Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([NH:17][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:16][CH2:15][CH2:14]1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: NC1CCC1
Solvent: CCO
Product: O[C@@H](CNC1CCC1)c1ccc2nnnn2c1

Procedure:
A solution of 0.75 g (4.62 mmol) of (R)-2-(tetrazolo [1,5-a]pyrid 6-yl)oxirane and 1.838 ml (22.8 mmol) of cyclobutyl amine in 1.8 ml of absolute ethanol was heated at 100° C. in a sealed reaction tube for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, wt. 0.997 g. Tlc, mass spectrum and 1H NMR spectra are consistent with good purity and chemical structure.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)(C)C.CCOC(C)=O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[C:11]=1[CH3:12]
Reactant: CN1CCNCC1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1c(N2CCN(C)CC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C

Procedure:
The 2,4-dichloro-5,7-difluoro-3-methylquinoline (300 mg, 1.20 mmol) and 1-methylpiperazine (140 μL, 1.20 mmol) were slurried in isopropanol (2.4 mL) and heated in a microwave reactor at 100° C. for 6 h. The reaction was cooled to rt and the resulting plug was slurried in EtOAc and filtered to give 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpiperazin-1-yl)quinoline. Mass Spectrum (ESI) m/e=312.1 (M+1).
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: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
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: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:9]([C@H:11]1[NH:14][C:13](=[O:15])[CH2:12]1)#[CH:10]>ClCCl.C(N(C(C)C)C(C)C)C>[Si:1]([N:14]1[C@H:11]([C:9]#[CH:10])[CH2:12][C:13]1=[O:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#C[C@@H]1CC(=O)N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#C[C@@H]1CC(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
tert-butyldimethylsilyl chloride (1.42 g) was added to a mixture of 4(S)-ethynyl-2-azetidinone (0.78 g) in dichloromethane (10 ml) and ethyldiisopropylamine (2.14 ml) at room temperature. The reaction mixture was stirred overnight, then evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with n-hexane-ethyl acetate (9:1) to give 1-tert-butyldimethylsilyl-4(S)-ethynyl-2-azetidinone (1.4 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(=O)c1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.5 %

Procedure:
A solution of 1-(4-hydroxyphenyl)ethanone (1.48 g, 10.9 mmol) and tributylphosphine (3.0 g, 14.9 mmol) in toluene (20 ml) was treated dropwise at 0° C. with a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (2 g, 9.94 mmol) and 1,1′-(azodicarbonyl)dipiperidine (2.75 g, 10.9 mmol) in toluene (20 ml). The mixture was stirred at room temperature for 2 days then partitioned between aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of methanol/dichloromethane (1:9) to afford the title compound (0.81 g, 23%); MS(ES−) m/e 318 [M−H]−.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:28](O)[CH2:29][CH3:30]>>[CH2:28]([O:14][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH2:29][CH3:30]
Reactant: CCCO
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCCOC(=O)c1ccc(C(=O)c2ccccc2)cc1
Yield: 76.3 %

Procedure:
A mixture of 10.0 grams (0.044 mole) of p-benzoylbenzoic acid, 100 milliliters of n-propanol and 0.25 milliliters of concentrated sulfuric acid was stirred under reflux for 5 hours. Aqueous sodium bicarbonate solution was then added. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. Volatiles were removed under vacuum with warming to provide 9.0 grams (76.3% yield) of n-propyl-p-benzoylbenzoate. The infrared spectrum revealed carbonyl absorption bands at 1670 and 1730 cm-1.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].Br[CH2:24][C:25]#[N:26].Cl>CS(C)=O.C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:3]=2[C:2]=1[O:1][CH2:24][C:25]#[N:26])=[O:8]
Reactant: N#CCBr
Reactant: COC(=O)c1sc2ccc(OC)cc2c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1OCC#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a room temperature solution of methyl 3-hydroxy-5-methoxybenzo[b]thiophene-2-carboxylate (1.00 g, 4.2 mmol) [Connor, et al., J. Med. Chem. 35:959 (1992)] in 20 mL of DMSO is added potassium t-butoxide (494 mg, 4.41mmol) followed by bromoacetonitrile (878 μL, 12.58 mmol). The mixture is stirred at room temperature for 1.5 hours, then poured into ethyl acetate and 1N HCl. The organic layer is washed with 1N HCl, followed by several portions of brine, and dried over MgSO4. Filtration followed by removal of solvent in vacuo and recrystallization of the residue from ethyl acetate:hexane gives 413 mg. An additional crop of 112 mg can be obtained from the mother liquor, mp 159.5°-160° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2[N:25]=[C:26]([NH2:29])[S:27][CH:28]=2)[CH:21]=[C:20]([Cl:30])[N:19]=1>C(#N)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2[N:25]=[C:26]([NH:29][C:13]([NH:12][S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:15])([F:1])[F:16])(=[O:11])=[O:10])=[O:14])[S:27][CH:28]=2)[CH:21]=[C:20]([Cl:30])[N:19]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: Nc1nc(-c2cc(Cl)nc(Cl)c2)cs1
Solvent: CC#N
Product: O=C(Nc1nc(-c2cc(Cl)nc(Cl)c2)cs1)NS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 93.8 %

Procedure:
7.53 g (0.03 mol) of 2-trifluoromethylphenylsulphonyl isocyanate are added to a solution of 7.38 g (0.03 mol) of [4-(2,6-dichloropyridin-4-yl)-thiazol-2-yl]-amine in 180 ml of acetonitrile at 75° C. in the course of 5 minutes, while stirring. The reaction mixture is stirred at 75° C. for a further 3 hours and then cooled to room temperature, and the solid which has precipitated out is filtered off with suction, washed twice with 10 ml of acetonitrile each time and dried at 45° C. under reduced pressure. 14 g (93.9% of theory) of N-[4-(2,6-dichloro-pyridin-4-yl)-thiazol-2-yl]-N'-(2-trifluoromethyl-phenylsulphonyl)-urea are obtained in this manner in the form of a solid substance with a melting point of >280° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@@H:9]1[C:18](OC)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:10][C@@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 83.4 %

Procedure:
To a solution of (2R,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine (11.21 g: 34.4 mmole) in a mixture of tetrahydrofuran (34 ml) and ethanol (51 ml), sodium borohydride (5.21 g: 137.7 mmole) is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 75 minutes at room temperature to give (2R,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (8.47 g). Yield: 83%. Colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2].S([O-])([O-])(=O)=[O:17].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+].O>CC(C)=O>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:17])[CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(=O)Nc1cc(F)cc2c1CCCC2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(F)cc2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a-solution of the compound obtained in (6) above (9.46 gm) in 420 ml of acetone was added 42 ml of 15% aqueous solution of magnesium sulfate. After cooling to 0° C., 21.7 gm of potassium permanganate was added to the mixture, a bit at a time. The mixture was stirred for 50 minutes at 0° C. and for 1 hour at room temperature. Upon addition of 1 l of water, the reaction product was extracted 3 times with chloroform. The chloroform layer was washed with water and saturated brine in this order, and dried over anhydrous-sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography using hexane-ethyl acetate (3:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to obtain 7.98 gm of the title compound.
Reaction SMILES: [C:1]1(=[O:25])[N:5]([CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH:11](CC2C=CC=CC=2)[OH:12])[C:4](=[O:20])[C:3]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:2]12>[Pd].CO.C(O)(=O)C>[C:4]1(=[O:20])[N:5]([CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:1](=[O:25])[C:2]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCNCCC(O)Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1CCNCCCO
Reaction time: 3 h
Yield: 84.6 %

Procedure:
N-Phthalimidoethyl(benzyl)-3-amino-1-propanol (4.62 g, 11.95 mmol), Pd/C 10% (1 g) and MeOH:acetic acid (95:5, v/v) (100 mL) was transferred to a 250 mL par hydrogenation flask. The flask was purged and filled with H2 three times and then left under H2 at 55 psi with shaking. The mixture absorbed 20 psi of H2 in 30 minutes. The shaking was stopped and the pressure was raised to 55 psi again. After 3 hrs the pressure was 45 psi so the pressure was increased to 55 psi once more. The reaction was complete as indicated by TLC dichloromethane:MeOH (9:1, v/v) in 4 hours. The reaction mixture was filtered though a bed of celite and the solvent evaporated under vacuo to leave a yellowish oil. The oil was purified by silica gel flash column chromatography using dichloromethane:MeOH (9:1, v/v) as the eluent. The appropriate fractions were combined and concentrated under vacuo to afford 2.51 g (68%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([NH2:21])([CH3:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:13]=2)[NH:8][CH:7]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.CO>C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1([CH3:20])[CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:13]=3)[NH:8][C:7]=2[CH:27]([C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([OH:23])[CH:25]=2)[NH:21]1)=[O:22]
Reactant: COCCOc1ccc2[nH]cc(CC(C)(N)C(=O)OC)c2c1
Reactant: O=Cc1cccc(O)c1
Solvent: CO
Solvent: ClCCl
Product: COCCOc1ccc2[nH]c3c(c2c1)CC(C)(C(=O)OC)NC3c1cccc(O)c1
Temperature: 25 °C
Yield: 14.2 %

Procedure:
To a solution of (+/−)-2-amino-3-[5-(2-methoxy-ethoxy)-1H-indol-3-yl]-2-methyl-propionic acid methyl ester (800 mg, 2.60 mmol) and 3-hydroxybenzaldehyde (383 mg, 3.14 mmol, 1.2 equiv) in dry dichloromethane (20 ml) trifluoroacetic acid (200 μl, 2.6 mmol, 1 equiv) is added and the mixture is stirred under argon at room temperature. When TLC indicated the disappearance of the starting material (1 day), a little methanol is added to dissolve the precipitated product. Then it is diluted with CH2Cl2 (250 ml) and washed with 2 M aqueous HCl, aqueous NaHCO3 and water, dried, and concentrated. Column chromatography (dichloromethane-ethyl acetate, 7:1→5:1) of the residue gives (1RS,3SR)-1-(3-hydroxy-phenyl)-6-(2-methoxy-ethoxy)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (839 mg, 78%) and (1RS,3RS)-1-(3-hydroxy-phenyl)-6-(2-methoxyethoxy)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester (152 mg, 14%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=O.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:30][O:29][C:22](=[O:28])[CH2:23][C:24]1[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:25]=1[CH3:27]
Reactant: COc1cccc(CC(=O)c2c(N)sc3c2CCCC3)c1
Reactant: COC(=O)CCC(C)=O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1Cc1cccc(OC)c1)CCCC3
Yield: 82.7 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(m-anisyl)methanone (0.287 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.327 g (85%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([O:19][CH3:20])=[O:18].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:40][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1CBr
Temperature: 80 °C

Procedure:
The compound of example 3 (5.7 g, 0.021 mol) was dissolved in carbon tetrachloride (125 mL). AIBN (350 mg) and NBS (4.1 g, 0.0231 mol) were added and the reaction mixture was refluxed at 80° C. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to obtain a crude material containing 85% mono bromo and 10% dibromo product and 5% starting material. The crude was used directly without purification for the preparation of the compound of example 5.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])=[CH:20][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCOc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Succinic anhydride (62.4 g) mashed by a mortar and pestle was placed in a 1 l three-necked flask, followed by adding heptyloxybenzene (100 g) and nitrobenzene (300 ml), portion-wise adding anhydrous aluminum chloride (150 g) under ice cooling, heating the mixture up to 50° C., agitating for 2 hours, allowing to stand overnight, after which the resulting reaction solution was poured in water, and subjected to steam distillation to distil off excess nitrobenzene, followed by ice-cooling, filtering off the resulting solids, heating under reflux together with toluene to remove water by means of Dien-Stark type drain tube, filtering off the solution while hot, recrystallizing from the filtrate, and further filtering off the resulting crystals, to obtain 3-(4-heptyloxybenzoyl)propionic acid (114.5 g). m.p.: 103.5°-105.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCl>[Br:13][CH2:12][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1CBr
Temperature: 80 °C
Reaction time: 16 h
Yield: 25.2 %

Procedure:
A mixture of methyl 5-chloro-2-methylbenzoate (3.13 g, 17.0 mmol), N-bromosuccinimide (3.17 g, 17.8 mmol), benzoyl peroxide (0.41 g, 1.70 mmol), and carbon tetrachloride (80 mL) was stirred at 80° C. for 16 h. After cooling to room temperature, the mixture was diluted with dichloromethane (200 mL) and washed with saturated sodium hydrogen carbonate aqueous (150 mL), and brine (150 mL). The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (60:1) to afford 1.13 g (25%) of the title compounds as colorless oil: 1H-NMR (CDCl3) δ 7.96 (1H, d, J=2.2 Hz), 7.46–7.40 (2H, m), 4.92 (2H, s), 3.96 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:11]4[CH:16]=[C:17]([C:20]([F:22])([F:21])[F:23])[CH:18]=[CH:19][C:10]=4[N:9]=3)[CH:3]=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C1CC(c2cccc(Br)c2)=Nc2ccc(C(F)(F)F)cc2N1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cc1

Procedure:
The title compound was prepared from 4-(3-bromo-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example B.2) (200 mg, 0.50 mmol) and commercially available 4-tert-butylsulfamoyl-benzeneboronic acid [CAS-no. 208516-15-8] (161 mg, 0.60 mmol) according to the general procedure II. Obtained as a white solid (125 mg, 46%). MS (ISP) 515.9 [(M+H)+]; mp 229-233° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Cl)[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2].[CH2:30]([OH:33])[CH2:31][OH:32]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:32][CH2:31][CH2:30][OH:33])[C:5]=1[NH:12][C:13](=[O:29])[CH2:14][CH:15]1[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(CCl)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: OCCO
Product: CC(C)c1cccc(COCCO)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Yield: 52 %

Procedure:
Following a procedure similar to that described in Preparation 1(ii), but using N-(2-isopropyl-6-chloromethylphenyl)-2-(9H-xanthen-9-yl)acetamide [prepared as described in Preparation 28(iv)] and ethylene glycol as starting materials, in relative amounts similar to those used in that Preparation, the title compound, melting at 153°-154° C. (after recrystallization from a mixture of diethyl ether and hexane), was obtained in a 52% yield.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12]O)=[CH:7]2.P(Br)(Br)[Br:15]>CCOCC>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][Br:15])=[CH:7]2
Reactant: BrP(Br)Br
Reactant: OCc1ccc2c(Br)cccc2c1
Solvent: CCOCC
Product: BrCc1ccc2c(Br)cccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a stirred suspension of 5-bromo-2-hydroxymethylnaphthalene (7.00 g, 29.5 mmol) in dry Et2O (100 mL) at 0° C. was added PBr3 (8.91 g, 33 mmol) in portions over 20 minutes. The reaction was stirred for an additional 30 minutes at 0° C., diluted with Et2O (100 mL) and quenched with H2O (100 mL) over 20 minutes. The heterogeneous solution was diluted further with H2O (100 mL) and the layers separated. The aqueous phase was extracted with Et2O (1×200 mL) and the combined organic layers were washed with H2O (1×100 mL) and saturated NaCl (1×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC (SiO2 : gradient hexane/EtOAc) to give the title compound as a white solid (4.60 g, 52%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])#[N:27]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:26]#[N:27])(=[O:36])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4C#N)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-cyanobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.