Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:17](=[O:18])[C:16]2[C:15](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([OH:21])=[N:5]1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO.Cl>CN(C)C=O>[Cl:20][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:19])[C:16]3[C:17](=[O:18])[N:4]([CH2:3][CH2:2][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)[N:5]=[C:6]([OH:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCN3CCN(c4ccccc4)CC3)c(=O)c12
Temperature: 25 °C
Reaction time: 120 h
Yield: 70.2 %

Procedure:
2(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]-quinoline-1,10-dione (0.500 g, 1.35 mM) was stirred in dimethylformamide (10 mL), and N-phenylpiperazine (10 mL, 10.6 g, 65.5 mM) was added. The resulting yellow suspension was heated to ~110° C. to form a clear yellow solution. The solution was heated for 6 hours during which time a precipitate formed. The suspension was cooled to room temperature and stirred for five days. The resulting yellow suspension was dissolved into aqueous methanol (500 mL, 50%). The pH of this solution was carefullyadjusted to pH=6 with 1N hydrochloric acid (~20 mL) which gave a yellow precipitate. This suspension was stirred for 1 hour and filtered togive the title compound contaminated with N-phenylpiperazine (0.753 g). This material was recrystallized from hot ethanol (200 mL) to give the title compound (0.428 g, 70%) as a yellow powder, mp 361°-364° C.; MS(CI): 452 (M+H). Analysis for C23 H22ClN5O3 : Calculated: C,61.10; H,4.91; N,15.50; Found: C,60.72; H,5.06; N,15.30; NMR: 7.95 (d, J=8.67 Hz, 1H),7.64 (br s, 1H),7.26-7.18 (m, 3H), 6.95 (d, J=8.07 Hz, 2H), 6.78 (t, J=7.32 Hz, 1H), 4.15 (br s, 2H), 3.55-2.85 (br m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][C:24]1[S:28][C:27]([NH2:29])=[N:26][CH:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:29][C:27]2[S:28][C:24]([CH3:23])=[CH:25][N:26]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: Cc1cnc(N)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Reaction time: 2 h
Yield: 69.8 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 84 mg, 0.24 mmol), 5-methyl-thiazol-2-ylamine (28 mg, 0.24 mmol) and N,N-diisopropylethylamine (127 μL, 0.73 mmol) were combined in methylene chloride (2 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (92 mg, 0.24 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(5-methyl-thiazol-2-yl)-acetamide (74 mg, 69%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C18H20ClN3O4S2 [M+] 441.06, found 442 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.66 (m, 4 H, 2×CH2), 1.89 (m, 4 H, 2×CH2), 2.45 (d, J=1.2 Hz, 3 H, ArCH3), 3.31 (s, 3 H, SO2CH3), 4.93 (m, 1 H, OCH), 7.15 (brq, 1 H, Ar), 7.59 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.70 (d, Jm=1.5 Hz, 1 H, Ar), 8.21 (d, Jo=8.2 Hz, 1 H, Ar), 10.03 (s, 1 H, NH).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][N:4]1[CH:5]=[CH:6][C:2]([NH2:1])=[N:3]1
Reactant: Clc1cccc(CBr)c1
Reactant: Nc1cc[nH]n1
Product: Nc1ccn(Cc2cccc(Cl)c2)n1

Procedure:
Prepared in analogy to example 10a) starting with 3-amino-1H-pyrazole and 3-chlorobenzyl bromide. The title compound was obtained as a brown oil (Yield=11%). MS ISP (m/e): 208.0 (100) [(M+H)+].
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[NH:14][C:13]1[C:8]3=[CH:9][CH:10]=[C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]2=1.[Br:22]Br.O>ClCCl>[Br:22][C:10]1[CH:9]=[C:8]2[C:13]([NH:14][C:15]3[C:7]2=[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=[CH:17][CH:16]=3)=[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=12
Reactant: BrBr
Reactant: c1ccc2c(c1)ccc1c2[nH]c2ccc3ccccc3c21
Solvent: O
Solvent: ClCCl
Product: Brc1cc2c([nH]c3ccc4ccccc4c32)c2ccccc12
Yield: 160.8 %

Procedure:
10.3 g of 7H-dibenzo[a,g]carbazole was dissolved in dichloromethane (150 mL) at 0° C. with stirring. To this was dropped a dichloromethane solution of bromine (3.1 g in dichloromethane). After being stirred at room temperature for 2 h, the solution was poured into 200 mL of water, filtered, and washed with 500 mL water. The white residue was recrystallized in ethanol and yielded 12-bromo-7H-dibenzo[a,g]carbazole as colorless crystals (10.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=O)[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:16]=2)[CH2:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:16]=2)[CH2:10][C:9]1([CH3:28])[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cccc(N2CC(C)(C)N(C(=O)OC(C)(C)C)CC2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1cccc(N2CCN(C(=O)OC(C)(C)C)C(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
3.47 ml of a borane-tetrahydrofuran complex (1.2 mol/l) (4.16 mmol) was added to a solution of 456 mg of 4-[3-(3-methoxypropoxy)phenyl]-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in the above reaction (1.16 mmol) in tetrahydrofuran (4.16 ml) under a nitrogen atmosphere and under ice-cooling over five minutes, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled in an ice bath. Then, 4.16 ml of a 1 N sodium hydroxide aqueous solution (4.16 mmol) was slowly added and the mixture was further stirred at room temperature for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=30/1-10/1) to obtain 370 mg of the title compound (yield: 82%).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=[O:9])=[O:2].I[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([O:9][C:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH:1]=[O:2])=[O:10])[CH3:13]
Reactant: O=Cc1ccsc1C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sccc1C=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Formyl-2-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (1.76 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours and poured into water. The mixture was extracted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 3-formyl-2-thiophenecarboxylic acid ethyl ester (2.91 g). 3-Formyl-2-thiphenecarboxylic acid ethyl ester (1.84 g) in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.45 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 3 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-difluoromethyl-2-thiophenecarboxylic acid ethyl ester (1.58 g). 3-Difluoromethyl-2-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (11 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced ppressure to give 3-difluoromethyl-2-thiophenecarboxylic acid (1.12 g) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[CH:6]([OH:15])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C1C=CC=CC=1.C(Cl)(=[O:33])C=C>C(Cl)Cl>[C:17]([OH:19])(=[O:33])[CH:16]=[CH2:5].[CH3:20][O:19][C:17]1[CH:16]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:18]=1)[CH:6]([OH:15])[C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC(=O)Cl
Agent: COc1cc(OC)cc(C(O)C(=O)c2ccccc2)c1
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: C=CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cooled solution of 0.8 g (2.94 mmoles) of 3',5'-dimethoxybenzoin prepared in (3) above and 1.13 ml dimethylaniline in 10 ml methylene chloride, under nitrogen, was slowly added a solution of 1.5 ml (18 mmoles) acryloyl chloride in 10 ml of mehtylene chloride. After the addition was complete, the mixture was stirred overnight at room temperature, diluted with methylene chloride, washed twice with 75 ml 5% aqueous HCl, once with 100 ml H2O, once with 100 ml 5% aqueous NaHCO3, once with 100 ml H2O, once with 100 ml saturated Na2SO4 and dried over anhydrous Na2SO4. The solvent was filtered and stripped off to yield an oil that crystallized to give 0.6 g (63%) of compound. Recrystalization from benzene/hexane (1/1) gave colorless crystals, mp 88°-89° C. Infrared, NMR, and mass spectrometric analyses showed that the above compound was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCC(=O)NCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NCCCCOS(C)(=O)=O
Yield: 105.7 %

Procedure:
To a solution of 2.00 g (8.22 mmol) of N-(4-hydroxybutyl)caprylamide and 1.37 ml (9.86 mmol) of triethylamine in 50 ml of methylene chloride was added 0.76 ml (9.86 mmol) of methanesulfonyl chloride under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 2.55 g of the desired compound (96.5%, colorless powder), mp: 59.0°-60.0° C.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[N:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[CH3:19][C:17]1[CH:18]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[N:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23]
Reactant: O=COc1ccccc1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)nnc1OCC(F)(F)F
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)nnc1OCC(F)(F)F
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (130 mg, colorless solid) from 4-chloro-2-((5-methyl-6-(2,2,2-trifluoroethoxy)pyridazin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (170 mg, 0.46 mmol, Intermediate-67) and phenyl formate (110 mg, 0.91 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: CC1(C)[O:7][CH:6]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:18][CH:17]=2)=[O:14])=[O:9])[C:5]([CH3:43])([CH3:42])[CH2:4][O:3]1.C(O)(=O)C>O>[OH:7][CH:6]([C:5]([CH3:42])([CH3:43])[CH2:4][OH:3])[C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:18][CH:17]=1)=[O:14])=[O:9]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(OC(=O)CCNC(=O)C2OC(C)(C)OCC2(C)C)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(OC(=O)CCNC(=O)C(O)C(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
A solution of 500 mg of 4-(Oleoylamino)phenyl 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate in a mixed solvent composed of 20 ml of acetic acid and 10 ml of water was stirred at room temperature for 15 hours. 20 ml of water was then added to the reaction mixture, which was then extracted with methylene chloride. The methylene chloride layer was washed with water, and dried over anhydrous sodium sulfate. After removal of the solvent under vacuum evaporation, the residue obtained was subjected to silica gel column chromatography to obtain 395 mg of the title compound (yield: 85%).
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:24])[NH2:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][C:42]=1[N+:51]([O-:53])=[O:52]>ClCCl>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([CH2:9][CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:11][CH2:12]3)=[CH:17][CH:18]=2)=[NH:23])(=[O:49])=[O:48])=[CH:43][C:42]=1[N+:51]([O-:53])=[O:52]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: N=C(N)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
A suspension of EXAMPLE 12B (0.421 g, 0.897 mmol) and diisopropylethylamine (0.50 mL) in dichloromethane (5 mL) was treated with 4-chloro-3-nitrobenzenesulfonyl chloride (0.252 g, 0.99 mmol), stirred at room temperature for 24 hours and concentrated. The resulting residue was purified by silica gel chromatography eluting with a gradient from 0%-10% methanol/dichloromethane to give the desired product (0.33 g, 60%). MS (ESI) m/e 614 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)([O-:13])=[O:12].[OH-].[K+]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Cc1ccc(CCO)cc1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Yield: 87.5 %

Procedure:
2-(4-Methylphenyl)ethyl alcohol (VIII) (2.72 g, 0.02 mole), 4-nitrochlorobenzene (IX: X=Cl) (3.15 g, 0.02 mole) and potassium hydroxide (1.4 g, 0.025 mole) were added to benzene (60 ml), and dicyclohexyl-18-crown-6 (0.2 g) was added thereto, followed by reaction at 60° C. for 10 hours. The reaction mixture was washed with water and concentrated, and the precipitated crystals were recrystallized from 95% ethanol to obtain 4.5 g of 4-[2-(4-methylphenyl)ethoxy]-nitrobenzene (VI) as white crystals (yield, 87.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:34]1([N:37]2[CH2:41][CH2:40][CH2:39][CH:38]2[CH2:42][NH2:43])[CH2:36][CH2:35]1>O>[CH:34]1([N:37]2[CH2:41][CH2:40][CH2:39][CH:38]2[CH2:42][NH:43][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:36][CH2:35]1
Reactant: NCC1CCCN1C1CC1
Reactant: COc1cc(N)c(S(=O)(=O)N(C)C)cc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(N)c(S(=O)(=O)N(C)C)cc1C(=O)NCC1CCCN1C1CC1
Temperature: 0 °C

Procedure:
68.5 g of 2-methoxy-4-amino-5-dimethylsulphamoyl benzoic acid (0.25 mole), 740 ml of water and 25.4 g of triethylamine (0.25 mole) are placed in a 2 liter flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The solution is cooled to about 0° C, and 34.1 g of isobutyl chloroformate (0.25 mole) is poured in drop by drop. The mixture is reacted for 40 minutes at room temperature then cooled, and 42 g of 1-cyclopropyl-2-aminomethylpyrrolidine is added drop by drop, while the temperature is kept between 0° and +5° C. The medium is reacted for 3 hours at room temperature, then the solution is evaporated dry under vacuum. The residue is dissolved in 250 ml of water and 50 ml of hydrochloric acid. The solution is extracted twice with 125 ml of methylene chloride, which is eliminated. The aqueous phase is made alkaline with 70 ml of soda lye.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:36]1[C:41]([CH3:42])=[N:40][C:39]([CH3:43])=[CH:38][N:37]=1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[C:41]([CH3:42])=[N:40][C:39]([CH3:43])=[CH:38][N:37]=2)[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Reactant: Cc1cnc(Cl)c(C)n1
Product: Cc1cnc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)c(C)n1
Yield: 72 %

Procedure:
The title compound was synthesized as described for Intermediate example I-28 in 72% yield starting from (S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-amine and 2-chloro-3,5-dimethylpyrazine (1.2 equiv); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (s, 1 H), 7.24-7.31 (m, 8 H), 7.17-7.22 (m, 2 H), 7.11-7.17 (m, 1 H), 6.82 (dd, 1 H), 6.74 (dd, 1 H), 4.27-4.34 (m, 1 H), 4.07 (t, 1 H), 3.56-3.67 (m, 4 H), 2.95-3.05 (m, 1 H), 2.56-2.67 (m, 1 H), 2.54 (s, 3 H), 2.28-2.40 (m, 1 H), 2.24 (s, 3 H); MS (APPI/APCI) m/z 436[M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=2[C:6]2[C:14]1=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: O=C1CCCc2c1c1cccc(F)c1n2Cc1ccccc1
Reaction time: 0.33 h
Yield: 69.7 %

Procedure:
8-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (2.23 g, 0.011 mol) is added to a slurry of pentane-washed NaH (0.59 g, 0.015 mol) in DMF (18 mL) and after stirring for 20 min, benzyl bromide (1.7 mL, 0.014 mol) is added. The mixture is stirred for 1 h at which time the mixture is partitioned between water and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting residue is chromatographed on silica gel (200 mL) using methanol/dichloromethane (1/99). The solids are then recrstallized from ethyl acetate/dichloromethane/hexane to give 2.25 g (70%) of the title compound; mp 183-184° C.; MS (ESI−) for C19H16FNO m/z 292.1 (M−H)−; IR (drift) 1639, 1631, 1495, 1459, 1434, 1359, 1246, 1219, 1193, 1125, 798, 789, 736, 730, 698 cm−1; 1H NMR (CDCl3) δ2.23, 2.58, 2.87, 5.51, 6.92, 7.03, 7.16, 7.29, 8.07. Anal. Calcd for C19H16FNO: C, 77.80; H, 5.50; N, 4.78. Found: C, 77.58; H, 5.59; N, 4.79.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CCC>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:18][CH2:19]1)([O-:10])=[O:9]
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: COc1ccccc1N1CCN(CCNc2ccccc2[N+](=O)[O-])CC1
Reaction time: 32 h
Yield: 32.1 %

Procedure:
A mixture of 3.03 g of 2-chloronitrobenzene, 4.52 g of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine, and 3.18 g of anhydrous potassium carbonate in 30 mL of n-butanol was stirred for 32 h at reflux. After cooling, the mixture was poured into H2O, then extracted with EtOAc and the organic phase dried on Na2SO4. The crude obtained by evaporating the solvent was purified by flash chromatography (EtOAc-petrolium ether 4:6) and the residue obtained after evaporation of the solvents was taken up with Et2O, stirred and filtered giving 2.2 g (31%) of the title compound. Melting point: 117-118° C.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([CH:2]([NH:1][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:19][CH:20]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:12][CH:11]=1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: COC(=O)C(N)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)c1ccc(C(C)(C)C)cc1)c1ccc(Br)cc1
Reaction time: 4 h
Yield: 87.7 %

Procedure:
Prepared using General Procedure 7. To a stirring solution of methyl 2-amino-2-(4-bromophenyl)acetate (421 mg, 1.5 mmol), 4-(tert-butyl)benzoic acid (321 mg, 1.8 mmol), and DIEA (831 μl, 4.5 mmol) in DMF (3 mL) cooled to 0° C. was slowly added a solution of HATU (380 mg, 1.65 mmol) in DMF (1.5 mL) in a drop-wise fashion. The reaction mixture was allowed to warm slowly and stirring continued for 4 h. The reaction mixture was poured onto ice-water and the solid was filtered. The solid was dissolved in DCM (10 mL), dried over MgSO4 and evaporated to afford 532 mg (88%) of methyl 2-(4-bromophenyl)-2-(4-(tert-butyl)benzamido)acetate. LCMS-ESI (m/z) calculated for C20H22BrNO3: 403.0. found 404.1 [M+H]+, tR=3.61 min. (Method 16).