Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[OH:25])[CH:20]=[O:21])[CH3:15].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8])[CH:20]=[O:21])[CH3:15]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (30.0 g), 3-ethoxy-4-hydroxybenzaldehyde (22.9 g), potassium carbonate (21.01 g) and N,N-dimethylformamide (300 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-ethoxy-4-[[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy]benzaldehyde as brown crystals (31.20 g, yield 69%). Recrystallization from ethyl acetate-hexane gave pale-yellow needle. melting point: 159-160° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:56]\[H])/[C:50]1[CH:55]=[CH:54][CH:53]=[N:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:7]1([C:6]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:5][CH2:4][N:3]([CH2:19][C:20]3[O:21][N:56]=[C:49]([C:50]4[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=4)[N:48]=3)[C:2]2=[O:1])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [H]/N=C(\NO)c1cccnc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3cccnc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxynicotinimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 9.23 (d, J=1.7, 1H), 8.76 (dd, J=1.7, 4.9, 1H), 8.27 (dt, J=1.9, 8.0, 1H), 7.50-7.25 (m, 11H), 4.91 (s, 2H), 3.59 (t, J=6.5, 2H), 2.90 (t, J=6.5, 2H); MS (DCI) m/z 397.1 (M+H)+.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH:12][C:13](OC(C)(C)C)=O)=[C:7]([N+:20]([O-:22])=[O:21])[CH:6]=1)(=[O:4])=[O:3].[C:23]1(=O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30]C=2)[CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)(C(F)(F)F)=O.ClCCl>[C:13]1(=[N:12]/[NH:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:6][C:7]=2[N+:20]([O-:22])=[O:21])/[CH2:30][CH2:29][CH2:28][C:27]2[C:32]/1=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: O=C1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)NNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(N/N=C2\CCCc3ccccc32)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A room temperature solution of Example 73A (145 mg,0.44 mmol) in 1:1 TFA/dichloromethane (10 mL) was stirred for 4 hours and concentrated. The concentrate was dissolved in ethanol (2 mL), treated with 3,4-dihydro-1(2H)-naphthalenone (8.2 mg, 0.06 mmol) and pyridinium p-toluenesulfonate (2 mg, 0.008 mmol), heated to reflux, stirred for 2 hours, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 359 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=O)([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[C:27]2[N:28]([N:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=2)[CH:29]=[CH:30][N:31]=1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]1[N:31]2[C:26]([C:27]3[N:28]([N:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=3)[CH:29]=[CH:30]2)=[N:13][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1cc2c(Cl)nccn2n1
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2c3cc(C(F)(F)F)nn3ccn12

Procedure:
A mixture of 7.7 mg (0.22 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 4.9 mg (0.22 mmol) of 4-chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrazine (Intermediate 39), and 0.5 mL of xylenes was stirred at reflux for 19 h. The cooled solution was concentrated to yield the title compound, sufficiently pure for use in the next step. LC-MS 515 (M+1).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([F:16])[C:13](Cl)=[N:12][C:11]=1[Cl:18])[CH3:7].O>C1COCC1>[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([F:16])[C:13]([S:3][CH2:1][CH3:2])=[N:12][C:11]=1[Cl:18])[CH3:7]
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(F)c(SCC)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
Ethanethiol (15.08 mL, 204 mmol) was added slowly to a stirred suspension of NaH (60% in Mineral oil, 8.15 g, 204 mmol) in THF and stirred for 30 min at room temperature to yield a white thick suspension. This suspension was diluted by cold THF, cooled to 0° C. and transferred to an already cooled solution of 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester (65) (48.5 g, 204 mmol) in THF at −20° C. under argon by maintaining the temperature below −10° C. The solution was stirred at −20° C. for 15 min and allowed to come at room temperature slowly. The solution was poured into water and extracted by ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure to yield 53 g (98%) of 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester (66) as brown liquid. 1H-NMR (DMSO-d6): δ 1.33 (m, 6H), 3.19 (q, J=7.2 Hz, 2H), 4.33 (q, J=7.2 Hz, 2H), 8.10 (d, J=9.6 Hz, 1H); EIMS m/z 264 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:16][C@@H:15]([C:17]2[CH:28]=[CH:27][C:20]3[O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24][C:19]=3[CH:18]=2)[O:14][C:13]1=[O:29])[CH2:2][C:3]#[CH:4].I[C:31]1[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:26][C:22]1([CH3:25])[O:21][C:20]2[CH:27]=[CH:28][C:17]([C@H:15]3[O:14][C:13](=[O:29])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][C:3]#[C:4][C:31]4[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=4)[CH2:16]3)=[CH:18][C:19]=2[CH2:24][O:23]1
Reactant: NS(=O)(=O)c1cccc(I)c1
Reactant: C#CCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCC#Cc4cccc(S(N)(=O)=O)c4)C(=O)O3)ccc2O1
Reaction time: 17 h
Yield: 94.7 %

Procedure:
(5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (1.79 g) was stirred with 3-iodobenzene sulphonamide (1.4 g) in acetonitrile:triethylamine (1:1, 42 ml) under nitrogen for 10 min. Cuprous iodide (0.083 g) and dichlorobis(triphenylphosphine)palladium (0.192 g) were added and the mixture was stirred for 17 h under nitrogen at 21°. The mixture was evaporated to dryness and the residue was chromatographed on silica gel (250 g) in 30% ethyl acetate:petroleum ether (bp 40–60°), then 50%, then 75% and finally ethyl acetate to give the title compound (2.35 g), LCMS RT=3.44 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32].Br[CH2:40][CH:41]([CH3:43])[CH3:42].C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(#N)C>[CH2:40]([N:36]1[CH2:35][CH2:34][N:33]([C:31]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][C:7]([O:11][C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:30])[C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)=[CH:8][CH:9]=3)=[O:32])[CH2:38][CH2:37]1)[CH:41]([CH3:43])[CH3:42]
Reactant: Cn1c(C(=O)N2CCNCC2)cc2cc(Oc3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cn3)ccc21
Reactant: CC(C)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)CN1CCN(C(=O)c2cc3cc(Oc4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cn4)ccc3n2C)CC1
Yield: 36.1 %

Procedure:
To a solution of N-{6-[1-methyl-2-(piperazine-1-carbonyl)-1H-indol-5-yloxy]pyridin-3-yl}-4-trifluoromethyl-benzamide (250 mg, 0.478 mmol) in acetonitrile (2 mL) were added 1-bromo-2-methylpropane (0.123 mL, 1.13 mmol), diisopropylethylamine (0.25 mL, 1.44 mmol) and sodium iodide (180 mg, 1.2 mmol). The reaction mixture was stirred under reflux for 14 hours. The solvent was removed under reduced pressure. Water was added to the residue and extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=40:1) and solidified with EtOH (2 mL). The precipitate was collected by filtration and dried to give 100 mg of the title compound as a white powder.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[OH:7])=[O:5].[Cl:18][CH2:19][C:20](Cl)=[O:21].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:18][CH2:19][C:20]([O:7][N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:4](=[O:5])[C:3]([CH3:17])([CH3:16])[CH2:2][Cl:1])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(CCl)C(=O)N(O)Cc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(CCl)C(=O)N(Cc1ccccc1Cl)OC(=O)CCl

Procedure:
This compound was prepared in the manner of Example 13, using 4.0 g (0.014 mole) of 3-chloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide (prepared in Example 1), 1.6 g (0.014 mole) of chloroacetyl chloride, and 1.2 g (0.015 mole) of pyridine, in 50 ml toluene. The product was a liquid, of which nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[CH:26][C:27]([F:36])=[C:28]([NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:29]=4)[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1F
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)ccc1F

Procedure:
Example 47 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.32–8.18 (m, 1H), 7.43–7.25 (m, 5H), 7.08–6.93 (m, 1H), 6.93–6.79 (br, 1H), 5.74–5.59 (br, 1H), 3.35–3.15 (m, 2H), 3.93–2.75 (m, 2H), 2.65–2.49 (m, 1H), 2.49–2.34 (m, 1H), 2.34–2.19 (m, 2H), 2.00–1.83 (m, 2H), 1.82–1.68 (m, 2H), 1.68–1.48 (m, 4H), 1.36–1.17 (m, 2H), 1.27 (d, 6H, J=6.8 Hz), 1.0 (s, 2H); ESMS m/e: 500.3 (M+H)+; Anal. Calc. for (HCl salt) C28H36Cl2FN3O2.0.45CHCl3: C, 57.85; H, 6.22; N, 7.11. Found: C, 57.61; H, 6.37; N, 7.30.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CC[Mg+].[Br-].[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]>>[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[C:16](=[NH:17])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: Nc1ccc(Cl)cc1
Agent: CC[Mg+]
Agent: [Br-]
Product: N=C(Nc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 103.4 %

Procedure:
Under argon, 4-chloroaniline (6.67 g, 52.5 mmol) was slowly added to EtMgBr (52 mL, 1 M in THF, 52 mmol) portion wise. After the solution was stirred for 0.5 h, 2,4-dichlorobenzonitrile (9.03 g, 52.5 mmol) was added. The resulting solution was stirred at rt overnight. The reaction mixture was carefully quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated. Crude product (16.26 g,) was obtained as a sticky brown foam which was used without purification for the next step. LC-MS m/z 299.3 (MH+), retention time 1.75 min (MDLC 1); 1H NMR (300 MHz, CDCl3) δ 4.92 (2H, br), 7.09-7.51 (7H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23](O)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:27][CH:28]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([F:47])([F:46])[F:45])[C:29]([NH:31][C:32]([CH3:37])([C:34]([NH2:36])=[O:35])[CH3:33])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:11](=[O:21])[N:10]([CH2:22][C:23]([NH:27][CH:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]([F:45])([F:46])[F:47])[C:29]([NH:31][C:32]([CH3:37])([C:34]([NH2:36])=[O:35])[CH3:33])=[O:30])=[O:24])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O
Reactant: CC(C)(NC(=O)C(N)c1ccccc1C(F)(F)F)C(N)=O
Agent: Cl
Product: CC(C)(NC(=O)C(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F)C(N)=O

Procedure:
Analogously to Example 1, 25 mg (69 μmol) of [3-(4-chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid (for the preparation, see WO 2007/134862, Example 156A) and 28 mg (76 mol) of the compound of Example 62A were employed. Purification by HPLC [Method 7] gave 28 mg (63% of theory) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1([S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH:40]2[CH:44]=[CH2:45])(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(CC)CC.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]1([S:36]([N:39]2[CH2:43][CH2:42][CH2:41][CH:40]2/[CH:44]=[CH:45]/[C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=2)(=[O:38])=[O:37])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C=CC1CCCN1S(=O)(=O)c1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/C3CCCN3S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (100 mg, 0.183 mmol) in acetonitrile (2 mL) is added 1-benzenesulfonyl-2-vinylpyrrolidine (43 mg, 0.183 mmol), NEt3 (0.038 mL, 0.274 mmol), Pd(OAc)2 (2 mg, 0.034 mmol), and 2-(di-t-butylphosphino)biphenyl (4 mg) and the mixture stirred at 80° C. for 48 h. The reaction is cooled to RT and partitioned between 1N HCl and EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure and the crude material purified by column chromatography using a gradient of 10-25% EtOAc/hexane to afford the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[S:1]1[C:5]2[CH2:6][N:7]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:30]=[CH:31][CH:32]=[CH:33][C:16]=4[CH3:15])=[CH:29][CH:28]=3)=[O:26])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)Cc1ccsc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3sccc3Cc3ccccc32)cc1
Yield: 59.4 %

Procedure:
A mixture of 400 mg of 9,10-dihydro-4H-thieno[2,3-c][1]benzazepine and 600 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride is stirred in 30 ml of methylene chloride in the presence of 3 ml of triethylamine for 8 hours. The volatiles are removed in vacuo to give a residue which is partitioned between water and chloroform. The organic layer is dried (Na2 SO4) and the filtrate evaporated in vacuo to give a residue which is purified by column chromatography on silica gel by elution with 30% ethyl acetate-hexane to give 518 mg of the desired product. M+1=439.
Reaction SMILES: CS([C:4]1[NH:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>CO>[CH3:12][C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH2:18][S:19][CH2:20][CH2:21][NH:22][C:4]1[NH:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CS(=O)c1[nH]ccc1[N+](=O)[O-]
Solvent: CO
Product: Cc1[nH]cnc1CSCCNc1[nH]ccc1[N+](=O)[O-]
Yield: 34.1 %

Procedure:
A solution of 2-methylsulphinyl-3-nitropyrrole (2g, 0.01 mol) and 2-(5-methyl-4-imidazolylmethylthio)-ethylamine (2g, 0.01 mol) in methanol (50 ml) was refluxed for 7 days and evaporated to dryness. The residue was chromatographed on a silica gel column eluted with ethyl acetate, and the eluate was evaporated to dryness and recrystallised from propan-2-ol to give 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-3-nitropyrrole (0.96g, 31%) m.p. 161-162°.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27]([OH:29])=[O:28])[C:21]=3[C:20]3=[N:30][O:31][C:32]([CH3:33])=[C:19]3[C:18]2=[O:34])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:36][CH3:37].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:36]([O:28][C:27]([C:22]1[C:21]2[C:20]3[C:19](=[C:32]([CH3:33])[O:31][N:30]=3)[C:18](=[O:34])[N:17]([CH:13]3[CH2:14][CH2:15][CH2:16][CH:11]([CH2:10][NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:12]3)[C:26]=2[CH:25]=[CH:24][CH:23]=1)=[O:29])[CH3:37]
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(C(=O)O)c21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc2c1c1noc(C)c1c(=O)n2C1CCCC(CNC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of Example 598, (0.05 g, 0.11 mmol) in DMF (1 ml) under N2 was added iodoethane (0.062 ml, 0.33 mmol) and Cs2CO3 (0.036 g, 0.11 mmol). The mixture was stirred overnight, diluted with EtOAc, washed (H2O then brine), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, acetone/dichloromethane gradient) gave the title compound (0.043 g, 80%). MS(FIA) (m/z) 488.4 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:17](Br)[CH3:18]>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH:17]([CH3:18])[O:9][C:4]=2[CH:3]=1
Reactant: CC(Br)Br
Reactant: Oc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1Oc2ccc(Br)cc2O1

Procedure:
To a solution of 4-bromobenzene-1,2-diol (500 mg, 2.65 mmol) in acetone (4 mL) was added cesium carbonate (1.90 g, 5.82 mmol) and 1,1-dibromoethane (1.09 g, 5.82 mmol). The mixture was microwaved to 120° C. for 3 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the product. 1H-NMR: 400 MHz, (CDCl3) δ 6.93-6.89 (m, 2H), 6.63 (d, J=8 Hz, 1H), 6.27 (q, J=9.6 Hz, 1H), 1.67 (d, J=4.4 Hz, 3H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:23])([F:22])[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9]>CCOC(C)=O>[F:23][C:7]([F:6])([F:22])[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCC(c2ccccc2)CC1)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
Chlorosulfonic acid (2 mL) was added to 2,2,2-trifluoro-1-(4-phenylpiperidin-1-yl)ethanone (1.0 g, 3.9 mmol) in a single portion, and the reaction was stirred for 20 minutes until gas evolution ceased (exothermic reaction). The solution was poured into a mixture of ice water (200 mL) and EtOAc (20 mL). The organic layer was concentrated and purified via silica gel chromatography using 8/2 hexanes/EtOAc to obtain 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chloride as a clear oil (1.3 g, 94%). 1H NMR (400 MHz, CDCl3) δ 8.02-8.00 (m, 2H), 7.48-7.45 (m, 2H), 4.78-4.73 (m, 1H), 4.19 (dd, J=14.0, 1.6 Hz, 1H), 3.32-3.25 (m, 1H), 3.02-2.86 (m, 2H), 2.03-2.02 (m, 2H), 1.81-1.70 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]([OH:12])[C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[H-].[Na+].CN(C=O)C.[CH3:21][CH2:22][CH2:23]Br>O>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[C:5]([O:12][CH2:21][CH2:22][CH3:23])[C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CCCBr
Reactant: COc1ccc([N+](=O)[O-])c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c([N+](=O)[O-])ccc(OC)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
2.0 g (10.93 mmol) of 3-methoxy-2-methyl-6-nitrophenol (prepared according to R. A. Raphael, P. Ravenscoft, J. Chem. Soc. Perkin Trans. I, (1988), 1823-1828) were added in portions under an argon atmosphere to a suspension of 525 mg (1 2.02 mmol) of NaH in 30 ml of abs. DMF cooled to 0° C. After stirring at 0° C. for 30 min, 1.17 ml (12.70 mmol) of n-propyl bromide were added dropwise. The reaction solution was stirred at 70° C. for 8 h. Subsequently, 70 ml of H2O were added with ice cooling, and the mixture was then concentrated to dryness. The residue was taken up in EA, and the solution was washed 3× with H2O, dried over Na2SO4, and concentrated. Drying in a high vacuum afforded 2.37 g of the title compound in the form of a brown oil.