Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=O.Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[N:12][OH:13]
Reactant: Cc1ccc(C=O)cc1Br
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C=NO)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a stirred suspension of 3-bromo-4-methylbenzaldehyde (1.0 g, 5 mmol, 1.0 eq) in methanol (50 mL) was added a solution hydroxylamine hydrochloride (434 mg, 6.3 mmol, 1.2 eq) in water (2 mL) at room temperature. The resulting solution was cooled to 0° C. and then treated with an aqueous solution of sodium carbonate (2M, 2 mL). After stirring for 1 h at room temperature, the solvent was removed under vacuum. The residue was taken into ethyl acetate (20 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (15 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under vacuum to afford 0.85 g of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.87 (s, 1H, D2O exchangeable) 7.76 (d, J=1.5 Hz, 1H), 7.43 (dd, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 2.44 (s, 3H); ESI-MS (m/z) 214, 216 [(MH)+, Br79,81].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:13]=1[CH:14]=[O:15].[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:14]([C:13]3[C:16]([Cl:21])=[CH:17][CH:18]=[C:19]([F:20])[C:12]=3[Cl:11])[OH:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=Cc1c(Cl)ccc(F)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C

Procedure:
To a stirred mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (0.100 g, 0.508 mmol) and 2,6-dichloro-3-fluorobenzaldehyde (0.107 g, 0.558 mmol) in MeOH (5 mL) was added potassium hydroxide (0.199 g, 3.553 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was then stirred at rt. overnight. The mixture was then poured into water (50 mL), acidified with 2N HCl and extracted with ethyl acetate (50 mL×3). The organics were combined, dried (Na2SO4) and concentrated under reduced pressure to give a crude residue which was then purified by chromatography (eluent: 20% ethyl acetate in hexane). MS (ES+): m/z=388.85, 390.84, 392.83 [MH+]. HPLC: tR=3.29 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][CH2:24][CH2:25][OH:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].Cl>ClCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][CH2:24][CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(COCCO)ccc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-Chloro-5-[(2-hydroxyethoxy)methyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.228 g, Example 25a) and triethylamine (0.21 ml) in dichloromethane (10 ml) were cooled to 5° C. under nitrogen and methanesulfonyl chloride (0.1 ml) was added. The mixture was stirred at room temperature for 20 h then poured into 2N hydrochloric acid, and extracted into ethyl acetate. The combined extracts were washed with 2N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution then brine, and dried over magnesium sulfate. The organics were filtered and concentrated under reduced pressure to afford the subtitled compound as a white solid (0.160 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=4[CH3:33])[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3)CCCCC2)CC1

Procedure:
Example 92 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.46–7.43 (m, 3H), 7.26–7.22 (m, 2H), 7.10 (d, 1H, J=8.4 Hz), 7.06–7.01 (m, 2H), 6.74 (brs, 1H), 3.31 (dd, 2H, J=6.0, 12.0 Hz), 2.96 (d, 2H, J=11.6 Hz), 2.68 (m, 1H), 2.52 (m, 1H), 2.36–2.32 (m, 4H), 2.29 (s, 3H), 2.03–1.90 (m, 4H), 1.74–1.61 (m, 12H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 522.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:9]=2[CH:10]=1)[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[O:7][C:8]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:9]=3[CH:10]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH3:2]
Reactant: CCOC(=O)Cc1cc2cc(C)ccc2o1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2cc3cc(C)ccc3o2)CCCC1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product of Step 3, above (57) (1.85 mmol), in 2 ml DMF was added 60% sodium hydride in oil (3.6 mmol) at ambient temperature. The reaction mixture was stirred for 15 minutes and then 1,4-dibromobutane (1.85 mmol) was added. The reaction mixture was heated to 80° C. for 2 hours, cooled to ambient temperature, diluted with EtOAc and washed with saturated sodium bicarbonate and brine. The combined organics were then dried over MgSO4, filtered and concentrated to dryness. The crude material was chromatographed on silica gel using 10% EtOAc in hexanes as the eluant to obtain the title compound (58).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([C:23](Cl)=[O:24])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].Cl>ClCCCl>[C:14]([N:17]1[CH2:18][CH2:19][CH:20]([C:23](=[O:24])[C:7]2[CH:6]=[CH:5][C:4]([O:8][CH3:9])=[CH:3][C:2]=2[F:1])[CH2:21][CH2:22]1)(=[O:16])[CH3:15]
Reactant: COc1cccc(F)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)c(F)c1
Reaction time: 1 h

Procedure:
A mixture of 155 parts of 1-fluoro-3-methoxybenzene, 75 parts of aluminium chloride and 650 parts of 1,2-dichloroethane is stirred and 113 parts of 1-acetyl-4-piperidinecarbonyl chloride are added portionwise. Upon completion, stirring is continued for 1 hour at 40°-50° C. The reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid. The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by high pressure liquid-chromatography over silica gel using a mixture of trichloromethane, hexane and methanol (47.5:47.5:5 by volume) as eluent. The first fraction (A-isomer) is collected and the eluent is evaporated, yielding 1-acetyl-4-(2-fluoro-4-methoxybenzoyl)-piperidine. The second fraction (B-isomer) is collected and the eluent is evaporated, yielding 40 parts (25%) of 1-acetyl-4-(4-fluoro-2-hydroxybenzoyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25].ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=C(CC)C=1OC.[CH3:54][N:55]1[C:59]([CH:60]=O)=[N:58][C:57]([CH3:62])=[N:56]1.CC1C=C(C)N2N=C(C=O)N=C2N=1>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:15][C:14]([OH:16])=[C:13]([CH2:60][C:59]3[N:55]([CH3:54])[N:56]=[C:57]([CH3:62])[N:58]=3)[C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25]
Reactant: Cc1nc(C=O)n(C)n1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc(Cl)c1OC
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Solvent: O
Product: Cc1nc(CC2=C(O)CC(CCc3ccc(C(C)(C)C#N)c(Cl)c3)(C3CCCC3)OC2=O)n(C)n1

Procedure:
The title compound was prepared analogously to example A(1): where 2-{2-chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile.from step 5 below, was substituted in place of 6-[2-(3-chloro-5-ethyl-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2,5-dimethyl-2H-[1,2,4]triazole-3-carbaldehyde was substituted instead of 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde in that example. 1H NMR (300 MHz, DMSO-d6): δ 1.47–1.74 (m, 8 H), 1.79 (s, 6 H), 2.01–2.11 (m, 8 H), 2.36–2.42 (m, 1 H), 2.56 (d, J=16 Hz, 1 H), 2.60–2.66 (m, 2 H), 2.77 (d, J=16 Hz, 1 H), 3.53 (d, J=16 Hz, 1 H), 3.62 (d, J=16 Hz, 1 H), 7.25 (dd, J=8.2, 1.8 Hz, 1 H), 7.4 (d, J=1.8 Hz, 1 H), 7.45 (d, J=8.2 Hz, 1 H). Anal. Calcd. For C27H33ClN4O3.0.25 H2O: C, 64.66; H, 6.73; N, 11.17. Found: C, 64.88; H, 6.74; N, 10.86. ESIMS (MH+): 498.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[CH:32]=2)[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:47].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C.C(Cl)Cl>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:45])=[N:14][C:15]2[N:16]([N:30]=[C:31]([C:33](=[O:44])[NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH3:43])[CH:37]=3)[C:32]=2[F:47])[C:17]=1[C:18]1[C:19]([CH3:29])=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[O:24][CH2:23][CH2:22][CH2:21]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(F)c(C(=O)NCc3ccc(F)c(C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Reaction time: 18 h
Yield: 26.1 %

Procedure:
To a slurry of (2S)-ethyl 2-(tert-butoxy)-2-(2-((4-fluoro-3-methylbenzyl)carbamoyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (82 mg, 0.132 mmol, 1 equiv) in acetonitrile (2.6 mL) was added Selectfluor (56 mg, 0.159 mmol, 1.2 equiv). After stirring 18 h, reaction is an orange slurry. LCMS indicated ˜50% conversion. The reaction was diluted with DCM and washed with saturated aqueous bicarbonate. The DCM layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (0-10% EtOAc in hexane) to provide desired product as a yellow solid (22 mg, 26% yield). 1H NMR (500 MHz, CDCl3) δ 7.20-7.16 (m, 1H), 7.15-7.10 (m, 1H), 7.04-6.99 (m, 1H), 6.99-6.94 (m, 1H), 6.87-6.81 (m, 1H), 4.95 (s, 1H), 4.57 (d, J=5.8 Hz, 2H), 4.35 (br. s., 2H), 4.19-4.11 (m, 2H), 2.80 (s, 3H), 2.78-2.73 (m, 2H), 2.27 (s, 3H), 2.18 (br. s., 2H), 1.81 (s, 3H), 1.29 (t, J=6.9 Hz, 3H), 1.17 (s, 9H); 19F NMR (471 MHz, CDCl3) d−119.41 (s, 1F), −139.50 (s, 1F), −175.35 (s, 1F); LCMS (ESI, M+1): 639.5.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([NH2:14])[NH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[C:24]([CH:28]=1)[C:25]([NH:14][C:11]1[NH:12][N:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:15])([F:1])[F:16])[CH:4]=2)[N:10]=1)=[O:26]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1nc(-c2cccc(C(F)(F)F)c2)n[nH]1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 5-(3-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3-amine (100 mg, 0.44 mmol, 1.00 equiv) in tetrahydrofuran (1 mL) was added sodium hydride (35 mg, 0.88 mmol, 2.00 equiv, 60%) followed by the dropwise addition of a solution of 5-chloro-2-nitrobenzoyl chloride (96.49 mg, 0.44 mmol, 1.00 equiv) in tetrahydrofuran (1 mL) and the resulting solution was stirred for 2 h at room temperature. The mixture was diluted with 50 mL of ethyl acetate, washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 120 mg (67%) of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.CO.[CH2:13](Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:13][O:9][C:8](=[O:10])[C:7]1[C:2]([Br:1])=[CH:3][CH:4]=[N:5][CH:6]=1
Reactant: ClCCCl
Reactant: O=C(O)c1cnccc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cnccc1Br
Temperature: 0 °C
Yield: 45.6 %

Procedure:
To a solution of 4-bromonicotinic acid (16.8 g, 83.2 mmol, 1.0 eq.) in DCM (250 mL) at 0° C. was added DMAP (1.0 g, 8.2 mmol, 0.1 eq.). MeOH (2.7 g, 83.7 mmol, 1.0 eq.) was added dropwise with stirring at 0° C. EDC (16.8 g, 87.6 mmol, 1.1 eq.) was then added. The resulting solution was stirred for 3 hours at 0° C. The reaction was then quenched with water (100 mL). The resulting solution was extracted with DCM. The organic layer was washed with saturated aqueous NaCl (3×100 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to yield 4-bromonicotinic acid methyl ester (8.2 g) as a yellow oil.
Reaction SMILES: C1([OH:7])C=CC=CC=1.[C:8]1([CH:14]([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]([OH:7])([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)c1ccccc1
Reactant: Oc1ccccc1
Product: CC(C)(O)c1ccccc1

Procedure:
From the synthesis of phenol by oxidation of cumene, a crude oxidate containing, after concentration, essentially cumenyl hydroperoxide (CHPO) and 2-phenyl-2-propanol was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(F)c2)c1-c1ccccc1

Procedure:
m-Fluoroaniline (5 mmol, 0.6 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in chloroform, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids filtered away and the solvents removed under vacuum. The named product was recrystallized from ethanol (m.p. 100° C.-101° C.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C@@H:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:24][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Product: Fc1ccc(CN[C@H]2CCCc3ccccc32)cc1C(F)(F)F

Procedure:
4-Fluoro-3-(trifluoromethyl)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:9][CH2:8]1.[O:18]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21](=[O:22])[C:20]([C:29](O)=[O:30])=[C:19]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C1C=CC=CN=1)C.CS(Cl)(=O)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:29]([C:20]2[C:21](=[O:22])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:18][C:19]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])[CH2:11][CH2:12]1
Reactant: O=C(O)c1c(-c2ccccc2)oc2ccccc2c1=O
Reactant: NCCCCN1CCN(c2ccccn2)CC1
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: O=C(NCCCCN1CCN(c2ccccn2)CC1)c1c(-c2ccccc2)oc2ccccc2c1=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
3.6 g of the 4-[4-(2-pyridyl)-piperazin-1-yl]butylamine obtained above were added to a reaction mixture cooled to -20° C. which contained, in 100 ml of absolute dichloromethane, a mixed anhydride produced in a manner analogous to Example 1 (a) from 4.0 g flavone-3-carboxylic acid, 3.367 g dimethylaminopyridine and 1.28 ml methanesulfonyl chloride. The reaction mixture was allowed to warm up to room temperature and stirred at room temperature for two hours. Subsequently the reaction mixture was worked up analogously to Example 3, and the resulting title compound was recrystallized from ethylacetate. There were obtained 4.7 g 3-{4-[4-(2-pyridyl)-piperazin-1-yl]-butylaminocarbonyl)-flavone. yl]-butylaminocarbonyl}-flavone.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:4]#[N:5].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O1CCCC1>[CH3:18][S:19]([O:1][N:2]=[C:3]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[C:4]#[N:5])(=[O:21])=[O:20]
Reactant: N#CC(=NO)c1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C(C#N)c1ccsc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
In general analogy to the reaction described under 3.2, 15.2 g (0.1 mol) of α-hydroxyimino-thiophene-3-acetonitrile and 15.2 g (0.15 mol) of triethylamine are dissolved in 150 ml of tetrahydrofuran and to this is added dropwise a solution of 12.6 g (0.11 mol) of methanesulfonyl chloride at 0-5° C. After the addition is complete, the mixture is stirred for 30 minutes at 0° C. and then overnight at room temperature. The reaction mixture is filtered, the filtrate is washed with dilute hydrochloric acid and with saturated sodium chloride solution and then dried over magnesium sulfate. The solvent is distilled off on a rotary evaporator, giving a solid residue which is then recrystallised from ethyl acetate/hexane (2:1). 11.2 g (49%) of α-(methylsulfonyloxyimino)thiophene3-acetonitrile are obtained in the form of a colourless powder having an m.p. of 116-124° C. The 1H-NMR spectrum shows it to be the pure cis-isomer (Example 5a).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[K+].[C:12](=S)=[S:13]>CCO>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:12](=[S:13])[NH:1][C:2]=2[CH:7]=1
Reactant: S=C=S
Reactant: Nc1cc(F)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C

Procedure:
2-Amino-4-fluorophenol (1.21 g, 9.52 mmol) and potassium hydroxide (0.64 g, 11.4 mmol) were dissolved in carbon disulfide (15 mL) and EtOH (25 mL), and the reaction mixture was heated to reflux overnight. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting solid was suspended in 1 M aqueous HCl and collected by filtration. This was washed with 1 M aqueous HCl (2×) and water (2×) and was air-dried. This gave 1.115 g (69%) of the title compound as a yellow solid. LC-MS: RT=6.89 min., [M+H]+=169.9.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.C[O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Cl:30])[CH:24]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C(O)(C)C>C1COCC1>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH:1]([CH3:6])[CH3:2])[C:22]([OH:21])=[O:31]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl
Yield: 73.1 %

Procedure:
Into a round bottom flask was added triphenylphosphine (62 g, 0.263 mol), 3-chloro-4-hydroxy-benzoic acid methyl ester (10 g, 0.0535 mol) and anhydrous THF (500 mL). The mixture was briefly stirred under nitrogen, then DBAD (19.75 g, 0.0858 mol) was added. The mixture was stirred for a few minutes before adding anhydrous isopropanol (5.125 mL, 0.067 mol). After the reaction mixture was stirred at room temperature under an atmosphere of nitrogen for about 3 hours, DBAD (19.75 g, 0.0858 mol) and anhydrous isopropanol (5.125 mL, 0.067 mol) were added and the mixture was left to stir at room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in minimum amount of ethyl acetate. Heptane was added and the precipitate was removed by filtration. The filtrate was brought up in methanol. Water was added until cloudy. Precipitate was filtered off. The methanol/water precipitation procedure was repeated two more times. The filtrate was taken up in THF (200 mL) and 5 M NaOH (200 mL). The mixture was stirred at room temperature overnight. The organic solvent was removed under reduced pressure. The aqueous layer was extracted three times with ethyl acetate. The aqueous layer was further acidified to pH 1-2 with 2 M HCl. The cloudy suspension was then extracted with ethyl acetate three times. The organic layers were combined, dried over magnesium sulfate, and concentrated to dryness to give 3-chloro-4-isopropoxy-benzoic acid (8.4 g, 71.4%) as a white solid.
Reaction SMILES: Br[CH:2]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10])=[O:6].[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>C(O)C>[C:23]([S:25][CH:2]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH2:4][C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10])=[O:6])(=[O:26])[CH3:24]
Reactant: O=C(c1ccccc1)C(Br)CCC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CC(=O)SC(CCC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2.0 g. of 1-(4-bromo-4-benzoylbutyryl)-L-proline (Example 42) in 20 ml. of ethanol is added 752 mg. of potassium thioacetate. The mixture is stirred at room temperature for 18 hours, evaporated to dryness and the residue is partitioned between dichloromethane and water. The dichloromethane layer is separated, washed with saline, dried over magnesium sulfate, treated with charcoal and evaporated to a gum. This gum is dissolved in ethyl acetate-hexane-acetic acid (75:25:2) and chromatographed on a 1"×15" silica gel column (100 ml. hold back volume) taking 50 ml. cuts. Cuts 3-6 are combined to give the desired product.