Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[C:11](Cl)=[CH:10][C:8]([NH2:9])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1>CN(C)C=O>[Cl:4][C:5]1[C:11]([S:2][CH3:1])=[CH:10][C:8]([NH2:9])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: C[S-]
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(N)c([N+](=O)[O-])cc1Cl
Yield: 85.7 %

Procedure:
Sodium methanethiolate (4.06 g, 58.0 mmol, Aldrich) was suspended in 80 ml dimethylformamide. 4,5-Dichloro-2-nitroaniline (10.0 g, 48.3 mmol, Aldrich) was added portionwise. Additional sodium methanethiolate (4.38 g, 62.5 mmol) was added over several h until starting material was consumed. The reaction mixture was poured into water (400 ml) and the resulting precipitate was collected by filtration and dried to give 9.05 g (41.4 mmol, 86% yield) of the title compound. 1H NMR (CDCl3) δ8.15 (s, 1H), 6.44 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:10]([OH:40])[CH2:11][NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH3:39])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=O)(C)(C)C.[Cl:45]CCl.[ClH:48].O>C(OCC)(=O)C>[ClH:45].[ClH:48].[NH2:8][C@@H:9]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH:10]([OH:40])[CH2:11][NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:25]([NH:27][C@H:28]([C:36]([O:38][CH3:39])=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: ClCCl
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NCC(O)[C@@H](N)CC(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 250 mg of N-[N-[N-[(3S)-3-[[(t-butyloxy)carbonyl]amino]-2-hydroxy-5-methylhexyl]-L-leucyl]-L-valyl]-L-phenylalanine, methyl ester (slower isomer) (see example 6C) in 3 ml of ethyl acetate and 1.5 ml of dichloromethane was cooled in an ice bath under nitrogen, and then treated with anhydrous hydrogen chloride gas to saturation. Once the reaction was saturated, the ice bath was removed, the reaction was stoppered, and stirred at ambient temperature. After one hour, the reaction was concentrated to dryness in vacuo, resuspended in 5 ml of ethyl acetate, cooled in an ice bath under nitrogen, resaturated with anhydrous hydrogen chloride and stoppered. After 30 minutes, the reaction was concentrated to dryness in vacuo, then recrystallized from methanol/ether at room temperature, and refrigerated overnight to afford 200 mg of the title compound as a hydrate with 0.4 mole of water, melting point 242°-252° C., dec.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([OH:10])[CH:3]=1.[Br:11]Br>CC(O)=O>[Br:11][C:9]1[C:2]([F:1])=[CH:3][C:4]([OH:10])=[C:5]([CH:8]=1)[CH:6]=[O:7]
Reactant: O=Cc1ccc(F)cc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c(F)cc1O
Temperature: 2.5 °C
Yield: 17 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 4-fluoro-2-hydroxybenzaldehyde (545 g, 3.89 mol, 1.00 equiv) in AcOH (5 L), followed by the addition of Br2 (623 g, 3.90 mol, 1.00 equiv) dropwise with stirring at 0-5° C. The resulting solution was stirred overnight at room temperature, quenched by the addition of 3 L of saturated aqueous Na2SO3 and diluted with 6 L of ice/water. The solids were collected by filtration, washed with 2×1.5 L of water and dried to afford 145 g (crude) of 5-bromo-4-fluoro-2-hydroxybenzaldehyde as a yellow solid.
Reaction SMILES: CN1C(=O)CCC(C)(C)[C:4]2C=C([N+]([O-])=O)C=C[C:3]1=2.[CH3:19][C:20]1([CH3:35])[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]2[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=[CH:31][C:21]1=2>>[CH2:3]([N:23]1[C:24](=[O:27])[CH2:25][CH2:26][C:20]([CH3:35])([CH3:19])[C:21]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:22]1=2)[CH3:4]
Reactant: CN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reactant: CC1(C)CCC(=O)Nc2cc([N+](=O)[O-])ccc21
Product: CCN1C(=O)CCC(C)(C)c2ccc([N+](=O)[O-])cc21

Procedure:
1-Ethyl-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was prepared in a manner analogous to the preparation of 1,5,5-Trimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one using 5,5-Dimethyl-8-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as starting material to yield a yellow solid (65%). mp 83° C.; LCMS: m/z=263.05 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.11 (m, 1H), 8.06 (m, 1H), 7.60 (d, 1H, J=8.6 Hz), 3.91 (m, 2H), 2.32 (m, 2H), 1.42 (s, 6H), 1.38 (m, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][C:15]([NH:17][C:18]3[CH:19]=[C:20]([C:24]([O-:26])=[O:25])[N:21]([CH3:23])[CH:22]=3)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C1COCC1.[Pd]>[CH:10]1[C:11]2[CH:12]([CH2:14][C:15]([NH:17][C:18]3[CH:19]=[C:20]([C:24]([OH:26])=[O:25])[N:21]([CH3:23])[CH:22]=3)=[O:16])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cc(NC(=O)CC2c3ccccc3-c3ccccc32)cc1C(=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cn1cc(NC(=O)CC2c3ccccc3-c3ccccc32)cc1C(=O)O
Yield: 64.3 %

Procedure:
To a solution of the benzylester (20a) (900 mg) dissolved in THF (10 ml) was added 10% Pd/C (100 mg). The solution was hydrogenated (1 atm) for 19 hours and worked up using standard methods to yield 580 mg (80%) of compound (21a). 1H NMR (DMSO-d6) δ9.4 (s, 1 H), 8.0 (m, 2 H), 7.8 (m, 2 H), 7.3 (m, 4 H), 7.1 (s, 1 H), 6.8 (s, 1 H), 4.6 (m, 2 H), 4.3 (m, 1 H), 3.8 (s, 3 H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[CH:27]=[C:26]([Br:28])[CH:25]=[C:24]3[C:20]=2[CH2:21][C:22](=[O:29])[NH:23]3)[C:10]1=[O:30])[CH2:6][CH2:7][CH3:8].[OH-].[Li+].Cl>O1CCOCC1.O>[Br:28][C:26]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:29])[NH:23]2)=[C:19]([CH2:18][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:9]([CH:5]([CH2:6][CH2:7][CH3:8])[CH2:4][C:3]([OH:31])=[O:2])[C:10]2=[O:30])[CH:27]=1
Reactant: CCCC(CC(=O)OC)n1c(=O)n(Cc2cc(Br)cc3c2CC(=O)N3)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(Br)cc3c2CC(=O)N3)c2ccccc21
Temperature: 25 °C
Yield: 93.7 %

Procedure:
3-[3-(6-Bromo-2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-hexanoic acid methyl ester 80 mg (0.16 mmol) is dissolved in 2.5 mL of dioxane and then lithium hydroxide (10 mg, 0.43 mmol in 1.5 mL of water) is added drop wise to the reaction mixture. The reaction is stirred at room temperature and monitored by LC/MS. Upon completion the reaction is acidified by the addition of 1N HCl, and diluted with 10 mL of water. A solid precipitated that is collected and dried to give the title compound (73 mg. 0.15 mmol 96%). LCMS (ESMS): m/z 473.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([C:9]([OH:23])=[C:10]3[C:19]=1[C:18](=[O:20])[C:17]1[CH2:16][C:15](=[O:21])[CH2:14][CH2:13][C:12]=1[C:11]3=[O:22])=[C:7]([OH:24])[CH:6]=[CH:5][CH:4]=2.FC(F)(F)C(O)=[O:28]>O>[OH:24][C:7]1[C:8]2[C:9](=[O:23])[C:10]3[C:19](=[C:18]([OH:20])[C:17]4[CH2:16][C:15](=[O:21])[CH2:14][CH2:13][C:12]=4[C:11]=3[OH:22])[C:2](=[O:28])[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC2=C(C1)C(=O)c1c(c(O)c3c(O)cccc3c1Cl)C2=O
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CCc2c(O)c3c(c(O)c2C1)C(=O)c1cccc(O)c1C3=O

Procedure:
A solution of ethylene acetal of 3,4-dihydro-11-chloro6,7-dihydroxy-2,5,12(1H)-naphthacenetrione (compound 11) (4 mg) in trifluoroacetic acid (2 ml) was heated at 80° under reflux for 1 h. The solution was cooled, diluted with distilled water (10 ml) and extracted with ethyl acetate. The combined organic layers were washed with distilled water, dried and evaporated to give the crude product (compound 8) which was recrystallized from ethyl acetate as brown microcrystals (2.5 mg 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13](CC4C=CC(OC)=CC=4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2[CH:34]=[C:33]([O:35][C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:31][C:30]=2[F:40])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2[CH:34]=[C:33]([O:35][C:36]([F:38])([F:37])[F:39])[CH:32]=[CH:31][C:30]=2[F:40])=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2c(=O)c3c(nc(Cc4cc(OC(F)(F)F)ccc4F)n3Cc3ccc(Cl)cc3)n(C)c2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Cc1cc(OC(F)(F)F)ccc1F)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (71 mg, 0.118 mmol) in DCM (1 mL) was added TFA (0.3 mL) and trifluoromethanesulfonic acid (0.2 mL). The reaction was stirred at room temperature for 16 h. The mixture was concentrated and the residue was partitioned between DCM and aqueous sodium bicarbonate. The organic layer was dried and concentrated to give 7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (39 mg, 68.4% yield) as a yellow syrup, which was directly without purification. LCMS retention time 1.686 min; LCMS MH+ 483.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[N:17][CH:16]=[CH:15]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([S:7]([NH:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[N:17][CH:16]=[CH:15]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2cnccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc2cnccc2c1)c1ccccc1
Yield: 28.9 %

Procedure:
Benzenesulphonyl chloride (4.9 g, 0.028M) in CH2Cl2 (15 ml) was added dropwise over 10 minutes to a cooled stirred mixture of 6-aminoisoquinoline (4.0 g, 0.028M) and pyridine (2.37 g, 0.03M) in CH2Cl2 (150 ml). The reaction mixture was stirred overnight at room temperature and was then washed with H2O. The CH2Cl2 solution was dried over MgSO4 and was then chromatographed on a silica gel column. After evaporation the residue was recrystallised from isopropanol to yield 6-phenylsulphonamidoisoquinoline (2.28 g, 33%), m.p. 204°-6° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].[C:9](Cl)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>[OH-].[Na+]>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
In the routine manner, H-D-Nva-OH is reacted with carbobenzoxy chloride in 2 N sodium hydroxide and the resultant compound is recrystallized from ethyl acetatepetroleum benzine. The procedure gives needles melting at 83°-84° C.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:15][CH:16]=1)=[O:22]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 15.6 h
Yield: 90.8 %

Procedure:
Ethyl difluoroacetate (2.78 g, 22.4 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (10 mL). To the stirred solution was added 25 weight % sodium methoxide (6.02 g, 27.8 mmol ) followed by 4'-(trifluoromethyl)acetophenone (3.80 g, 20.2 mmol) and THF (20 mL). The reaction was stirred at room temperature overnight (15.6 hours), then treated with 3N HCl (20 mL). The organic layer was collected and washed with brine, dried over MgSO4, concentrated in vacuo to give a brown oil (4.88 g, 91%). 1H NMR (acetone d6) 300 MHz 15.10 (br s, 1H), 8.03 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 6.59 (s, 1H), 6.02 (t, J=54.2 Hz, 1H); 19F NMR (acetone d6) 300 MHz: - 63.70 (s), -127.10 (d); M+ 266.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:22]#[N:23])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1>CCOC(C)=O>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:22]#[N:23])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: N#CC1(c2ccccc2Cl)CCNCC1

Procedure:
A solution of EtOAc saturated with HCl (200 ml) was added to 4-(2-chlorophenyl)-4-cyano-N-(1,1-dimethylethoxycarbonyl)piperidine, (880 mg, 2.74 mmol). The resulting mixture was allowed to react for 1 hour at room temperature. The EtOAc was removed in vacuo affording 4-(2-Chlorophenyl)-4-cyanopiperidine hydrochloride as a white solid.
Reaction SMILES: [IH:1].CS[C:4]1[NH:5][CH2:6][CH:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:8]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCOCC>C(O)C>[IH:1].[OH:18][CH2:17][CH2:19][NH:20][C:4]1[NH:5][CH2:6][CH:7]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:8]=1
Reactant: CSC1=NC(c2c(Cl)cccc2Cl)CN1
Reactant: NCCO
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: OCCNC1=NC(c2c(Cl)cccc2Cl)CN1
Temperature: 130 °C

Procedure:
5.0 gm (0.0129 mol) of 2-methylmercapto-4-(2',6'-dichloro-phenyl)-2-imidazoline hydroiodide and 7.9 gm (0.13 mol) of ethanolamine were dissolved in 30 ml of ethanol, and the solution was heated in an autoclave for 3 hours at 130° C. Thereafter, the reaction solution was cooled and then admixed with ether, and the crystals precipitated thereby were collected, washed with acetone and recrystallized from ethanol/ether, yielding 1.5 gm (29% of theory) of the pure compound of the formula ##STR14##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>>[CH:22]([C:21]1[CH:24]=[CH:25][C:18]([O:17][CH2:16][CH2:15][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=3)[CH:3]=[CH:2]2)=[CH:19][CH:20]=1)=[O:23]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=Cc1ccc(OCCBr)cc1
Product: COC(=O)c1ccc2ccn(CCOc3ccc(C=O)cc3)c2c1

Procedure:
Methyl 1H-indole-6-carboxylate was alkylated with 4-(2-bromoethoxy)benzaldehyde as described in Example 3, Step 1 to provide methyl 1-(2-(4-formylphenoxy)ethyl)-1H-indole-6-carboxylate.
Reaction SMILES: O=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([N:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)=[O:4].Cl.[NH2:35][OH:36].N1C(C)=CC=CC=1C>CCO>[OH:36][N:35]=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3]([N:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=1)[C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(C(=O)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: CCO
Product: O=C(C(=NO)c1ccccc1)N(CCc1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 45.7 %

Procedure:
To a solution of 2-oxo-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-N-(6-trifluoromethyl-pyridin-3-yl)-acetamide (46 mg, 0.1 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (14 mg, 0.2 mmol) and 2,6-lutidine (32 mg, 0.3 mmol) and the mixture stirred at ambient temperature for 36 h then concentrated and redissolved in EtOAc (5 mL), washed with 10% aqueous citric acid (3×5 mL), dried over Na2SO4, filtered, then purified by chromatography (SiO2, heptane:ethyl acetate=95:5 to 50:50) to afford the title compound (22 mg, 46%) as a white solid. MS m/e: 480.3 [M+H]+.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C(=O)=O.[CH2:7]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:1][OH:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCCCCCCCCCCCCCNCc1ccccc1
Reactant: C1CO1
Agent: O=C=O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCN(CCO)Cc1ccccc1
Reaction time: 3 h

Procedure:
40 ml of ethylene oxide cooled with dry ice are added dropwise into a mixture of 65.9 g of N-benzyl-octadecyl amine and 200 ml of methanol at room temperature within 2 hours; the mixture is stirred for further 3 hours, the solvent removed and the residue purified by column chromatography (silica gel//chloroform).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([O:14]C)=[CH:4][N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([OH:14])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)nc1N1CCOCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1cnc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A mixture of 4-(2-chloro-5-methoxy-pyrimidin-4-yl)-morpholine (5.0 g, 1.0 eq.) and CH2Cl2 (20 ml) was added dropwise to a slurry of aluminum chloride (23.22 g, 8.0 eq.) in CH2Cl2 (30 ml) in ice bath. After dropping, the resulting solution was stirred overnight at room temperature. The resultant mixture was extracted with EA and the combined organic layers were washed with brine and dried in vacuo to give a light yellow solid (4.18 g, 89.23%) as a product.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:25]([F:28])([F:27])[F:26])([C:5]1[N:6]([CH3:24])[C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)[NH2:4].[CH:31]1(C(Cl)=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>N1C=CC=CC=1>[CH:31]1([C:24]2[N:6]3[C:7]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:8]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[N:9]=[C:5]3[C:3]([C:2]([F:29])([F:1])[F:30])([C:25]([F:26])([F:27])[F:28])[N:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cn1c(C(N)(C(F)(F)F)C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: Fc1ccc(-c2nc3n(c2-c2ccc(F)cc2)C(C2CCCCC2)=NC3(C(F)(F)F)C(F)(F)F)cc1
Temperature: 130 °C
Yield: 46.9 %

Procedure:
To a solution of α,α-bis(trifluoromethyl)-4,5-bis(4-fluorophenyl)-1-methyl-1H-imidazole-2-methanamine (3.38 gr, 7.8 mmole) in pyridine (1.7 gr) was added cyclohexane carbonyl chloride (3.5 gr, 23.9 mmole). The reaction mixture was heated at 130° C. for 4 hours. The mixture was purified by column chromatography, eluting with hexane, then mixture of hexane-ethylacetate (9:1) to give 5-cyclohexyl-2,3-bis(4-fluorophenyl)-7,7-bis(trifluoromethyl)-7H-imidazo[1,5-A]-imidazole (1.88 gr, 37%) as a white solid: mp 162.2-162.6. Anal. Calcd for C25H19F8N3 :C,58.60;H,3.54;N,8.20. Found: C,58.43;H,3.79;N,8.16.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:20]=[C:19]([CH:21]=[N:22][C:23]3[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=3[CH:32]([CH3:34])[CH3:33])[CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Li])([CH3:37])[CH3:36].O>CCOCC>[CH:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:20]=[C:19]([CH:21]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH:35]([CH3:37])[CH3:36])[NH:22][C:23]3[C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][CH:26]=[CH:27][C:28]=3[CH:29]([CH3:30])[CH3:31])[CH:18]=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [Li]c1ccccc1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1N=Cc1cccc(-c2ccccc2CNC2CCCCC2)n1
Solvent: CCOCC
Solvent: O
Product: CC(C)c1ccccc1C(Nc1c(C(C)C)cccc1C(C)C)c1cccc(-c2ccccc2CNC2CCCCC2)n1
Temperature: 25 °C

Procedure:
Et2O (10 mL) was added to compound 9 (0.189 g, 0.417 mmol) to form a clear pale yellow solution. At −80° C., an Et2O (5 mL) solution of 2-isopropylphenyllithium (0.136 g, 1.08 mmol) was added dropwise to form a red-purple solution. The mixture was allowed to slowly warm to ambient temperature overnight. Water (50 mL) was then added followed by Et2O (50 mL). The organics were separated, dried with brine and then MgSO4. Evaporation of the volatiles afforded compound 10, which did not require any purification. Yield: 0.224 g, 76.2%. 1H NMR (CD2Cl2): δ 7.67 (t, 2H), 7.1-7.53 (m, 10H), 7.00 (m, 3H), 5.44 (d, 1H), 4.40 (d, 1H), 3.69 (s, 2H), 3.11 (sept, 1H), 2.91 (sept, 2H), 2.24 (m, 1H), 1.5-1.7 (m, 6H), 1.25 (d, 3H), 1.1-1.2 (m, 4H), 0.97 (d, 12H), 0.93 (d, 6H).
Reaction SMILES: CN(C)C=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.S([O-])([O-])(=O)=O.[Na+].[Na+].[Br:27][C:28]1[CH:29]=[C:30]([NH:36][C:37](=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=O)[CH:31]=[C:32]([Br:35])[C:33]=1[OH:34]>O>[Br:27][C:28]1[CH:29]=[C:30]([N:36]2[C:37](=[O:43])[CH:38]=[CH:39][C:40]2=[O:42])[CH:31]=[C:32]([Br:35])[C:33]=1[OH:34]
Reactant: O=C(O)/C=C\C(=O)Nc1cc(Br)c(O)c(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C=CC(=O)N1c1cc(Br)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
In a reactor, 70 ml of dimethylformamide, 8.3 g (0.058 moles) of phosphorus pentoxide and 7.1 g (0.05 moles) of sodium sulfate were charged, to which 36.5 g (0.10 mole) of N-(3,5-dibromo-4-hydroxyphenyl) maleamic acid were gradually added at 25° C. with vigorous stirring. Thereafter, the reaction was continued at 60° C. for 3 hours. After cooling to room temperature, the resulting reaction mixture was added with water to precipitate N-(3,5-dibromo-4-hydroxyphenyl) maleimide in the form of crystals. The crystals were then separated by filtration, washed with water and dried to obtain 26.3 g (0.0757 moles) of N-(3,5-dibromo-4-hydroxyphenyl) maleimide (yield 75.7%).
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([OH:17])[C:15](Br)=[C:8]3[C:9]=2[C:4](=[CH:5][CH:6]=[CH:7]3)[C:3]1=[O:18].C=O.CN.[CH2:23]([N:25](CC)[CH2:26]C)C>O1CCOCC1>[OH:1][N:2]1[C:3](=[O:18])[C:4]2[C:9]3[C:8]([CH:7]=[CH:6][CH:5]=2)=[C:15]2[N:25]([CH3:26])[CH2:23][O:17][C:14]2=[CH:13][C:10]=3[C:11]1=[O:12]
Reactant: O=C1c2cccc3c(Br)c(O)cc(c23)C(=O)N1O
Reactant: CCN(CC)CC
Agent: C=O
Agent: CN
Solvent: C1COCCO1
Product: CN1COc2cc3c4c(cccc4c21)C(=O)N(O)C3=O
Temperature: 25 °C
Reaction time: 220 h
Yield: 32.5 %

Procedure:
To a suspension of 175 mg (0.57 mmol) of 2,5-dihydroxy-6-bromo-benzo[de]isoquinoline-1,3-dione (from Example 125) in 4 mL dioxane was added 0.6 mL (22 mmol) of 37% aqueous formaldehyde, 0.2 mL (2.32 mmol) of 40% aqueous methylamine, and 0.078 mL (0.57 mmol) of triethyl amine. The reaction mixture was stirred at room temperature for 220 hours and quenched with 20 mL water. The precipitate was isolated, washed with water, and dried to yield 50 mg of the title compound, mp 263-265° C.