Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C@H:22]4[CH2:26][CH2:25][CH2:24][NH:23]4)[N:19]=[C:18]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C=O.[C:39]([BH3-])#N.[Na+]>CO.CC(O)=O>[CH3:39][N:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[C:20]1[N:19]=[C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:34])[F:35])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=3)=[CH:12][CH:13]=2)[CH:21]=1
Reactant: [BH3-]C#N
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-n3cc([C@H]4CCCN4)nc3-c3ccccc3C(F)(F)F)cc2)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC[C@@H]1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into an 8 mL vial was weighed 20.7 mg (40 μmol) of 1-(3′-(methylsulfonyl)biphenyl-4-yl)-4-((R)-pyrrolidin-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole. The material was dissolved in MeOH (400 μL) and HOAc (100 μL). The solution was treated with 20 μL (240 μmol) of 37% aqueous formaldehyde solution, and then 8 mg (125 μmol) of sodium cyanoborohydride was added at ambient temperature. After stirring for 15 minutes at ambient temperature LC/MS analysis of the reaction showed complete conversion to product. The reaction solution was directly injected into the reverse phase preparative HPLC and eluted with acetonitrile/water. (Phenomenex Axia Gemini C18 30×100 mm 5 μm, A=H2O with 0.1% trifluoroacetic acid, B=acetonitrile with 0.1% trifluoroacetic acid, 17 minute gradient from 10% B to 100% B at 35 mL/minute). Product fractions were combined, made basic by the addition of sat. NaHCO3, and concentrated in vacuo to remove the acetonitrile. The resulting basic aqueous was extracted with CH2Cl2 (3×), and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The resulting 4-((R)-1-methylpyrrolidin-2-yl)-1-(3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl)-1H-imidazole was isolated as a white foam, yield: 16.9 mg (79%); 1H NMR (400 MHz, CDCl3): δ 8.10-8.07 (m, 1H), 7.93-7.90 (m, 1H), 7.83-7.79 (m, 1H), 7.72-7.68 (m, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.54-7.48 (m, 4H), 7.43-7.38 (m, 1H), 7.27-7.18 (m, 4H), 3.41-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.08 (s, 3H), 2.44 (s, 3H), 2.41-2.26 (m, 2H), 2.13-1.94 (m, 2H), 1.90-1.79 (m, 1H); MS (ES): 526.5 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>S(=O)(=O)(O)O>[CH2:19]([O:5][C:4](=[O:6])[CH2:3][CH:2]([OH:1])[CH3:7])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCO
Reactant: CC(O)CC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCOC(=O)CC(C)O
Yield: 62.6 %

Procedure:
A 500 ml one neck round bottom flask equipped with a Dean Stark trap, condenser and nitrogen inlet/outlet was charged with 72.0 g (0.69 moles) 3- hydroxybutyric acid, 268.5 g (1.45 moles) dodecyl alcohol, and 0.36 g sulfuric acid (based on 0.5 g/mole 3-hydroxybutyric acid). The mixture was heated to 115 degrees for 48 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 100 ml saturated sodium bicarbonate solution. The organic layer was collected and dried over magnesium sulfate. Excess dodecyl alcohol was removed by high vacuum distillation to yield 117.65 g (60% yield) of clear oil (91% pure by GC).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1OC)[CH:5]=[O:6].[CH2:12]([Mg]Br)[CH3:13]>>[CH3:12][CH2:13][CH:5]([OH:6])[C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: CC[Mg]Br
Reactant: COc1ccc(C=O)cc1C
Product: CCC(O)c1ccccc1

Procedure:
The synthesis of the title compound (26F) was accomplished in a four-step, three-pot reaction sequence. Commercially available 3-methyl-p-anisaldehyde was reacted with ethylmagnesium bromide to provide its phenylpropanol derivative. This alcohol was then oxidized to the corresponding ketone in the usual manner with PCC. This ketone was subsequently reacted with (R)-naphthyl-1-ethylamine in the presence of Ti(i-PrO)4 to provide the imine. This imine was reduced in high diastereoselective yield by catalytic hydrogenation in the presence of Raney-nickel.
Reaction SMILES: [C:1](NC1CCC(=O)CC1)(=O)C.Cl.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21]N.CS(O)(=O)=O.[C:28]([NH:31][CH:32]1[CH2:44][C:43]2[C:42]3[C:37](=[C:38]([F:46])[CH:39]=[C:40]([F:45])[CH:41]=3)[NH:36][C:35]=2[CH2:34][CH2:33]1)(=[O:30])[CH3:29]>C(O)C>[C:28]([NH:31][CH:32]1[CH2:44][C:43]2[C:42]3[C:37](=[C:38]([F:46])[CH:39]=[C:40]([F:45])[CH:41]=3)[NH:36][C:35]=2[CH2:34][CH2:33]1)(=[O:30])[CH3:29].[CH2:35]([NH:36][CH:37]1[CH2:38][C:39]2[C:16]3[C:15](=[C:14]([F:13])[CH:19]=[C:18]([F:20])[CH:17]=3)[NH:21][C:40]=2[CH2:41][CH2:42]1)[CH:43]([CH3:44])[CH3:1]
Reactant: CC(=O)NC1CCC(=O)CC1
Reactant: NNc1ccc(F)cc1F
Agent: CC(=O)NC1CCc2[nH]c3c(F)cc(F)cc3c2C1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCO
Product: CC(C)CNC1CCc2[nH]c3c(F)cc(F)cc3c2C1

Procedure:
A solution of 15.5 g. of 4-acetamidocyclohexanone, 18 g. of 2,4-difluorophenylhydrazine hydrochloride and 10 g. of methanesulfonic acid in 200 ml. of absolute ethyl alcohol was heated under reflux for two hours, cooled, filtered, and the filtrate was evaporated to dryness under reduced pressure. The residual oil was triturated with water and the resulting solid was collected by filtration, triturated with ether, and recrystallized by dissolving in methanol, adding toluene, and evaporating the methanol to give 8.5 g. of 3-(acetamido)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole, m.p. 179°-183° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[Br-:10].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[Br:10][C:5]1[C:6]([NH2:9])=[CH:7][N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: CSc1ncc(N)cn1
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CSc1ncc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 4.8 %

Procedure:
A stirred solution of 2.0 g (14.2 mmol) of 2-methylsulfanylpyrimidin-5-ylamine in 50 mL of dichloromethane and 10 mL of methanol was cooled in an ice bath. 6.08 g (15.6 mmol) of benzyltrimethylammonium tribromide was added in portions over a period of 10 minutes. The mixture was stirred at 0° C. for 15 minutes and then at room temperature for 3 minutes. The mixture was quenched with saturated aqueous sodium bicarbonate solution until the pH was 8. The organic layer separated and was removed. The aqueous layer was extracted with two 200 mL portions of ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude mixture was absorbed onto silica gel and chromatographed on silica gel using ethyl acetate-hexanes to afford 150 mg (5%) 4-bromo-2-methylsulfanylpyrimidin-5-ylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].CC([O-])(C)C.[K+].Cl[CH2:16][C:17]1[C:18]([CH3:23])=[N:19][O:20][C:21]=1[CH3:22].O>CN(C=O)C>[CH3:23][C:18]1[C:17]([CH2:16][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[C:21]([CH3:22])[O:20][N:19]=1
Reactant: Cc1noc(C)c1CCl
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C)c1Cn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To 4-nitro-1H-pyrazole (Example 4-1d) (3.8 g, 34 mmol) in DMF (80 mL) cooled to 0° C., via an ice/water bath, was added t-BuOK (4.2 g, 38 mmol). After addition of the base the ice bath was removed and the mixture was stirred for 30 minutes followed by the addition of 4-(chloromethyl)-3,5-dimethylisoxazole (5 g, 34 mmol). The reaction was refluxed for 16 hours then cooled to ambient temperature. H2O was added to the reaction mixture and the precipitate formed was collected by filtration. The precipitate was washed with additional H2O then dried under high vacuum to afford 3,5-dimethyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)isoxazole (5.8 g, 78%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz): 2.23 (s, 3H), 2.46 (s, 3H), 5.08 (s, 2H), 8.02 (s, 1H), 8.08 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:21])=O.O>COCCOC>[NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:6]([Cl:21])[N:7]=1
Reactant: COc1ccc(-c2c[n+]([O-])c(N)c(C#N)n2)cn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2nc(C#N)c(N)nc2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
3-Amino-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile 4-oxide (6.65 g) was dissolved in DME (133 ml). To the solution was added phosphorus oxychloride (12.6 g) at 25° C. The mixture was stirred at ambient temperature for 2 hours. To the mixture was added water (520 ml). The solution was stirred at 20-25° C. for 15 hours. The precipitated crystals were collected by filtration and dried in vacuo, to give 3-amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile as powder (4.6 g). The filtrate was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO4. Evaporation of solvent in vacuo gave oily residue. The residue was purified by chromatography on silica gel (EtOAc:n-Hexane=1:1, v/v) to give 3-amino-5-chloro-6-(6-methoxy-3-pyridyl)-2-pyrazinecarbonitrile as powder (1.0 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:14].[Na+]>CO>[OH:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C(=O)CO)cc1
Yield: 50 %

Procedure:
To a solution of 2-Bromo-1-(4-cyanophenyl)ethanone (15 g, 0.067 mol) in methanol (200 ml) was added sodium formate (13.6 g, 0.201 mol) at RT. The reaction mixture was refluxed for 15 h and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved with ethyl acetate, washed with water and brine solution, dried over Na2SO4 and evaporated. The crude material was purified by column chromatography using petroleum ether and ethyl acetate (60:40) as an eluent to afford (5.4 g, 50%) of title compound as an off white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.06-8.04 (dd, J=1.9, 6.7 Hz, 2H), 8.00-7.98 (dd, J=1.9, 6.7 Hz, 2H), 5.27-5.24 (t, J=5.9 Hz, 1H), 4.82-4.80 (d, J=5.9 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[CH3:13])(=O)[CH3:2].C([O-])(=O)C.[NH4+:19]>C(O)(=O)C>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:11]=[C:12]([CH3:13])[N:19]=[C:1]2[CH3:2]
Reactant: [NH4+]
Reactant: CC(=O)Nc1ccc(Br)cc1C(C)=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1nc(C)c2cc(Br)ccc2n1
Temperature: 100 °C
Yield: 23.4 %

Procedure:
415 mg N-(2-acetyl-4-bromophenyl)acetamide and 0.624 g of ammonium acetate was dissolved in 5 mL of glacial acetic acid and heated for 2 days at 100° C. The solvent was removed and the residue suspended in water and extracted with DCM. The organic phase was concentrated and purified via FCC (25 g SiO2, DCM:MeOH 100:0→70:30) to yield 90 mg of 6-bromo-2,4-dimethylquinazoline as oil. Analysis: HPLC-MS: Rt=1.26 min (method V003—003), M+H=237/239.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19](Cl)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:25][S:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19]([C:30]4[CH:31]=[CH:32][C:27]([S:26][CH3:25])=[CH:28][CH:29]=4)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(Oc2ccnc3c(Cl)cccc23)CC1
Reactant: CSc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2cccc3c(OC4CCN(C(=O)OC(C)C)CC4)ccnc23)cc1

Procedure:
In a 25 mL round-bottomed flask equipped with a reflux condenser and N2 inlet septum was placed a stir bar, 4-(8-chloro-quinolin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (198 mg, 0.57 mmol), 4-methylthiophenylboronic acid (287 mg, 1.7 mmol), tetrakis(triphenylphosphine)palladium (98 mg, 0.085 mmol), 2M sodium carbonate (0.6 mL) and toluene (4 mL). The mixture was refluxed 36 h under N2. The resulting mixture was diluted with ethyl acetate and extracted with H2O. The organic extract was dried and concentrated to give the crude product. The crude product was purified by column chromatography to using 50% EtOAc/Hexane and preparative HPLC to give the desired product. 1H NMR (CDCl3, 400 MHz) δ 1.27 (d, 6H), 2.04 (m, 2H), 2.17 (m, 2H), 2.55 (s, 3H), 3.59 (m, 2H), 3.83 (m, 2H), 4.97 (m, 1H), 5.09 (m, 1H), 7.14 (s, 1H), 7.41 (m, 4H), 7.81 (t, 1H), 7.90 (d, 1H), 8.38 (d, 1H), 9.11 (s, 1H). Exact mass calculated for C25H28N2O3S 436.18, found 437.2 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)=[CH:10][C:9]2=[O:24])([O-])=O.O.[SH-].[Na+]>CO.O>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)=[CH:10][C:9]2=[O:24]
Reactant: O=c1cc(-c2cccc(C(F)(F)F)c2)oc2c([N+](=O)[O-])cccc12
Agent: [Na+]
Agent: [SH-]
Solvent: CO
Solvent: O
Product: Nc1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Temperature: 25 °C
Yield: 87.4 %

Procedure:
8-nitro-2-(3-(trifluoromethyl)phenyl)-4H-chromen-4-one 2 (300 mg, 0.90 mmol) was taken up in 10 mL of MeOH. Sodium hydro sulfide hydrate (250 mg, 4.5 mol) was added as a solution in 4 mL of H2O. The reaction mixture was stirred under reflux for 45 min. It was then cooled to room temperature and concentrated under reduced pressure. The resulting aqueous mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 240 mg of 178. MS (ESI) calcd for C16H10F3NO2: 305.07. found: 306 [M+H].
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7](=[N:20][CH:21]1[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C>C1COCC1.CC(O)C>[C:7](=[N:20][C:21]1([CH2:3][C:2]#[CH:1])[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CN1CCC(N=C(c2ccccc2)c2ccccc2)C1=O
Agent: C#CCBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCN(C)C1=O
Reaction time: 2 h

Procedure:
Potassium tert-butoxide 1.7M in THF (32.8 mL, 55.76 mmol) was added dropwise over a period of 80 minutes (by syringe pump) to a solution of the 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (14.11 g, 50.692 mmol) (which may be prepared as described in Description 1) and propargyl bromide (6.78 mL, 60.83 mmol) in THF (250 mL) at 0° C. under nitrogen. The reaction was stirred for 2 hours. Additional KOtBu (5 ml) was added dropwise and stirring was continued for 15 mins. The reaction was quenched by the addition of satd. aq. NaHCO3 and diluted with EtOAc. The phases were separated, the organic layer was dried (Na2SO4) and the solvent evaporated to afford a crude brown oil which solidified on standing. This waxy-solid was suspended in IPA (approx. 30 ml) and stirred for 1 hr. The solid was filtered off, washed with a little IPA to afford 3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D2) as a light brown solid (6.26 g);
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[CH:10]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].OS(O)(=O)=O>N1CCCCC1.N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1/[CH:10]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: Cn1cc([N+](=O)[O-])cc1C=O
Agent: O=S(=O)(O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cn1cc([N+](=O)[O-])cc1/C=C/C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
Alternatively, a mixture of 1-methyl-4-nitro-2-pyrrolecarboxaldehyde (0.20 g, 1.30 mmol), malonic acid (0.68 g, 6.5 mmol), piperidine (2 drops), and pyridine (2 mL) was stirred at room temperature at for 20 h and at 100° C. for 4 h, then 30% aqueous H2SO4 (10 mL) was added. The precipitate that formed was removed by filtration and washed with water to give (E)-1-methyl-4-nitro-2-pyrroleacrylic acid as fine yellow needles (0.23 g, 92%). 1H NMR [(CD3)2SO] δ 12.35 (br s, 1 H, CO2H), 8.13 (d, J=1.9 Hz, 1 H, H-5), 7.44 (d, J=15.9 Hz, 1 H, H-β), 7.41 (d, J=1.9 Hz, 1 H, H-3), 6.46 (d, J=15.9 Hz, 1 H, H-α), 3.79 (s, 3 H, NCH3); 13C NMR δ 167.4 (CO2H), 135.3, 129.9 (C-2,4), 130.6, 127.0, 118.6, 105.8 (C-3,5,α,β), 34.8 (NCH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1F)[CH:19]=[O:20]>CN(C)C=O>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:19]=[O:20]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccc(F)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.2 %

Procedure:
A mixture of 4-fluorobenzenethiol (0.93 g), potassium carbonate (3.1 g) and N,N-dimethylformamide (25 mL) was treated with 3,4-difluorobenzaldehyde (1.0 g), and the resulting mixture was stirred at room temperature for 16 hours. The mixture was partitioned between water and ethyl acetate, and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a colourless gum (0.18 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:16][CH2:17][CH2:18][CH2:19]Cl)=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1.[CH2:32]([NH2:36])[CH:33]([CH3:35])[CH3:34]>>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][NH:36][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1
Reactant: CC(C)CN
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NCCCCl)C3)c1C
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NCCCNCC(C)C)C3)c1C
Yield: 62 %

Procedure:
Reaction and post-treatment were performed in the same manner as in Example 18 using 4-amino-N-(3-chloropropyl)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carboxamide of Example 17 (30 mg) and isobutylamine (2 mL), followed by purification by NH silica gel column chromatography (dichloromethane-methanol) to obtain the title compound (20 mg, 62%) as a solid.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:14][S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].CCN(C(C)C)C(C)C>C(#N)C>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[C:16]([S:15][CH3:14])[CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CSc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(Nc1cccc(SC)c1)c1ccccc1
Temperature: 100 °C
Yield: 78.8 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 mL, 1.23 mmol), 3-(methylthio)aniline (0.22 mL, 1.85 mmol), and DIPEA (0.32 mL, 1.85 mmol) are dissolved in acetonitrile (3 mL) and heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile is evaporated and the crude residue is purified by flash chromatography (petroleum ether/EtOAc=85/15) to obtain intermediate I98 as a colorless oil (292 mg, 79% yield).
Reaction SMILES: N1C2OC3C=CC=CC=3NCC=2C=CC=1.FC1C=C(F)C=CC=1C(Cl)=O.[F:27][C:28]1[CH:33]=[C:32](F)[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[N:48]=[CH:49][CH:50]=[CH:51][C:39]=2[CH2:38]1)=[O:36].[Na].[CH3:53][C:54]1[CH:58]=[CH:57][NH:56][N:55]=1>>[F:27][C:28]1[CH:33]=[C:32]([N:56]2[CH:57]=[CH:58][C:54]([CH3:53])=[N:55]2)[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[N:48]=[CH:49][CH:50]=[CH:51][C:39]=2[CH2:38]1)=[O:36]
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1F)N1Cc2cccnc2Oc2ccccc21
Agent: O=C(Cl)c1ccc(F)cc1F
Agent: [Na]
Agent: c1cnc2c(c1)CNc1ccccc1O2
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Oc4ccccc43)c(F)c2)n1

Procedure:
The title compound may be prepared in a manner analogous to that of the 2-chloro analog of Example 16, by reacting 6H-pyrido[2,3-b][1,5]benzoxazepine of Example 16, Step A with 2,4-difluoro benzoylchloride of Example 9, Step A. Subsequent reaction of the intermediate (2,4-difluoro-phenyl)-(11H-5-oxa-4,10-diaza-dibenzo[a,d]cyclohepten-10-yl)-methanone with the sodium salt of 3-methylpyrazole in a manner analogous to that of Example 16, Step C will provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH3:14].[C:16]([CH2:24][C:25](=O)[CH3:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>C(O)C.C(O)=O>[C:16]([CH:24]=[C:25]([NH:1][CH2:2][CH:3]([OH:15])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH3:14])[CH3:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: CC(=O)CC(=O)c1cccnc1
Reactant: CCOc1ccccc1OCC(O)CN
Solvent: O=CO
Solvent: CCO
Product: CCOc1ccccc1OCC(O)CNC(C)=CC(=O)c1cccnc1
Temperature: 25 °C

Procedure:
4.2 g of (-)-1-amino-3-(o-ethoxyphenoxy)-propan-2-ol (laevo-rotatory) ##STR38## are dissolved in 30 ml of ethanol, 3.3 g of the nicotinoyl-acetone ##STR39## are then added and the mixture is heated for 4 hours under reflux, with addition of 1 drop of formic acid as the catalyst. The clear solution is cooled to room temperature and concentrated in a water pump vacuum. An oil is left, which solidifies after a short time. The solid product is recrystallised from toluene. (-)-1-(2-Nicotinoyl-1-methyl-vinylamino)-3-(o-ethoxyphenoxy)-propan-2-ol (laevo-rotatory) is thus obtained ##STR40##
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13].[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][C@@H:23]([NH2:32])[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:33][N:20]([CH3:19])[CH2:21][CH2:22][C@@H:23]([NH:32][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[CH2:24][S:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CN(C)CC[C@@H](N)CSc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (685 mg, 2.3 mmol), (R)—N1,N1-dimethyl-4-phenylsulfanyl-butane-1,3-diamine (500 mg, 2.3 mmol), and DIPEA (0.78 mL, 4.5 mmol) in DMA (18.8 mL) was heated to 100° C. for 6 hours. The reaction was cooled to room temperature and diluted with EtOAc/heptanes (1:1, 50 mL). This solution was washed with water, the layers were separated, and the aqueous layer was extracted with EtOAc/heptanes (1:1) (50 mL×3). The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated to afford the title compound as a yellow solid (965 mg, 82% yield). MS (ESI) m/e (M+H+): 512.2