Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S([O:13][CH3:14])(OC)(=O)=O>O>[CH3:2][C:1]1([CH3:4])[CH2:3][CH2:2][C:1]([CH3:4])([CH3:3])[C:14]1=[O:13]
Reactant: CC(C)(C)O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CCC(C)(C)C1=O

Procedure:
After cooling, 100 ml of t-butanol was slowly added dropwise thereto to decompose excess sodium hydride, and then 1.0 l of water was added thereto. The reaction mixture was further heated for 2 hours under reflux to decompose excess dimethyl sulfate. After cooling, the resulting two layers were separated and the organic layer was washed with aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue was distilled under reduced pressure, whereby 59 g of 2,2,5,5-tetramethylcyclopentanone was obtained (b.p. 55° C./20 mmHg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li+].C[Si]([N-:50][Si](C)(C)C)(C)C.Cl>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH2:50])[CH:7]=3)=[CH:12][CH:11]=[N:10]2)=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Fc1ccc(-n2nccc2-c2ccnc(Cl)c2)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(-c2ccnn2-c2ccc(F)cc2)ccn1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
A 10 mL vial is charged with 2-Chloro-4-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-pyridine (160 mg, 0.59 mmol), Tris(dibenzylideneacetone)dipalladium (54 mg, 0.058 mmol) and 2-(dicyclohexylphosphino)biphenyl (53.3 mg, 0.15 mmol) in dry THF (3 mL) and Argon is bubbled through the mixture for 5 min. Additional THF (1 mL) and LiHMDS (1M in toluene, 1.14 mL, 1.5 mmol) are added and the reaction mixture is heated at 65° C. for 14 hours. Then 5 mL of 3.0 M HCl solution is added and the mixture is stirred for 10 min. Additional water (10 mL) is added and the mixture is extracted with EtOAc (2×10 mL). The aqueous layer is separated and its pH is adjusted to 10 by adding saturated Na2CO3 aquaous solution. The mixture is then extracted with EtOAc three times and the organic layers are combined, washed with brine and dried over anhdrous Na2SO4. Removal of solvent gives the desired product (83 mg).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][C:8]1[C:12]([CH3:13])=[C:11]([CH:14]=[O:15])[NH:10][C:9]=1[CH2:16][C:17]1[NH:18][C:19]([CH2:26][C:27]2[NH:28][C:29]([CH:40]=[O:41])=[C:30]([CH3:39])[C:31]=2[CH2:32][CH2:33][CH2:34][O:35]C(=O)C)=[C:20]([CH2:24][CH3:25])[C:21]=1[CH2:22][CH3:23])(=O)C.[Li+].[OH-]>CO>[CH:40]([C:29]1[NH:28][C:27]([CH2:26][C:19]2[NH:18][C:17]([CH2:16][C:9]3[NH:10][C:11]([CH:14]=[O:15])=[C:12]([CH3:13])[C:8]=3[CH2:7][CH2:6][CH2:5][OH:4])=[C:21]([CH2:22][CH3:23])[C:20]=2[CH2:24][CH3:25])=[C:31]([CH2:32][CH2:33][CH2:34][OH:35])[C:30]=1[CH3:39])=[O:41]
Reactant: CCc1c(Cc2[nH]c(C=O)c(C)c2CCCOC(C)=O)[nH]c(Cc2[nH]c(C=O)c(C)c2CCCOC(C)=O)c1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(Cc2[nH]c(C=O)c(C)c2CCCO)[nH]c(Cc2[nH]c(C=O)c(C)c2CCCO)c1CC
Temperature: 25 °C
Yield: 93.6 %

Procedure:
7H, FIG. 7B. 2,5-Bis[(3-acetoxypropyl-5-formyl-4-methylpyrrol-2-yl)methyl]-3,4-diethylpyrrole 7G (5.98 g, 0.011 mol) and LiOH (1.76 g, 0.042 mol) were added to 400 mL of 95% methanol, which had been degassed with nitrogen prior to use, and the mixture heated to reflux under a nitrogen atmosphere. The reaction became homogeneous when heated. After heating for 1.25 hours, the reaction was allowed to cool to room temperature. The product precipitated as a tan color solid as the reaction cooled. The volume of the reaction mixture was reduced to 75 mL on a rotary evaporator and the resulting slurry placed in the freezer for several hours. The product was filtered and then purified by forming a slurry with 400 mL of methanol and 50 mL of water and heating close to boiling. The slurry was first cooled to room temperature, reduced to 1/2 volume under reduced pressure, and placed in the freezer for several hours. The product was collected by filtration and vacuum dried to yield 4.96 g of a tan powder (94%): 1H NMR (CD3OD, 300 MHz): δ0.96 (6H, t, CH2CH3), 1.49 (4H, p, CH2CH2CH2OH), 2.25 (6H, s, pyrrole-CH3), 2.32-2.43 (8H, m, CH2CH3 and CH2CH2CH2OH), 3.46 (4H, t, CH2CH2CH2OH), 3.85 (4H, s, (pyrrole)2 -CH2),9.34 (2H, s, CHO); CI MS (M+) 480; HRMS (M)+, 481.2942 (calc for C28H39N3O4, 481.2941).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:14][C:15]#[N:16])[CH:12]=2)[N:5]2[CH:20]=[CH:21][N:22]=[C:4]2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41](B(O)O)[CH:42]=2)[CH2:37]1)=O)(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].C(Cl)Cl.C(O)(C(F)(F)F)=O>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[CH:17]1([CH:13]([N:11]2[CH:12]=[C:8]([C:6]3[N:5]4[CH:20]=[CH:21][N:22]=[C:4]4[CH:3]=[C:2]([C:41]4[CH:42]=[C:43]5[C:38](=[CH:39][CH:40]=4)[CH2:37][NH:36][CH2:45][CH2:44]5)[N:7]=3)[CH:9]=[N:10]2)[CH2:14][C:15]#[N:16])[CH2:19][CH2:18]1
Reactant: N#CCC(C1CC1)n1cc(-c2nc(Cl)cc3nccn23)cn1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(B(O)O)ccc2C1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CCC(C1CC1)n1cc(-c2nc(-c3ccc4c(c3)CCNC4)cc3nccn23)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To 3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-cyclopropyl-propanenitrile (Preparation M; 50 mg, 0.16 mmol) in dioxane (5 mL) was added K2CO3 (66 mg, 0.48 mmol), diacetoxypalladium (1.8 mg, 0.0080 mmol), 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-ylboronic acid (89 mg, 0.32 mmol) and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (8.2 mg, 0.016 mmol). The reaction mixture was degassed with argon, sealed and heated to 80° C. for 5 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH 10:1) to give the intermediate product, to which was added DCM/TFA (1 mL/1 mL). The reaction mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (20 mg, 31% yield). MS (apci) m/z=410.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:63][CH:64]1[CH2:69][CH2:68][N:67](C(OCCCC)=O)[CH2:66][CH2:65]1>O1CCCC1.ClCCl>[NH:67]1[CH2:68][CH2:69][CH:64]([NH:63][C:23](=[O:25])[C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:16]3[N:17]=[C:10]4[C:9]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:28])[CH:4]=5)=[CH:14][CH:13]=[CH:12][N:11]4[N:15]=3)=[CH:27][CH:26]=2)[CH2:65][CH2:66]1
Reactant: CCCCOC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(NC1CCNCC1)c1ccc(Nc2nc3c(-c4cccc(C(F)(F)F)c4)cccn3n2)cc1
Reaction time: 16 h
Yield: 42.3 %

Procedure:
To a solution of 4-(8-(3-(trifluoromethyl)phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino)benzoic acid (1.0 g, 2.5 mmol, 1 equiv), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3.00 mmol, 1.2 equiv), N,N-diisopropylethylamine (484 mg, 3.74 mmol, 1.5 equiv) in 2:1 tetrahydrofuran/dichloromethane (50 mL) was added text-butyl 4-amino-1-piperidinecarboxylate (0.60 g, 3.0 mmol, 1.2 equiv) at room temperature. After 16 h, the reaction mixture was filtered, and the filtrate was concentrate. The resulting residue was dissolved in 1:1 trifluoroacetic acid/tetrahydrofuran (50 mL) at room temperature. After 2 h, the reaction mixture was concentrated in vacuo. Purification by preparative HPLC provided product (508 mg, 42%). LCMS (ESI) m/z: 481.0; 1H NMR (400 MHz, DMSO-d6) δ: 10.06 (s, 1 H), 8.85 (d, J=7.6 Hz, 1 H), 8.60 (s, 1 H), 8.38 (d, J=8.8 Hz, 1 H), 7.98 (d, J=8.8 Hz, 1 H), 7.84 (br s, 2 H), 7.72-7.79 (m, 3 H), 7.32 (d, J=7.6 Hz, 2 H), 7.15 (m, 1 H), 4.02 (m, 1 H), 3.27-3.32 (m, 2 H), 2.95-3.05 (m, 2 H), 1.87-1.94 (m, 2 H), 1.41-1.48 (m, 2 H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[N:12]1([C:18](=[O:38])[CH2:19][CH2:20][CH2:21][N:22]2[C:34]3[C:33]4[N:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N:27]=[CH:26][C:25]=3[N:24]=[C:23]2[CH2:35][CH2:36][CH3:37])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[OH-].[NH4+:40].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[N:12]1([C:18](=[O:38])[CH2:19][CH2:20][CH2:21][N:22]2[C:34]3[C:33]4[N:32]=[CH:31][CH:30]=[CH:29][C:28]=4[N:27]=[C:26]([NH2:40])[C:25]=3[N:24]=[C:23]2[CH2:35][CH2:36][CH3:37])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
mCPBA (1.18 g, 6.86 mmol) was added to a solution of 1-(4-morpholin-4-yl-4-oxobutyl)-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridine (1.80 g, 4.90 mmol) in chloroform (25 mL); the reaction was stirred for two hours at ambient temperature. Ammonium hydroxide (10 mL) was added followed by p-toluenesulfonyl chloride (1.03 g, 5.39 mmol). The reaction was stirred for one hour and partitioned between saturated aqueous sodium bicarbonate (75 mL) and dichloromethane (70 mL). The aqueous layer was extracted with dichloromethane (2×25 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown solid was triturated twice with acetonitrile and then purified by column chromatography using a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc.; Charlottesville, Va., USA) using a FLASH 40+M cartridge (also available from Biotage, Inc.). The polar component of the eluent was chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The purification was carried out eluting with chloroform:CMA in a gradient from 100:0 to 75:25. The resulting solid was dried under high vacuum at 80° C. to provide 0.583 g of 1-(4-morpholin-4-yl-4-oxobutyl)-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as an off-white powder, mp 196-197° C.
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[O:27])[CH:21]=3)=[CH:16][CH:15]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[CH:26]([C:22]1[CH:21]=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:5]3[CH:4]=[C:3]([OH:2])[N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=4)[N:6]=3)=[CH:19][CH:18]=2)[CH:25]=[CH:24][CH:23]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3cccc(C=O)c3)cc2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: O=Cc1cccc(-c2ccc(-c3cc(O)n(-c4ccccn4)n3)cc2)c1

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 46 of Example C-20 was used in place of Compound 27 of Example C-1.
Reaction SMILES: B(Cl)(Cl)Cl.ClCCl.[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:39])[NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[O:37]C)=[CH:22][CH:21]=1)[O:15][CH2:14][CH2:13][CH:12]2[C:40]([OH:42])=[O:41]>>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:39])[NH:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[OH:37])=[CH:22][CH:21]=1)[O:15][CH2:14][CH2:13][CH:12]2[C:40]([OH:42])=[O:41]
Reactant: COc1cc(Cl)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=C(NCCc1ccc(Cl)cc1O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a stirred, chilled (0° C.) solution of boron trichloride in dichloromethane (13.6 mL; 1.0 M; 7 eq.) was added, portionwise over 2 minutes, solid 6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (1.0 g; 1.94 mmol) under nitrogen atmosphere. The resulting mixture was allowed to warm to ambient temperature, stirred for 8 hours and then heated to 35° C. for 24 hours. The reaction was quenched with 5 mL water (significant effervescence observed while adding first 2 mL) and then 6 mL of saturated Na2CO3 was added to bring the pH to 4. During the last 1 mL of addition, significant amounts of precipitates formed in the lower organic layer. The warm bath was removed and replaced with an ice bath. The material was stirred for 5 minutes in ice bath, then solids collected on a medium frit, washing once with 5 mL chilled MTBE. This material was purified via Biotage chromatography with methanol in ethyl acetate to provide the desired 6-chloro-7-(4-(4-chloro-2-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (195 mg). MS (apci, neg) m/z=500. 1H NMR (400 MHz, D6 DMSO) δ 8.45 (t, 1H), 7.82, (d, 2H), 7.46 (s, 1H), 7.06 (d, 1H), 6.95 (d, 2H), 6.83 (d, 1H), 6.75 (dd, 1H), 6.60 (s, 1H), 4.22 (m, 1H), 4.12 (t, 1H), 3.72 (br s, 1H), 3.60 (t, 1H), 2.76 (t, 2H), 2.22 (m, 1H), 1.99 (m, 1H), 1.76 (m, 1H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14](=[N:20][OH:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Br:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([Br:33])[C:31]=1[OH:32])[C:26](O)=O>N1C=CC=CC=1>[Br:22][C:23]1[CH:24]=[C:25]([C:26]2[O:21][N:20]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=2)[CH:29]=[C:30]([Br:33])[C:31]=1[OH:32]
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)c1cc(Br)c(O)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1noc(-c2cc(Br)c(O)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.32 g, 10 mmol) was added in one portion to a stirred solution of ethyl 2-amino-2-(hydroxyimino)acetate (1.32 g, 10 mmol) plus 3,5-dibromo-4-hydroxybenzoic acid (2.95 g, 10 mmol) in pyridine (20 mL), the resulting solution was stirred at room temperature for 2 h and then at 90° C. for 5 h. After standing at room temperature overnight the pyridine was evaporated in vacuo and the residue was purified by flash chromatography (silica gel, 10% ethyl acetate/dichloromethane) to give the title compound (0.48 g, 12%) as a colourless solid. 1H NMR δ (ppm) (DMSO-d6): 1.48 (3H, t), 4.47 (2H, d), 8.13 (2H, s), 11.54 (1H, s, br).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>ClCCl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[C:16]1[C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc2ccccc2[nH]1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(1H-Indole-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (0.165 g) in dichloromethane (10 mL) was treated with trifluoroacetic acid (2 mL) and stirred at ambient temperature for 1 h. The solvent was removed under reduced pressure to afford (1H-Indol-2-yl)-piperazin-1-yl-methanone trifluoroacetate salt. (1H NMR (400 MHz, CDCl3): δ 7.63 (d, J=8.07 Hz, 1H), 7.44 (dd, J=8.3, 0.8 Hz, 1H), 7.24 (m, 1H), 7.08 (m, 1H), 6.91 (s, 1H), 4.12 (t, J=5.0 Hz, 4H), 3.35 (t, J=5.3 Hz, 4H)). This intermediate was dissolved in acetone (5 mL), treated with potassium carbonate (0.22 g), iodohexane (0.106 g) and heated at 50° C. for 10 h. Evaporation of the solvent under reduced pressure afforded crude product which was purified via preparative thin layer chromatography eluting with 10% methanol/dichloromethane to give the title compound (0.06 g). 1H NMR (400 MHz, CD3OD): δ 7.60 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.21(ddd, J=8.1, 7.1, 1.1 Hz, 1H), 7.16-7.04 (m, 1H), 6.81 (s, 1H), 3.89 (br s, 4H), 2.56 (t, J=5.0 Hz, 4H), 2.43-2.40 (m, 2H), 1.58-1.52 (m, 2H), 1.34 (br s, 6H), 0.94-0.90 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][N:3]1[CH3:14].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]2[CH2:6][N:2]([CH3:1])[N:3]([CH3:14])[CH2:4]2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN1CC(Nc2ccccc2)CN1C
Solvent: ClC(Cl)Cl
Product: CN1CC(N(C(=O)c2ccc(Cl)cc2)c2ccccc2)CN1C
Temperature: 25 °C

Procedure:
To a solution of 10 g. (0.0525 mole) of 1,2-dimethyl-4-anilinopyrazolidine in 50 ml. of chloroform was added with stirring 9.15 g. (0.0525 mole) of p-chlorobenzoyl chloride with the temperature not exceeding 50° C. On completion of addition the solution was refluxed for one hour, cooled to room temperature and extracted with dilute sodium hydroxide. The chloroform layer was dried over sodium sulfate and concentrated at reduced pressure to give an oil which crystallized upon cooling. The solid was recrystallized twice from ligroin. Yield 13.1 g. (76%); m.p. 104°-108° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][N:11]([CH3:31])[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[NH:23][CH:22]([CH2:24][C:25]([O:27]C)=[O:26])[C:21](=[O:29])[NH:20][CH2:19][C:18]=2[CH:30]=1)=[O:13].O.[OH-].[Na+].FC(F)(F)C(O)=O>CO>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][N:11]([CH3:31])[C:12]([C:14]1[CH:15]=[CH:16][C:17]2[NH:23][CH:22]([CH2:24][C:25]([OH:27])=[O:26])[C:21](=[O:29])[NH:20][CH2:19][C:18]=2[CH:30]=1)=[O:13]
Reactant: COC(=O)CC1Nc2ccc(C(=O)N(C)Cc3nc4ccccc4[nH]3)cc2CNC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CN(Cc1nc2ccccc2[nH]1)C(=O)c1ccc2c(c1)CNC(=O)C(CC(=O)O)N2
Reaction time: 16 h

Procedure:
A solution of methyl (±)-7-[[[(2-benzimidazolyl)methyl]methylamino]carbonyl]-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.040 g, 0.09 mmol) in a mixture of methanol (7.0 mL), water (0.7 mL), and 1.0 M NaOH (0.7 mL) was kept 16 h at RT. Trifluoroacetic acid (0.5 mL) was added and the solvents were removed to give the crude product. Purification by semi-preparative HPLC (YMC ODS-AQ, 15:85; acetonitrile:water, 0.1% TFA) gave the title compound: MS (ES) m/e 408.2 (M+H)+ ; 1H NMR (250 MHz, DMSO-d6) δ 8.19 (br t, J=4.5 Hz, 1H), 7.72 (m, 2H), 7.38 (m, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.22 (br s, 1H), 5.05 (m, 1H), 4.95 (s, 2H), 3.74 (dd, 15.8, 7.4 Hz, 1H), 3.15 (s, 3H), 2.75 (dd, J=16.4, 8.5 Hz, 1H), 2.50 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].CN(C=O)C.[OH-].[K+]>O>[F:15][C:16]1[CH:17]=[C:18]([NH:19][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: Nc1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNc1cccc(F)c1)Nc1ccccc1C(=O)O
Yield: 78.3 %

Procedure:
A solution of 2-(N-bromoacetylamino) benzoic acid from Example 79 (8.00 g, 31.0 mmol), meta-fluoroaniline (7.45 mL, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature, and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. to yield 7.00 g (78%) of the title compound as a grey solid; 1H NMR (DMSO-d6) δ 13.5 (broad s, 1H), 11.94 (s, 1H), 8.70 (d, J=8.4, 1H), 7.94 (dd, J=7.8, J=1.4, 1H), 7.60 (td, J=8.0, J=1.4, 1H), 7.15-7.07 (m, 2H), 6.83 (broad s, 1H), 6.43-6.35 (m, 3H), 3.88 (s, 2H); 13C NMR (DMSO-d6) δ 170.29, 169.12, 163.25 (J=240.3), 150.17 (J=10.6), 140.52, 134.18, 131.13, 130.43 (J=10.6), 122.73, 119.40, 115.98, 108.42, 103.09 (J=21.2), 98.97 (J=25), 48.48; MS (EI, m/z) 388 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C-:11]#[N:12].[K+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[C:11]#[N:12]
Reactant: [C-]#N
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(O)c1c(Cl)cccc1Cl
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a stirred and cooled suspension of 438 g of 2,6-dichlorobenzaldehyde in 2000 g of glacial acetic acid there was added dropwise a solution of 203 g of potassium cyanide in 350 g of water, keeping the temperature below 25° C. Stirring was continued overnight at room temperature. The reaction mixture was concentrated and the residue, which solidified upon cooling, was filtered off and dried, yielding 438 g of (±)-2,6-dichloro-α-hydroxybenzeneacetonitrile; mp. 90° C. (interm. 1).
Reaction SMILES: [C:1]12([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:21][C:22]1[CH:34]=[CH:33][C:25]([O:26][C:27]([CH3:32])([CH3:31])[C:28](Cl)=[O:29])=[CH:24][CH:23]=1.N1C=CC=CC=1>O>[C:1]12([CH2:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:28](=[O:29])[C:27]([O:26][C:25]4[CH:33]=[CH:34][C:22]([Cl:21])=[CH:23][CH:24]=4)([CH3:32])[CH3:31])=[CH:18][CH:19]=3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: O=C(CC12CC3CC(CC(C3)C1)C2)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)Oc1ccc(C(=O)CC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 4 h

Procedure:
6.75 g (25 mmol) of p-(1-adamantylacetyl)-phenol and 6 g (25.7 mmol) of 2-(p-chlorophenoxy)-isobutyric acid chloride was mixed with 60 ml of dry pyridine and kept at 40° C. for 4 hours. After addition of 40 ml of water a crystalline product was obtained which was sucked off, washed with water and dried.