Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:20](F)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]2[CH2:34][NH:33][CH2:32][CH2:31][NH:30]2)[CH:26]=[CH:27][CH:28]=1>>[F:1][C:2]1[C:20]([N:33]2[CH2:32][CH2:31][NH:30][CH:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=3)[CH2:34]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: Fc1cccc(C2CNCCN2)c1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(c5cccc(F)c5)C4)cc3nc21
Yield: 86.2 %

Procedure:
The reaction is performed under the conditions of Example 16, but starting with 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (1.3 g) and (RS)-2-(3-fluorophenyl)piperazine (1.8 g). After 1 recrystallization in dimethylformamide (50 cc) containing ethanol (50%), (RS)-7-fluoro-8-[3-(3-fluorophenyl)-1-piperazinyl]-1-methyl-4-oxo -1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid (1.74 g) is obtained in the form of a yellow solid, m.p. 254° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([C:8]1[CH:14]=[CH:13][C:11]([OH:12])=[CH:10][C:9]=1[OH:15])[CH3:7].[H-].[Na+].[P:18](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[CH2:5]([O:1][P:18]([O:12][C:11]1[CH:13]=[CH:14][C:8]([CH2:6][CH3:7])=[C:9]([O:15][P:18]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH:10]=1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:4]1[CH:29]=[CH:30][CH:31]=[CH:2][CH:3]=1
Reactant: O=P(Cl)(OCc1ccccc1)OCc1ccccc1
Reactant: CCc1ccc(O)cc1O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1OP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a tetrahydrofuran solution (10 ml) of 4-ethylresorcinol (423 mg), sodium hydride (60% dispersion in liquid paraffin) (269 mg) was added and stirred at 0° C. for 30 minutes. Then, dibenzyl chlorophosphate (10 w/v % solution in benzene) (20 ml) was added dropwise. After stirring at room temperature for 3 hours, water (10 ml) was added to the reaction mixture, and the extraction was carried out with ethyl acetate (30 ml). Then, the extract was washed with saturated brine (10 ml), dried with anhydrous sodium sulfate and then concentrated. The residue (2.16 g) was subjected to silica gel chromatography (silica gel 60 g, chloroform to chloroform:methanol=50:1), to give 1,3-bis(dibenzylphosphonooxy)-4-ethylbenzene (1.65 g, yield: 84%) as a yellow liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:23]=[C:22]([C:24]2([CH3:27])[CH2:26][CH2:25]2)[CH:21]=[CH:20][C:19]=1[C@@H:28]([NH2:30])[CH3:29].CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CS(C)=O>[F:17][C:18]1[CH:23]=[C:22]([C:24]2([CH3:27])[CH2:25][CH2:26]2)[CH:21]=[CH:20][C:19]=1[C@@H:28]([NH:30][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1)[CH3:29]
Reactant: C[C@H](N)c1ccc(C2(C)CC2)cc1F
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C3(C)CC3)cc2F)n1
Temperature: 110 °C
Yield: 5.3 %

Procedure:
To a microwave vial with stir bar was added (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (30 mg, 0.12 mmol) and DMSO (1 mL). To this reaction mixture was added (S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethanamine (51 mg, 0.22 mmol) and DIEA (0.09 ml, 0.50 mmol). The vial was capped and the reaction mixture was heated in a preheated oil bath at 110° C. for 18 hr. Solution was purified by reverse phase HPLC. Product fractions combined, frozen and lyophilized to afford (S)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (3.3 mg, 6.3 μmol, 5% yield) as a TFA salt. 1H NMR (400 MHz, CD3OD) δ 0.58 (br. s., 3H) 0.77 (td, J=5.23, 1.76 Hz, 5H) 0.80-0.86 (m, 2H) 1.38 (s, 3H) 1.57 (d, J=6.94 Hz, 3H) 4.34-4.41 (m, 2H) 4.67 (br. s., 1H) 5.33 (d, J=7.97 Hz, 1H) 6.95-7.05 (m, 2H) 7.22 (t, J=7.97 Hz, 1H) 7.67 (d, J=6.85 Hz, 1H) 8.14 (d, J=6.65 Hz, 1H). LCMS m/z 399.4 (M+H)+, Rt 0.93 min. HRMS(A) m/z 399.2202 (M+H)+, Rt 2.23 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[S:7][CH:8]=[CH:9][N:10]=2)=[CH:2]1.N1[C:24]2[C:15](=CC=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[O:33]1[CH2:38]COC[CH2:34]1>[Cu]I>[CH3:34][O:33][C:38]1[CH:12]=[C:13]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[S:7][CH:8]=[CH:9][N:10]=3)=[CH:2]2)[CH:14]=[CH:15][C:24]=1[C:23]1[CH:18]=[CH:19][CH:20]=[CH:21][N:22]=1
Reactant: c1csc(-c2cc[nH]c2)n1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: C1COCCO1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-n2ccc(-c3nccs3)c2)ccc1-c1ccccn1

Procedure:
A solution of 2-(1H-pyrrol-3-yl)-1,3-thiazole (0.100 g, 0.67 mmol) 3-(3-iodophenyl)pyridine (0.248 g, 0.8 mmol), copper(I) iodide (0.038 g, 0.2 mmol), 1,10-Phenanthroline (0.360 g, 2 mmol), potassium phosphate (0.440 g, 2.0 mmol) in dioxane (2 mL) was heated to 200° C. for ½ hr under microwave irradiation. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (EtOAc 100%) to give 2-{2-methoxy-4-[3-(1,3-thiazol-2-yl)-1H-pyrrol-1-yl]phenyl}pyridine as a slightly yellow oil. The free base in anhydrous diethyl ether was treated with 1.5 equivalent HCL (1M in Ether) to give HCl salt.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
To a solution of pentan-1-ol (9.2 mL, 85 mmol) in CH2Cl2 (70 mL) and pyridine (50 mL) was added 4-(dimethylamino)pyridine (0.52 g, 4.3 mmol) followed by p-toluenesulfonyl chloride (16.2 g, 85 mmol). The mixture was allowed to stir at ambient temperature for 18 h then was quenched with 5% aqueous HCl (10 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (13.1 g, 53.9 mmol, 63% yield). MS (DCI/NH3) m/z 260 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1.C(N(CC)CC)C.O>CS(C)=O>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(CO)cn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 g (71.9 mMol) of 2-methoxy-5-hydroxymethylpyridine (preparation see Heterocycl. Commun. 1999, 5, 257) are dissolved in 160 ml of DMSO and 30 ml (215 mMol) of triethylamine. At RT (exothermic-cool!), 34.3 g (215 mMol) of sulfur trioxide pyridine complex in 160 ml DMSO are added dropwise, and the mixture is stirred 1 h at RT. The mixture is poured into water and extracted three times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and evaporated to yield the title compound: HPLC(Grad5-40) tRet=12.9.
Reaction SMILES: C([N:8]1[C@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:13][C@H:12]1[NH:8][C@H:9]([CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@@H](C)N2)cc1
Reaction time: 0.58 h
Yield: 94.4 %

Procedure:
To a stirred solution of methyl 4-[N-Boc-5-(R)-methyl-2-(S)-pyrrolidinylmethoxy]benzoate (1.29 g, 3.70 mmol) in CH2Cl2 (30 ml) was added trifluoroacetic acid (10 ml) at rt, and the resulting mixture was stirred for 35 min. The mixture was concentrated in vacuo and poured into aq.NaHCO3, then extracted with CHCl3. The organic layer was washed with water, drying over anhydrous Na2SO4, and concentrated in vacuo to give methyl 4-[5-(R)-methyl-2-(S)-pirrolidinyl methoxy]benzoate (871 mg, 95%) as a colorless oil. The product was used for next reactions without further purification. 1H-NMR (CDCl3) δ1.18 (d, J=6.4 Hz, 3 H), 1.30-1.40 (m, 1 H), 1.59-1.67 (m, 1 H), 1.87-1.97 (m, 2 H), 3.19-3.27 (m, 1 H), 3.49-3.55 (m, 1 H), 3.87 (s, 3 H), 3.89-4.05 (m, 2 H), 6.89 (d, J=8.8 Hz, 2 H), 7.96 (d, J=8.8 Hz, 2 H); MS (ESI) m/z, 250 (M++H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[N:10]([CH2:20][C:21]([N:23]([CH3:34])[C:24]3[CH:33]=[CH:32][C:27]4[N:28]=[C:29]([CH3:31])[O:30][C:26]=4[CH:25]=3)=[O:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:41](I)[CH3:42]>CN(C=O)C.O>[CH2:41]([O:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][N:10]([CH2:20][C:21]([N:23]([CH3:34])[C:24]3[CH:33]=[CH:32][C:27]4[N:28]=[C:29]([CH3:31])[O:30][C:26]=4[CH:25]=3)=[O:22])[C:11]2=[O:19])=[CH:16][CH:15]=1)[CH3:42]
Reactant: Cc1nc2ccc(N(C)C(=O)Cn3nc(-c4cccc(F)c4)c4ccc(O)cc4c3=O)cc2o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2c(-c3cccc(F)c3)nn(CC(=O)N(C)c3ccc4nc(C)oc4c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
2-(4-(3-fluorophenyl)-7-hydroxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (6.5 g, 14.19 mmol) was dissolved in DMF (60 mL), treated with K2CO3 (3.04 g, 21.2 mmol) and stirred at rt for 30 min. After cooling to 0° C., EtI (1.26 mL, 15.59 mmol) was added dropwise and the reaction was warmed to rt for 1 h. It was diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The organics were washed with brine (300 mL), dried over Na2SO4, and concentrated to give crude material which was purified by chromatography (40% EtOAc/hexane) to yield 2-(7-ethoxy-4-(3-fluorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (3.5 g) (487.52 [M+H]). 1H NMR: (400 MHz, DMSO) δ: 1.39-1.42 (t, 3H), 2.62 (s, 3H), 3.24 (s, 3H), 4.22-4.24 (d, J=7.2, 2H), 4.72 (s, 2H), 7.37-7.49 (m, 5H), 7.58-7.65 (m, 3H), 7.71-7.73 (d, J=8.4, 1H), 7.90 (s, 1H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([NH:49][CH:50]([CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:51](Cl)=[O:52])(=[O:48])=[O:47])=[CH:42][CH:41]=1.CO>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:51](=[O:52])[CH:50]([NH:49][S:46]([C:43]3[CH:42]=[CH:41][C:40]([CH3:39])=[CH:45][CH:44]=3)(=[O:48])=[O:47])[CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)NC(Cc2ccccc2)C(=O)Cl)cc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccccc2)C(=O)N2Cc3c(nc(C(C)C)c(C(OC(C)(C)C)C(=O)O)c3-c3ccc(F)cc3)C(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10 mg, 0.023 mmol) in CH2Cl2 (5 mL) was added Et3N (0.020 mL, 0.140 mmol) and the resulting mixture cooled to 0° C. Added to this was 2-(4-methylphenylsulfonamido)-3-phenylpropanoyl chloride (23.65 mg, 0.070 mmol) and the mixture stirred at room temperature (mixture became a clear colorless solution over time). After 1 h, 0.5 mL MeOH was added and the mixture was concentrated under a stream of air and taken up in MeOH and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm column) The product-containing fractions were concentrated to remove the organic solvent and the resulting precipitate was collected by filtration to give 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2-(4-methylphenylsulfonamido)-3-phenylpropanoyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (3.7 mg, 21% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.56-7.80 (1H, m), 6.91-7.57 (12H, m), 6.71-6.92 (1H, m), 4.85 (1H, s), 3.99-4.26 (1H, m), 3.78-4.00 (0.5H, m), 3.46-3.77 (1.5H, m), 3.36-3.46 (2H, m), 3.13-3.28 (1H, m), 2.60-2.87 (2H, m), 2.11-2.50 (3H, m), 0.85-1.46 (21H, m). 19F NMR (400 MHz, CD3OD) δ ppm −114.16, −115.11, −117.98, −118.41. LCMS (M+H) calcd for C41H49FN3O6: 730.33. found: 730.03.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]#[C:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:28])[C:12]([C:17]4[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=4)=[CH:13][O:14]3)=[CH:9][CH:8]=2)[CH2:2]1.FC(F)(F)C(O)=O.[C:36](=O)([O:43]N1C(=O)CCC1=O)[O:37][CH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:38]1([O:37][C:36]([N:1]2[CH2:4][CH:3]([C:5]#[C:6][C:7]3[CH:16]=[C:15]4[C:10]([C:11](=[O:28])[C:12]([C:17]5[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=5)=[CH:13][O:14]4)=[CH:9][CH:8]=3)[CH2:2]2)=[O:43])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)Nc1ccc(-c2coc3cc(C#CC4CNC4)ccc3c2=O)cc1
Reactant: O=C(OC1CCCC1)ON1C(=O)CCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2coc3cc(C#CC4CN(C(=O)OC5CCCC5)C4)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(4-(7-(azetidin-3-ylethynyl)-4-oxo-4H-chromen-3-yl)phenyl)methanesulfonamide.trifluoroacetic acid salt (55 mgs, 0.140 mmol) in dichloromethane (3 mL) was added cyclopentyl 2,5-dioxopyrrolidin-1-yl carbonate (95 mgs, 0.42 mmol) and diisopropylethylamine (0.2 mL, 1.4 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under reduced pressure, and chromatographed (SiO2, 25% ethyl acetate/dichloromethane) to provide cyclopentyl-3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl)ethynyl)azetidine-1-carboxylate:
Reaction SMILES: Cl[C@H:2]([CH2:18][CH3:19])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[C:7]([CH3:17])([CH3:16])[CH2:6]1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C@H:2]([C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=3)[C:7]([CH3:17])([CH3:16])[CH2:6]2)=[O:4])[CH2:18][CH3:19])[CH2:29][C@H:28]1[CH3:33])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC[C@@H](Cl)C(=O)N1CC(C)(C)c2ccc(C#N)cc21
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC[C@@H](C(=O)N1CC(C)(C)c2ccc(C#N)cc21)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 50 °C
Reaction time: 36 h
Yield: 14.5 %

Procedure:
To a suspension of (R)-1-(2-chlorobutanoyl)-3,3-dimethylindoline-6-carbonitrile (0.1 g, 0.36 mmol), (R)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.072 g, 0.36 mmol) in acetonitrile (2.5 mL) was added potassium carbonate (0.049 g, 0.36 mmol) and the reaction heated to 50° C. for 48 h followed by 80° C. for 24 h and 60° C. for 36 h. The reaction mixture was then diluted with ethyl acetate and washed with water. The organics were separated, dried with sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel; eluting with 20-30% ethyl acetate in heptane to give (R)-4-[(S)-1-(6-cyano-3,3-dimethyl-2,3-dihydro-indole-1-carbonyl)-propyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.023 g). MS: [M+H]+=441.
Reaction SMILES: BrC1C=CC(C2C=CC=C3C=2CC(=O)N3)=CC=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2C=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][CH:29]=2)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Agent: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCn2ccnn2)c[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 160.6 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[44-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide as a yellow solid (88 mg, 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.[CH3:18][CH:19]([CH2:34][C:35](=O)[CH3:36])[C:20](=O)[CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C=O>C1C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:2]2[N:1]3[C:35]([CH3:36])=[CH:34][C:19]([CH3:18])=[C:20]3[CH2:21][N:22]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:12])[C:3]=2[CH:13]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: CC(=O)CC(C)C(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1cc(C)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Yield: 54.3 %

Procedure:
2-Amino-2',5-dichlorobenzophenone (200 mg, 0.752 millimole) and 3-methyl-1-phthalimidohexane-2,5-dione (225 mg, 0.823 millimole) were dissolved in 10 ml of benzene, and 20 mg of p-toluenesulfonic acid was added. The mixture was heated under reflux for 4 hours, and 2 ml of N,N-dimethylformamide was added. The benzene was evaporated under reduced pressure, and 8 ml of ethanol and 0.3 ml of hydrazine hydrate were added. The mixture was heated under reflux for 30 minutes. The ethanol was evaporated under reduced pressure, and 25 ml of benzene was added. The mixture was heated under reflux for 5 minutes. After cooling, the solid was separated by filtration. The filtrate was washed with water and an aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the concentrate was chromatographed on silica gel. The column was first eluted with benzene to recover unchanged 2-amino-2',5-dichlorobenzophenone, and then with benzene-ethyl acetate (49:1) to afford 145 mg of 8-chloro-6-(2-chlorophenyl)-1,3-dimethyl-4H-pyrrolo[1,2-a][1,4]benzodiazepine as yellow crystals in a yield of 54%. The product showed the same spectral data as those of the compound obtained in Example 32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:34]=[CH:33][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br.O>CN(C)C=O>[CH3:37][O:38][C:39](=[O:46])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:34]=[CH:33][C:15]2[N:16]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: COc1ccc(-n2c(-c3ccccc3)nc3cc(NS(=O)(=O)c4ccc(Cl)cc4)ccc32)cc1
Reactant: COC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccc(OC)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
75 mg of 4-chloro-N-[1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-5-yl]benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 6 mg of sodium hydride and stirred for 30 minutes at 20° C. 44 mg of 6-bromohexanoic acid methyl ester was added, allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:23](#[N:25])[CH3:24].[C:26](O)(=O)C>>[C:23]([CH2:24][CH2:26][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)=[CH:6][CH:7]=1)#[N:25]
Reactant: Nc1ccc(CCCN2CCN(c3ccccc3)CC2)cc1
Reactant: CC#N
Reactant: CC(=O)O
Product: N#CCCNc1ccc(CCCN2CCN(c3ccccc3)CC2)cc1
Yield: 81.3 %

Procedure:
A mixture consisting of 29.5 gm (0.1 mol) of N-[γ-(p-amino-phenyl)-n-propyl]-N'-phenyl-piperazine (m.p. 102°C), 5.8 gm (0.11 mol) of acetonitrile and 20 ml of glacial acetic acid was refluxed for 20 hours. Thereafter, the solvent was distilled off in vacuo, and the residue was recyrstallized from dilute methanol, yielding 28.3 gm (81.3% of theory) of N-[γ-(p-[β-cyanoethyl-amino]-phenyl)-n-propyl]-N'-phenyl-piperazine, m.p. 141° - 143°C.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][P:10]([C:15](Cl)([Cl:22])[C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])([O:12][CH2:13][CH3:14])=[O:11])[CH3:8].C(Cl)(Cl)Cl>O.C(O)C>[CH2:7]([O:9][P:10]([CH:15]([Cl:22])[C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17])([O:12][CH2:13][CH3:14])=[O:11])[CH3:8]
Reactant: CCCOC(=O)C(Cl)(Cl)P(=O)(OCC)OCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCOC(=O)C(Cl)P(=O)(OCC)OCC
Temperature: 8 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
A solution of sodium sulphite (78.6 g) in water (2000 cm3) was added dropwise to a cooled solution of propyl diethylphosphonodichloroacetate (95.7 g) in ethanol (408cm3) over a period of 70 minutes, the temperature of the mixture being maintained below 8° C. during the addition by external cooling. The mixture was stirred at 8° C. for 10 minutes, then without external cooling for a further 15 minutes. Chloroform (100cm3) was added and the mixture stirred vigourously for 3 minutes. The chloroform phase was separated and combined with further chloroform extracts of the aqueous phase, The combined organic layers were dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure to give the crude product as a yellow oil from which volatile compounds were removed by storage under high vacuum. The crude product was purified by distillation under reduced pressure to give a colourless liquid (75.2 g)