1CNCCS1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC1CN(C(=O)c2ccc(C(=O)NCc3nc4cc(Cl)ccc4[nH]3)cc2Cl)CCS1

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 2-methylthiomorpholine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.78 minutes; C21H20C12N4O2S (463.39); mass spectrum: (M+H)+=463.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C1([O:21][C:22]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:22]([O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: Brc1ccc(OC2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
2.7 g (7.58 mmol) of 4-[(4-bromophenyl)-oxy]piperidine, prepared in Step 4.2, and 1.70 g (7.6 mmol) of ethyl {[(phenyloxy)carbonyl]oxy}acetate, prepared in accordance with Example 1.1, are mixed in 40 ml of toluene and the solution is heated at 50° C. for 20 hours. After cooling, it is evaporated to dryness and the product is purified by chromatography on silica gel, eluting with a 40/60 mixture of ethyl acetate and cyclohexane. The eluate is subsequently triturated in diisopropyl ether, to give 2.9 g of product in powder form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[NH:5][CH2:6][CH3:7].C(O[C:16](=[O:18])[CH3:17])(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[N:5]([CH2:6][CH3:7])[C:16](=[O:18])[CH3:17]
Reactant: CCNc1ccc(F)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCN(C(C)=O)c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84461.5 %

Procedure:
A solution of 3-chloro-N-ethyl-4-fluoroaniline (97.4 g, 0.56 mmol) in glacial acetic acid (225 ml) is treated at 5° with acetic anhydride (105 ml, 1.12 mol). The solution is stirred for one hour, then poured on to ice/water (250 ml) and extracted with ethyl acetate (2×200 ml). The combined phases are washed in succession with water (100 ml), 2N sodium hydroxide solution (100 ml), saturated sodium bicarbonate solution (100 ml), water (10 ml) and 10 percent sodium chloride solution (100 ml). The solution is dried over magnesium sulfate and evaporated. The residue is recrystallized from n-hexane. There are obtained 102 g (84.2%) of 3'-chloro-N-ethyl-4'-fluoroacetanilide.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH3:48])=[CH:41][CH:40]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>O.C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH3:48])=[CH:41][CH:40]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCOc1ccc(-n2c(C)nc(CCC)c(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-n2c(C)nc(CCC)c(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2=O)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.32 g), sodium hydrogen carbonate (1.92 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-6-oxo-1-(4-propoxyphenyl)-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.91 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.73 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:21][C:20](=[O:22])[CH2:19][CH2:18][N:17]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:15])[CH3:12])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>CO.O>[OH:22][CH:20]1[CH2:19][CH2:18][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:16]([C:14](=[O:15])[NH:13][C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH3:12])[CH2:21]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(=O)CCN2C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(O)CCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
To an ice cooled solution of (R)-tert-butyl 2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-4-oxopiperidine-1-carboxylate (D60) (300 mg, 0.75 mmol) in MeOH (25 ml) under nitrogen, NaBH4 (142 mg, 3.75 mmol) was added portionwise and the resulting mixture was stirred at RT for 18 hrs. The mixture was diluted with water (10 ml) and extracted with EtOAc (3×10 ml). The organic phases were collected, washed with NaCl sat. (20 ml) dried over Na2SO4 and evaporated in vacuo to afford the title compound (D61) (261 mg).
Reaction SMILES: ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH3:14][C:15]1[CH:20]=C(NC)[CH:18]=[CH:17][C:16]=1/[CH:23]=[CH:24]/[S:25]([N:28]1[CH2:49][CH2:48][C:31]2([N:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]([F:46])([F:45])[F:44])[CH:37]=3)[NH:33][C:32]2=[O:47])[CH2:30][CH2:29]1)(=[O:27])=[O:26].[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH2:54].C[C:57]([N:59]([CH3:61])[CH3:60])=[O:58]>C1COCC1>[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH:54][C:57](=[O:58])[N:59]([CH3:61])[C:60]1[CH:18]=[CH:17][C:16](/[CH:23]=[CH:24]/[S:25]([N:28]2[CH2:29][CH2:30][C:31]3([N:35]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([O:42][C:43]([F:45])([F:44])[F:46])[CH:37]=4)[NH:33][C:32]3=[O:47])[CH2:48][CH2:49]2)(=[O:26])=[O:27])=[C:15]([CH3:20])[CH:14]=1
Reactant: CC(=O)N(C)C
Reactant: CNc1ccc(/C=C/S(=O)(=O)N2CCC3(CC2)N=C(c2cccc(OC(F)(F)F)c2)NC3=O)c(C)c1
Reactant: CN(C)CCN
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: Cc1cc(N(C)C(=O)NCCN(C)C)ccc1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(OC(F)(F)F)c1)NC2=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
4-Nitrophenyl chloroformate (35 mg, 0.17 mmol) was added to a solution of 8-[(E)-2-(2-methyl-4-methylamino-phenyl)-ethenesulfonyl]-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (80 mg, 0.15 mmol) in THF (1 ml) at room temperature, and the mixture was then stirred at 70° C. for 30 minutes. The reaction mixture was extracted with AcOEt, and then dried over sodium sulfate and concentrated under reduced pressure. The resulting intermediate (83a) (20 mg, 0.029 mmol) was dissolved in DMA (0.1 ml), and N,N-dimethylethylenediamine (0.1 ml, 0.91 mmol) was added. The mixture was then stirred at 140° C. for one hour and at 100° C. for one hour. The resulting reaction mixture was purified by silica gel column chromatography to give 3-(2-dimethylamino-ethyl)-1-methyl-1-(3-methyl-4-{(E)-2-[4-oxo-2-(3-trifluoromethoxy-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-urea as an amorphous (12 mg, yield 66%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:29]=[C:28]([C:30]2[C:39]3[C:40]4[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=4[S:42][C:38]=3[C:37]([Br:47])=[C:36]3[C:31]=2[CH:32]=[CH:33][CH:34]=[CH:35]3)[CH:27]=[C:26]([Br:48])[C:15]=1[O:16][C@H:17]([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].BrC[C:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[CH:53][CH:52]=1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[C:21]([O:20][C:18](=[O:19])[CH:17]([O:16][C:15]1[C:26]([Br:48])=[CH:27][C:28]([C:30]2[C:39]3[C:40]4[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=4[S:42][C:38]=3[C:37]([Br:47])=[C:36]3[C:31]=2[CH:32]=[CH:33][CH:34]=[CH:35]3)=[CH:29][C:14]=1[Br:13])[CH2:25][C:53]1[CH:52]=[CH:51][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C[C@@H](Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)OC(C)(C)C
Reactant: BrCc1cccc2ccccc12
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C(Cc1ccc2ccccc2c1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Temperature: -74 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
Diisopropylamine (distilled over CaH2, 0.233 mL, 1.78 mmol) was added to anhydrous tetrahydrofuran (0.91 mL) and cooled to -74° C. under a dry argon atmosphere. n-Butyllithium (2.5 M in hexane, 0.71 mL, 1.78 mmole) was added dropwise and the mixture was warmed to 0° C. for ca. 20 minutes then recooled to -75° C. Hexamethylphosphoramide (2 mL) was added followed 10 minutes later by the slow (0.5 hour) dropwise addition of a solution of (R)-2-[2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-propionic acid, tert-butyl ester (1.004 g, 1.48 mmole) in anhydrous tetrahydrofuran (3 mL). After stirring one hour at -75° C., 2 bromomethylnaphthalene (0.393 g, 1.78 mmol) was added dropwise. After stirring 0.5 hour at -80° C. the reaction mixture was allowed warm to room temperature overnight. The reaction mixture was quenched with dilute aqueous ammonium chloride and was partritioned between water (100 mL) and a 1:1 methylene chloride: ether solution (200 mL). After one more extraction with methylene chloride the organic layers were combined, washed with water (100 mL) and purification by flash chromatographed (eluent 7:3 pet ether:ethyl acetate) and HPLC (2 times) (First column:Waters Silica Prep Pak; isocratic, 98:2 hexane:ethyl acetate; Flow rate =225 mL/min; Second column: Waters Silica Prep Pak; gradient, 75:25 to 60:40 petroleum ether:methylene chloride) to provide the title compound as a white solid (0.280 g, 23%); NMR (CDCl3); δ8.35 (d, J=8 Hz, 1 H), 7.88-7.80 (m, 5 H), 7.66 (ddd, J=6, 5, 1 Hz, 1 H), 7.61 (d, J=2 Hz, 1 H), 7.60 (d, J=2 Hz 1 H) 7.58-7.56 (m, 2 H), 7.51-7.41 (m, 4 H), 7.18 (ddd, J=7, 1, 1 Hz, 1 H), 6.83 (dd, J=7, 1 Hz, 1 H) 5.44 (t, J =8 Hz, 1 H), 1.34 (s, 9 H); MS (FAB+): [M+], 3 bromine pattern, 814 (30%) 816 (95%) 818 (100%) 820 (42%); Anal. Calc. for C39H29Br3O3S: C, 57.30; H, 3.58, N, 0.00. Found: C, 57.55; H, 3.75, N, 0.02.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[C:7]([C:10]1[N:11]=[C:12]([CH3:16])[O:13][C:14]=1[CH3:15])(=[O:9])[CH3:8]>>[CH3:16][C:12]1[O:13][C:14]([CH3:15])=[C:10]([C:7]([C:2]2[CH:6]=[CH:5][O:4][CH:3]=2)([OH:9])[CH3:8])[N:11]=1
Reactant: CC(=O)c1nc(C)oc1C
Reactant: Brc1ccoc1
Product: Cc1nc(C(C)(O)c2ccoc2)c(C)o1

Procedure:
Starting with 3-bromofuran and 4-acetyl-2,5-dimethyloxazole and following the general method of Example 4 the title compound was prepared.
Reaction SMILES: O[CH:2]1[CH:7]([C:8](=[S:11])[NH:9][CH3:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]1([CH2:20][O:21][CH3:22])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:22][O:21][CH2:20][C:3]1([CH3:19])[CH:2]=[C:7]([C:8](=[S:11])[NH:9][CH3:10])[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4]1
Reactant: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(C)(COC)C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=S)C1=CC(C)(COC)Oc2ccc([N+](=O)[O-])cc21
Yield: 70.6 %

Procedure:
A mixture of 0.9 g of 3,4-dihydro-3-hydroxy-2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 0.12 g of p-toluenesulfonic acid monohydrate and 25 ml of toluene was refluxed with heating for 2 hours. Ethyl acetate was added to the mixture. After it was washed with water and dried, the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution. MeOH:CH2Cl2 =1:99) to obtain 600 mg of 2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide with a melting point of 146°-148° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH2:38])[CH2:14][CH2:15][CH2:16][NH:17]/[C:18](/[NH2:37])=[N:19]/[S:20]([C:23]2[C:24]([CH3:36])=[C:25]([CH3:35])[C:26]3[O:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]=3[C:33]=2[CH3:34])(=[O:22])=[O:21])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].[Cl-].[OH:43][S:44]([OH:47])(=O)=O.[CH2:48]1[CH2:52]O[CH2:50][CH2:49]1>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:39])[C@@H:13]([NH:38][S:44]([C:48]2[C:52]([CH:25]([CH3:26])[CH3:35])=[CH:24][C:23]([CH:33]([CH3:27])[CH3:34])=[CH:50][C:49]=2[CH:13]([CH3:14])[CH3:12])(=[O:47])=[O:43])[CH2:14][CH2:15][CH2:16][NH:17]/[C:18](/[NH2:37])=[N:19]/[S:20]([C:23]2[C:24]([CH3:36])=[C:25]([CH3:35])[C:26]3[O:30][C:29]([CH3:31])([CH3:32])[CH2:28][C:27]=3[C:33]=2[CH3:34])(=[O:22])=[O:21])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: C1CCOC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCN/C(N)=N/S(=O)(=O)c2c(C)c(C)c3c(c2C)CC(C)(C)O3)NS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)CC1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
To a solution of compound G (1.0 g, 1.8 mmol) in THF (7 mL) was added 3.1N aqueous NaOH (4.0 mL) and stirred for 5 min. The reaction mixture was cooled to ˜5° C., and then a solution of tripsyl chloride added drop wise (2.2 g, 7.3 mmol) in THF (5 mL) and stirred at room temperature overnight (˜18 h). The reaction mixture was diluted with H2O (130 mL), acidified with 2% H2SO4 (15 mL) and extracted with EtOAc (3×80 mL). Organic layer were combined and washed with H2O (2×400 mL), saturated NaHCO3 (100 mL), H2O (200 mL) and brine (200 mL). The organic layer was separated dried over MgSO4 and solvent removed in vacuo to afford (2.9 g) of crude product. This was purified by normal phase flash chromatography (5-10% MeOH/DCM) to afford compound H (0.52 g, 1.0 mmol). LC-MS [M+H] 833.8 (C41H64N6O8S2+H, calc: 834.1).
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[Na+:10]>O>[OH:9][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O-:7])=[O:8].[Na+:10]
Reactant: [OH-]
Reactant: O=C1CCCCCO1
Agent: [Na+]
Solvent: O
Product: O=C([O-])CCCCCO
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH electrode were added 17.1 g of 6-hexanolactone, 16 g of water, and 24 g of a 25 wt % aqueous NaOH solution. The mixture was stirred for 30 min while cooling down slowly. The sodium 6-hydroxyhexanoate solution formed was cooled to 4° C. and to this solution 70 mg of N-methylmorpholine was added. Then, 16.2 g of isopropyl chloroformate was added in 2 min. The reaction mixture was stirred for 90 min at 10° C. Chloroformate level in the organic layer was low and mixed anhydride was formed according to analysis by FT-IR. The water layer was separated and 19.3 g of a 70 wt % aqueous tert-butyl hydroperoxide solution (ex Lyondell) was added. With stirring, 0.5 g of Na2CO3 was added and 12.5 g of a 25 wt % aqueous NaOH solution was dosed in 20 min at 10° C. The reaction mixture was stirred for 60 min at 10° C. For a fast layer separation some water and diethyl ether were added. The water layer was separated and the organic layer was extracted with an aqueous sodium sulfite solution in order to reduce all hydroperoxide present. The organic layer was washed with an aqueous NaHCO3 solution to a neutral pH and the product was dried over MgSO4. After removal of the ether in vacuum at 20° C. a colourless liquid was obtained with a perester content of 92% in a yield of 62% based on the starting chloroformate.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][CH2:16][NH2:17].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CS(C)=O>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:13]([C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]=2)[CH2:14][CH2:15][CH2:16][NH2:17])=[CH:21][CH:20]=1
Reactant: NCCCNc1ccc2ccccc2n1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: NCCCN(Cc1ccc(Br)cc1)c1ccc2ccccc2n1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
To a mixture of sodium hydride (2.64 g, 60% dispersion in mineral oil, 63.79 mmol) in dry dimethylsulfoxide (100 ml) was slowly added a solution of N-(quinolin-2-yl)propane-1,3-diamine (12 g, 56.62 mmol) in dry dimethylsulfoxide (25 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred until gas evolution was ceased. To the resulting mixture a solution of 4-bromobenzylbromide (16.27 g, 63.79 mmol) in dry dimethylsulfoxide (50 ml) was slowly added at room temperature. The reaction mixture was stirred for 4 days at room temperature poured on to ice water (800 ml) and extracted with ethyl acetate (5×150 ml). The combined organic extracts were washed with water (4×150 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue (22.27 g) was washed with n-heptane (30 ml) which afforded 20.41 g of crude N-(4-bromobenzyl)-N-(quinolin-2-yl)propane-1,3-diamine which was purified by column chromatography on silica gel (900 ml) using a mixture of dichloromethane/methanol/triethylamine 9:0.5:0.5 as eluent affording 13.9 g (63%) of N-(4-bromobenzyl)-N-(quinolin-2-yl)propane-1,3-diamine as an oil.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][NH2:28])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl.CCOC(C)=O>[F:29][C:30]([F:35])([F:34])[C:31]([O-:33])=[O:32].[F:29][C:30]([F:35])([F:34])[C:31]([O-:33])=[O:32].[NH2:28][CH2:27][CH2:26][CH2:25][C:23]1[N:22]=[CH:21][NH2+:20][CH:24]=1.[NH2:28][CH2:27][CH2:26][CH2:25][C:23]1[N:22]=[CH:21][NH2+:20][CH:24]=1
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NCCCC1=C[NH2+]C=N1
Product: O=C([O-])C(F)(F)F
Reaction time: 2 h
Yield: 61 %

Procedure:
0.5 g (1.4 mmol) of 3-(1-trityl-1H-imidazol-4-yl)propylamine is dissolved in 8 mL of dichloromethane with 2 mL of trifluoroacetic acid. After 2 hours, the medium is concentrated. The beige-coloured solid obtained is taken up in EtOAc and water, and the aqueous phase is then concentrated to dryness. 0.3 g of 4-(3-aminopropyl)-1H-imidazol-1-ium bis(trifluoroacetate) is obtained in a yield of 61%.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16]1>CS(C)=O.CCOCC>[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CC1CCCCN1
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC1CCCCN1c1ccc(C#N)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 4-fluoro-3-(trifluoromethyl)benzonitrile (50.0 g, 0.26 mol, Combi-Blocks AN-1049) and 2-methylpiperidine (156 mL, 1.32 mol) in DMSO (500 mL) was heated at 100° C. under nitrogen for 12 hours. The reaction mixture was diluted with Et2O and washed with water, a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of NH4Cl. The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure to give the title compound as a beige powder. UPLC/MS, M−(ESI): 269.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.19 (d, J=2.0 Hz, 1H), 8.12 (dd, J=8.4, 2.0 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 3.13 (m, 1H), 2.88 (m, 1H), 2.56 (m, 1H), 1.77-1.25 (m, 6H), 0.72 (d, J=6.0 Hz, 3H).
Reaction SMILES: CS(OC[CH2:7][CH2:8][C@@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH3:17])[CH2:11][CH2:10]1)(=O)=O.[H-].[Na+].[CH3:33][NH:34][C:35](=[O:37])[CH3:36].[CH2:38](Cl)Cl>>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([C@@H:16]([N:12]2[CH2:11][CH2:10][C@:9]([CH2:8][CH2:7][CH2:33][N:34]([CH3:38])[C:35](=[O:37])[CH3:36])([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:14][C:13]2=[O:15])[CH3:17])=[CH:23][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccccc2)OC1=O
Reactant: CNC(C)=O
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Product: CC(=O)N(C)CCC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl methanesulfonate (234 mg, 0.24 mmol) in CH2Cl2 (3 mL) was added NaH (82 mg, 3.4 mmol) at 0° C. The mixture was stirred at rt for 30 min. Then N-methylacetamide (204 mg, 2.8 mmol) was added the above mixture. The formed mixture was stirred at 80° C. for 5 h. After the reaction was over, the reaction was quenched with water and the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylacetamide (150 mg, 68%). LC-MS Method 2 tR=1.50 min, m/z=497, 495, 475, 473. 1H NMR (400 MHz, CDCl3): δ=1.41 (m, 1H), 1.48 (t, 3H), 1.73 (m, 1H), 1.83-1.95 (m, 2H), 2.01 (m, 3H), 2.1-2.3 (m, 3H), 2.71 (m, 1H), 2.81 (s, 3H), 3.1 (m, 1H), 3.2 (m, 1H), 5.5 (m, 1H), 6.72 (m, 2H), 7.10 (m, 2H), 7.20 (m, 2H), 7.37 (m, 3H).