Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[C:10]([Cl:22])[CH:9]=2)=[O:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[Cl:22])[N:7]=[C:6]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(Cl)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1
Reactant: C1CCNC1
Product: O=C(O)c1c(N2CCCC2)nc2cc(Cl)c(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 25 step D from 2,6,7-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 25 step C) and pyrrolidine. Brown solid. MS (ESI): 387.1 (M+H)+.
Reaction SMILES: O[C:2]1([C:12]([NH2:14])=[O:13])[CH:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClC(Cl)Cl>[C:22]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][C@H:2]1[C:12]([NH2:14])=[O:13])(=[O:24])[CH3:23]
Reactant: NC(=O)C1(O)Nc2ccccc2C1O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1c2ccccc2C[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
2,3-Dihydroxy-1H-indole-2-carboxamide (0.030 mol) was suspended in trichloromethane (400 ml). The mixture was cooled to 0° C. Triethylamine (0.045 mol) was added. Acetyl chloride (0.045 mol) was added over 2 minutes. After 30 minutes, TLC showed the reaction was incomplete. While the flask was still cool, more Triethylamine (6.26 ml) was added, followed 15 minutes later with more acetyl chloride (3.21 ml). TLC showed the reaction was still incomplete. The reaction was continued to allow to stir, cooled to 0° C., and more triethylamine (6.26 ml) was added. Over 2 minutes, more acetyl chloride (3.21 ml) was added neat. TLC showed 80% completion after 60 minutes, and no progress after 30 more minutes. A third portion of acetyl chloride and triethylamine was added. After an additional 15 minutes, ice cold water (200 ml) was added. The mixture was stirred for 10 minutes, filtered, and rinsed with water (3×100 ml) and trichloromethane (2×75 ml). The sample was allowed to dry overnight, yielding 4.71 g of (S)-1-acetyl-2,3-dihydro-1H-indole-2-carboxamide (intermediate 1, mp. >260° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.[Br-]>CS(C)=O.O>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Clc1ccccc1CBr
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCCc2nc3ccccc3c(NCc3ccccc3Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
To a suspension of 9-amino-3,4-dihydroacridin-1(2H)-one (8.0 g) in 75 ml of dimethyl sulfoxide was added pulverized potassium hydroxide (6.2 g). This was stirred for 0.5 hour at ambient temperature. To this solution was added 2-chlorobenzyl bromide (9.4 g). After 1 hour, an additional 1 ml of the bromide was added. This was stirred for an additional hour. At this time, 200 ml of water was added, and the precipitate was filtered and washed with water. The solid was taken up in dichloromethane and dried over anhydrous magnesium sulfate. The compound was purified via flash chromatography to yield 6.75 g of solid, mp 150°-161° C. A portion of this was recrystallized from methanol to give analytically pure needles, mp 162°-165° C. ANALYSIS: Calculated for C20H17ClN2O: 71.32%; 5.09%H; 8.32%N; Found: 71.17%C; 5.25%H; 8.24%N
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=1.C([OH:23])C.CN(C)C=O>[OH-].[Na+]>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:4]2[NH:3][C:2](=[O:23])[C:11]3[C:6](=[N:7][CH:8]=[CH:9][N:10]=3)[N:5]=2)=[CH:15][CH:16]=1
Reactant: CCO
Reactant: Cc1ccc(OCc2nc(N)c3nccnc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2nc3nccnc3c(=O)[nH]2)cc1

Procedure:
Obtained using the procedure described in section b of Example 9, starting with 2.5 g (0.0094 mole) of 4-amino-2-[(4-methylphenoxy)methyl]pteridine in 68.1 ml of 5% aqueous sodium hydroxide. Heating time: 3 hours 15 minutes at 85° C. Yld: 1.3 g (52%), m.p. 232°-233° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([C:10]2[CH:11]=[N:12][N:13]([C:15]3([CH2:21][C:22]#[N:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)=[N:3][CH:2]=1.[CH3:24][S:25][C:26](SC)=[N:27][C:28]#[N:29].CS(C)=O.N1CCCCC1>C(O)(C)C.C(#N)C.C(#N)C.O>[C:28]([N:27]=[C:26]([N:18]1[CH2:17][CH2:16][C:15]([CH2:21][C:22]#[N:23])([N:13]2[CH:14]=[C:10]([C:4]3[C:5]4[CH:9]=[CH:8][NH:7][C:6]=4[N:1]=[CH:2][N:3]=3)[CH:11]=[N:12]2)[CH2:20][CH2:19]1)[S:25][CH3:24])#[N:29]
Reactant: CSC(=NC#N)SC
Reactant: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CCNCC1
Solvent: O
Solvent: CC#N
Solvent: CS(C)=O
Product: CSC(=NC#N)N1CCC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]piperidin-4-ylacetonitrile (361 mg, 1.17 mmol) and N-cyano-S,S′-dimethyldithioimido carbonate (344 mg, 2.35 mmol) were dissolved in isopropyl alcohol (2.5 mL) and DMSO (2.5 mL) at 20° C. After 16 h reaction time, LCMS analysis showed the presence of some product, M+H 406; of the reagent, M+H 147; and of the piperidine, M+H 308. HPLC analysis showed about 2% reaction. The HPLC method was: Zorbax SB C18, 5 μm, 15 cm, 35° C., flow 1.2 mL/min, 5% ACN—H2O (0.05% TFA), 1.5 min, to 100% ACN in 15.0 min; detector set at 324, 225, and 265 nm. The retention time of the starting material was 4.9 min (UV max 224, 262, 292, & 325 nm); of the product, 6.5 min (UV max 226, 262, 290, & 324 nm); and of the reagent, 7.7 min (UV max 265 nm). To the product was added TEA (327 μL, 2.35 mmol), and the resulting mixture was stirred at RT. After stirring for 3 h, HPLC and LCMS analyses showed 60% reaction. The product and the unreacted piperidine were isolated by prep HPLC using a 30 mm×100 mm C18 column; 5% ACN—H2O (0.1% TFA), 1.0 min, to 35% at 6 min; 60 mL/min; detector set at 326 nm. The retention time for the product was 5.9 min; and for the starting piperidine was 3.5-4.3 min. The product was freeze dried to yield 301 mg of a white solid TFA salt. 1H NMR (d6-DMSO) δ 12.85 (s, 1H); 9.01 (s, 1H); 8.90 (s, 1H); 8.59 (s, 1H); 7.85 (m, 1H); 7.30 (m, 1H); 4.23 (m, 2H); 3.35 (m, 2H); 3.30 (s, 2H); 2.78 (m, 2H); 2.68 (s, 3H); 2.16 (m, 2H). MS(ES) 406 (M+H).
Reaction SMILES: [I-:1].[Na+].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:13][CH2:14][CH2:15]Cl)[CH:11]=2)[C:6]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:5]1>CC(=O)CC>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:13][CH2:14][CH2:15][I:1])[CH:11]=2)[C:6]([C:19]2[N:27]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:5]1
Reactant: [I-]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI
Yield: 81.2 %

Procedure:
0.260 g of sodium iodide is added to a solution of 0.59 g of 2-[1-methyl-5-methoxy-6-(2-chloroethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 42 ml of 2-butanone, under an inert argon atmosphere at a temperature in the region of 20° C. The reaction medium is refluxed for 24 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is purified by flash-pack chromatography (silica, dichloromethane as eluent). The fractions containing the product are concentrated under reduced pressure. 0.565 g of 2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.[NH:44]1[CH2:49][CH2:48][CH:47]([NH:50][C:51](=[O:53])[CH3:52])[CH2:46][CH2:45]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:51]([NH:50][CH:47]1[CH2:48][CH2:49][N:44]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:45][CH2:46]1)(=[O:53])[CH3:52]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), N-(piperidin-4-yl)acetamide (52.5 mg, 0.37 mmol, 2.41 equiv), potassium iodide (12.7 mg, 0.08 mmol, 0.50 equiv), and potassium carbonate (42.4 mg, 0.31 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 80.4 mg (50%) of a yellow solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 8.93-8.92 (d, J=5.2 Hz, 1H), 8.67-8.65 (d, J=8.8 Hz, 1H), 8.44 (s, 1H), 8.13-8.09 (m, 3H), 7.88-7.87 (m, 1H), 7.78-7.67 (m, 5H), 7.62-7.54 (m, 1H), 4.72 (s, 2H), 4.44 (s, 2H), 3.91 (s, 1H), 3.66-3.63 (t, J=5.2 Hz, 4H), 3.57-3.54 (m, 2H), 3.20-3.14 (m, 2H), 2.17-2.13 (m, 2H), 2.05-2.00 (m, 4H), 1.93 (s, 3H), 1.82-1.70 (m, 4H). MS (ES, m/z): 713 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[NH:13][C:12](=[O:14])[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH:16]([CH3:19])[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:15][CH:16]([CH3:19])[CH2:17][N:13]1[C:12](=[O:14])[O:11][N:10]=[C:9]1[O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(OCc2ccccc2)no1
Reactant: CC(C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Cn1c(OCc2ccccc2)noc1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A 50 mL round bottom flask equipped with a thermometer, a stirrer, addition funnel and nitrogen inlet was charged with 3-(phenylmethoxy)-1,2,4-oxadiazol-5(4H)-one (1 g, 5.2 mmol), 2-methyl propanol (0.45 g, 6 mmol), triphenylphosphine (1.57 g, 6 mmol) and tetrahydrofuran (5 mL). The mixture was cooled to 0° C. and a solution of diethyl azodicarboxylate (1.04 g, 6 mmol) in tetrahydrofuran (2 mL) was added dropwise over a period of 10 min. The reaction mixture was allowed to warm to room temperature, and stirred for 18 h. The entire mixture was flash chromatographed (silica gel, 8:2 hexane-ethyl acetate) to provide 1.1 g (84%) of the title compound as a white solid melting at 53-60° C.
Reaction SMILES: Cl[Si](C)(C)C.[C:6]1([CH2:12]Br)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cu]C#N.[Cl-].[Li+].[CH3:19][C:20]1[N:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:24](=[O:31])[C:23]([N+:32]([O-:34])=[O:33])=[C:22](OS(C(F)(F)F)(=O)=O)[CH:21]=1.Cl>O1CCCC1.[Zn].ClCCl>[CH3:19][C:20]1[N:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:24](=[O:31])[C:23]([N+:32]([O-:34])=[O:33])=[C:22]([CH2:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:21]=1
Reactant: COC(=O)Cn1c(C)cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1=O
Reactant: BrCc1ccccc1
Agent: N#C[Cu]
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)Cn1c(C)cc(Cc2ccccc2)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
200 μl of chlorotrimethylsilane are added at room temperature to 2 g (30.6 mmol) of zinc in suspension in 50 ml of tetrahydrofuran, the mixture is kept stirred for 0.5 hour at room temperature and then it is cooled to 0° C. 4.5 g (26.3 mmol) of phenylmethyl bromide in solution in 20 ml of tetrahydrofuran are then added dropwise and then the reaction medium is kept stirred for 2 hours at this temperature. Next, the mixture is transferred to a three-necked flask containing 2.24 g (25 mmol) of copper(I) cyanide and 2.12 g (50 mmol) of lithium chloride at −10° C., the mixture is stirred at this temperature for 5 minutes and then cooled to −70° C. 7.3 g (19.5 mmol) of methyl 6-methyl-3-nitro-2-oxo-4-[[(trifluoromethyl)sulphonyl]oxy]-1,2-dihydropyridine-1-acetate in solution in 50 ml of tetrahydrofuran are then added dropwise, the temperature of the reaction medium is allowed to return to 0° C. and the stirring is maintained for 1 hour at this temperature. The mixture is then poured over 100 ml of a 1 N hydrochloric acid solution and 200 ml of dichloromethane are added. The precipitate is filtered, the filtrate is allowed to settle out and the aqueous phase is extracted with dichloromethane. The organic phases are combined, they are dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting with a dichloro-methane:methanol (98:2) mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][C:4]=1[NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16].[Cl-].[Al+3].[Cl-].[Cl-].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>ClCCCl>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[C:29]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=2)(=[O:11])=[O:10])[CH:30]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1NC(=O)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(S(=O)(=O)c2cc(Br)ccc2OC)cc1NC(=O)C(F)(F)F

Procedure:
In a 500 mL 3-neck round bottom flask equipped with reflux condenser, N2 inlet, thermometer socket and magnetic bar inside was added 4-Methoxy-3-(2,2,2-trifluoroacetylamino)benzenesulfonyl chloride (17 grams, 53.5 mmol) in 1,2-dichloroethane (200 mL). To the stirred solution of above reactions mass, Aluminium chloride (7.86 grams, 58.89 mmol) and 4-bromo anisole (20 grams, 107 mmol) were added slowly. Then the reaction mass was stirred under reflux temperature for 20 hours. Reaction mass was quenched into ice cold water and acidified with 2N hydrochloric acid (50 mL) until the pH was ˜4 and extracted the product with ethyl acetate (3×200 mL). The combined organic layers were washed with brine solution (1×50 mL), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to obtain the technical product. It was further purified by column chromatography to obtain the title product, the eluent being 15% ethyl acetate in n-hexane. Yield: 18.4 grams
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14].[OH-].[Na+]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:11]([F:10])[CH:12]=2)[N:7]=1
Reactant: Cc1ccc(N)cc1F
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1F
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To cyanuric chloride (1.4821 g, 8 mmol) dissolved in acetone (115 mL) stiffing at 0-5° C., was added a solution of 3-fluoro-4-methylaniline (1.0017 g, 8 mmol) in acetone (15 mL) followed by the addition of 2.5 N NaOH (3.2 mL, 8 mmol). The reaction mixture was allowed to stir at 0-5° C. for 1 hour under nitrogen. The reaction mixture was poured over crushed ice and neutralized with 10% NaOH. The solid that formed was collected by vacuum filtration and the resulting solid was dried overnight under vacuum. The product was used with no further purification, (156a, 1.88 g, 86%), mp 130° C.; HPLC: Inertsil ODS-3V C 18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 36.8 min, 99.1% purity;
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:30][C:31]([OH:33])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:35]([O:38][NH2:39])[CH:36]=[CH2:37].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:35]([O:38][NH:39][C:31](=[O:33])[CH2:30][N:9]1[CH2:10][CH2:11][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:27])([F:28])[F:29])=[N:19]3)[CH2:13][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:36]=[CH2:37]
Reactant: COc1ccc(N2CCN(CC(=O)O)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Reactant: C=CCON
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCONC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1
Reaction time: 3 h
Yield: 68.4 %

Procedure:
A solution of (S)-2-(2-benzyl-4-(8-methoxy-2-(trifluoromethyl)quinolin-5-yl)piperazin-1-yl)acetic acid (115 mg, 0.25 mmol) in CH2Cl2 (2 mL) at 0-5° C. was treated with O-allylhydroxylamine hydrochloride (31 mg, 0.28 mmol), triethylamine (38 μL, 0.28 mmol), catalytic DMAP, and finally DCC (57 mg, 0.28 mmol). The reaction mixture was stirred for 3 h after which time the mixture was treated with EtOAc (5 mL), filtered and evaporated. The residue was purified by silica gel flash chromatography with 50% EtOAc/hexane, then 100% EtOAc, as eluant to afford the title compound as an oil (88 mg, 68%). LC/MS (Method A) 5.66 min, [M+1]+ 515.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[OH:18])[C:6](=[O:19])[C:5]=2[CH:4]=1.C[O-].[Na+].Cl.Cl[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>CO.ClC1C=CC=CC=1>[CH2:26]([N:27]([CH2:30][CH3:31])[CH2:28][CH2:29][O:18][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]2=[O:19])[CH3:25]
Reactant: COc1cc(OC)c2c(c1)C(=O)c1cccc(O)c1-2
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: CCN(CC)CCOc1cccc2c1-c1c(OC)cc(OC)cc1C2=O
Yield: 64.9 %

Procedure:
Similar to example 3D1, prepare a solution of 2,4-dimethoxy-5-hydroxy-fluoren-9-one (0.33 g, 1.3 mmol) in methanol (8 mL) and 24 mL chlorobenzene with sodium methoxide (0.11 g, 2.0 mmole), and react the free base of 2-chloro-ethyl-diethyl amine hydrochloride 2.1 g (12 mmole) in order to obtain 0.30 g of the title compound as a reddish-orange powder. m.p. 178° C.-180° C. Analysis calculated for C21H25NO4.HCl: C, 64.36; H, 6.69; N, 3.58. Found: C, 63.99; H, 6.75; N, 3.62.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[O:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>[Cl-].[Na+].O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:17]2[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:14][CH2:15][CH2:16]2)[CH:11]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: c1ccc2c(c1)CNCCO2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Clc1cc(N2CCOc3ccccc3C2)nc2ccccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 382.9 %

Procedure:
The mixture of 2,4-dichloroquinoline (198 mg, 0.1 mmol), 2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (186 mg, 0.1 mmol), diisopropylethylamine (0.4 mL) and 5 mL of N-methyl-2-pyrrolidone was heated with stirring at 100° C. overnight. The mixture was cooled to room temperature, diluted with brine, and extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with brine. The solvent was dried over sodium sulfate and removed under reduced pressure to give a residue which was purified by column chromatography on silica gel to give 119 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 311.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:11].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[S:18]([N:15]1[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16]1)(=[O:20])=[O:19]
Reactant: Oc1cccnc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(COc1cccnc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 11.4 %

Procedure:
3-hydroxy pyridine (97 mg, 1.02 mmol), 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) and anhydrous potassium carbonate (0.352 g, 2.55 mmol) were stirred for over night in dry acetonitrile (20 mL). The mixture was poured into a large volume of water and the solution extracted with ether. Un-reacted phenol was removed with cold 1N NaOH solution. The ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by re-crystallization to yield the title compound (40 mg, 11.46% yield) as an off-white solid. 60% of the un-reacted starting material was also recovered from the reaction.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[S:37]>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:36]([NH:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]([F:26])([F:38])[F:39])=[S:37])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: FC(F)(F)Oc1ccccc1N=C=S
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccccc5OC(F)(F)F)c4c(c23)C1=O
Temperature: 25 °C

Procedure:
250 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.75 mmole) were dissolved in 10 ml of acetonitrile. 240 μL (2 molar equivalents) of 2-(trifluoromethoxy)phenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 20 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 368 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=89%) which was characterized as follows: