Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])[CH3:3].CC[N:32](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C[Si](C)(C)N[Si](C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[NH2:32][C:10]([C@@H:9]1[CH2:13][CH2:14][C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])=[O:11]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@H]1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3)cc2)CC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a solution of (5R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-{4-[(phenylmethyl)oxy]phenyl}-L-proline (D7, 1.44 g, 3.62 mmol) in dry DMF (20 ml) were added DIPEA (1.26 ml, 7.24 mmol), then TBTU (1.23 g, 3.98 mmol) and after 20 minutes, 1,1,1,3,3,3-hexamethyldisilazane (1.15 ml, 5.43 mmol). The reaction mixture was stirred at room temperature for 2 h, then it was treated with aqueous 5% NaHCO3 solution (30 ml) and stirred for further 30 minutes. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic phase was then washed twice with brine/ice, dried over Na2SO4 and evaporated to give a colourless oil. This crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (7:3 to 5:5) to afford the title compound (1.25 g, 87%); Rt (HPLC): 5.51 min; Rf (cyclohexane:ethyl acetate=1:1): 0.29. MS: (ES/+) m/z: 419 [M+Na+]; C23H28N2O4 requires 396.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C@H:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)=[CH:5][CH:4]=1.[Na+].[I-].Cl[Si](C)(C)C.OS([O-])=O.[Na+]>C(#N)C.C(Cl)Cl>[O:14]=[C:11]1[CH2:12][CH2:13][C@H:9]([C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=2)[CH2:10]1
Reactant: COc1ccc([C@H]2CCC(=O)C2)cn1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])O
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CC[C@H](c2ccc(=O)[nH]c2)C1
Temperature: 100 °C

Procedure:
(3S)-3-(6-methoxy-3-pyridyl)cyclopentanone (preparation 3) (560 mg, 2.9 mmol) was dissolved in acetonitrile (12 mL) and treated with NaI (1.32 g, 8.8 mmol) followed by chlorotrimethylsilane (0.74 mL, 5.9 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 5 min. Following the addition of DCM and aqueous NaHSO3, the mixture was washed with water. The organic phase was dried over MgSO4 and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, DMSO) δ 11.43 (s, 1H), 7.50 (dd, 1H), 7.19 (d, 1H), 6.32 (d, 1H), 3.21-3.06 (m, 1H), 2.46-2.35 (m, 1H), 2.33-2.11 (m, 4H), 1.90-1.69 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4]([NH:27][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[N:3]=1
Reactant: NCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccccc2F)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccn2)nc(N)nc1-c1ccccc1F

Procedure:
From 2-amino-4-(2-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-picolylamine in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1.C(=O)(O)[O-].[Na+]>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9]2)=[CH:4][C:3]=1[Br:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1CC(c2ccc(N)nc2)CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN1CC(c2cnc(N)c(Br)c2)CC1=O
Reaction time: 0.25 h

Procedure:
To 4-(6-aminopyridin-3-yl)-1-methylpyrrolidin-2-one (90 mg, 0.377 mmol) in Acetonitrile 3 mL) in ice bath was added NBS (60.3 mg, 0.339 mmol). The reaction mixture was stirred in ice bath for 15 min and room temperature for 30 min. LC-MS shows mixture of SM and product. Added 0.1 equiv. more of NBS and stirred another 1h at room temperature. Reaction mixture was diluted with EtOAc and added 2 mL of Satd sodium bicarbonate. Stirred 10 min. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. Proceed for next step (73%). LCMS (m/z): 270.2/272.2 (MH+), 0.302 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]#[C:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BrH:30].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[Br:30][C:16]1[CH:15]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:17]=1
Reactant: Br
Reactant: COc1ccc(S(=O)(=O)NCC#CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2cc(Br)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 86.3 %

Procedure:
To a stirred solution of 3-(p-methoxyphenylsulfonylamino)-1-propinyl 3,4,5-trimethoxy-phenyl ketone (2.02 g, 2.78 mmol, Example 94c) in CH2Cl2 (10 ml) a solution of HBr (732 μl, 1.5 equiv., 33% in acetic acid) is added at 4° C. The reaction mixture is stirred for 45 min at 4° C., and poured onto ice, saturated aqueous NaHCO3 solution and ethyl acetate. The organic layer is dried (MgSO4), the solvents are evaporated and the residue chromatographed on SiO2 with ethyl acetate/hexane (1:3) to yield the title compound (2.0 g, 86.3%) as a pink solid. 1H-NMR (300 MHz, DMSO-d6): 7.65 (d, J=1.9, 1H); 7.38 (d, J=9.0, 2H); 7.02 (d, J=9.0, 2H); 6.40 (m, 3H); 3.82 (s, MeO); 3.72 (s, MeO); 3.69 (s, 2MeO).
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:31]C2CCCCO2)/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([O:14]C3CCCCO3)[CH2:12][C:11](=[O:21])[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]1=2>C(O)(=O)C.O.C1COCC1>[S:1]1[C:5]([C@H:6]([OH:31])/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:21])[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]1=2
Reactant: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](OC2CCCCO2)[C@@H]1/C=C/[C@@H](OC1CCCCO1)c1cc2ccccc2s1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
(Z)-7-((1R,2R,3R)-2-((3R,E)-3-(Benzo[b]thiophen-2-yl)-3-(tetrahydro-2H-pyran-2-yloxy)prop-1-enyl)-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (33) was dissolved in a 4:2:1 solution of acetic acid-water-THF (0.5 M). The solution was stirred for several days at room temperature until the reaction was complete, as judged by TLC. The crude product was purified by flash chromatography on regular silica gel using ethyl acetate-hexane-0.5% acetic acid as eluent to afford the title compound 14a; TLC: Rf=0.20 (silica on 10 mm aluminum plates, eluent: 40:60:1 hexanes-ethyl acetate-acetic acid); MS (−cESI) m/z 413 (M−1); LC/MS: Sample prep-diluent, methanol. Sample prepared in 100 μL, unknown final concentration, analytical method: column: Phenomenex Synergi Hydro-RP 4p 250×2.00 mm, flow rate 0.2 mL/min, detection UV (210 nm), column temperature 25° C., HPLC mobile phase: isocratic mobile phase consisting of 31.3% solvent A, 68.7% solvent B, Solvent A=10:90:0.1 methanol-water-acetic acid, Solvent B=90:10:0.1 methanol-water-acetic acid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]([CH3:46])([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[CH:18]=[CH:17][S:16][C:5]=4[C:6](=[O:15])[NH:7][C:8]=3[C:9]([CH3:14])=[CH:10][C:11]=2[O:12][CH3:13])[CH:23]=[CH:22][C:21]=1[C:35]([CH3:46])([CH3:45])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)(C)CNC(=O)OC(C)(C)C)c(F)c1
Yield: 55.3 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.46 mmol) was reacted with tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropylcarbamate (270 mg, 0.64 mmol) to afford the desired product (130 mg, 56%) as a light brown solid: ESI MS m/z 511 [C28H31FN2O4S+H]+.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].S([O-])(=O)(=O)C>C(#N)C>[N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:9][CH2:10][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)[CH2:14][CH2:13]3)[CH:9]=[C:8]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCN(CCN2CCNCC2)CC1

Procedure:
The N-protected 2-hydroxyethylpiperazine (3.0 g), triethylamine (1.42 g) and methylene chloride (30 ml) is cooled to 0° in an ice bath under nitrogen. A mixture of methanesulfonyl chloride (1.64 g) in methylene chloride (30 ml) is added dropwise over 10 min. The cooling bath is removed and the mixture allowed to warm to 20°-25° for 30 min. The mixture is then washed with water (60 ml), dried over sodium sulfate and the solvent removed to give crude mesylate. 4-[2,6-Bis(1-pyrrolidinyl)-4-pyrimidinyl]piperazine (4.23 g), potassium carbonate (1.93 g) and acetonitrile (150 ml) are added to the crude mesylate. The mixture is heated at reflux for 18 hr. The acetonitrile is removed under reduced pressure and the residue distributed between chloroform (200 ml) and water (200 ml). The phases are separated, the organic phase is washed with saline, dried over sodium sulfate and the solvent removed under reduced pressure to give an oil. The oil is flash chromatographed on silica gel (200 g) with ethyl acetate/methanol/ammonium hydroxide (9.5/0.4/0.1). The appropriate fractions are pooled and concentrated to give the N-protected form of the title compound as a solid, mp 148°-149°.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[CH:15]1[C:20]2[C:21]3[C:32](=O)[C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:22]=3[O:23][C:24](=[O:25])[C:19]=2[CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[O:25]=[C:24]1[C:19]2[C:20](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:21]2[C:22](=[O:23])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]=2[N:13]1[CH2:12][C:11]([O:10][CH3:9])=[O:14]
Reactant: COC(=O)CN
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)Cn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Triethylamine (2.7 mL, 19.4 mmol) was added to a stirred solution of glycine methyl ester hydrochloride (1.57 g, 12.5 mmol) in chloroform (30 mL). After 1 h, benz[d]indeno[1,2-b]pyran-5,11-dione (2) (1.24 g, 5.0 mmol) was added to the mixture. The red mixture stirred an additional 4 h before CHCl3 (100 mL) was added and the mixture washed with H2O (3×50 mL) and brine (1×50 mL), dried (MgSO4), and concentrated under reduced pressure to give an orange-red solid (1.48 g, 92%): mp 248-251° C.; IR (thin film) 2956, 1735, 1667, 1609, 1502, 1426, 1227, 981 cm−1; 1H NMR (CDCl3, 300 MHz) δ8.68 (d, 1H, J=8.0 Hz), 8.32 (d, 1H, J=8.2 Hz), 7.73 (td, 1H, J=7.1, 1.3 Hz), 7.61 (m, 1H), 7.47 (td, 1H, J=7.1, 1.1 Hz), 7.37 (m, 2H), 7.26 (m, 1H), 5.34 (s, 2H), 3.79 (s, 3H); CIMS m/z (relative intensity) 320 (MH+, 100). Anal. Calcd for C19H13NO4: C, H, N.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30](=[O:33])[NH:31][CH3:32])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1.CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][C@H:21]1[C:30](=[O:33])[NH:31][CH3:32])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CNC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc(CS)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
1.80 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 5.70 ml of 4-methoxybenzyl mercaptan dissolved in 100 ml of dry tetrahydrofuran, and the mixture was then stirred at 0° to 5° C. for 30 minutes. At the end of this time, a solution of 11.00 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-methanesulfonyloxy-2-methylcarbamoylpyrrolidine [prepared as described in step (2) above] in 80 ml of dry dimethylformamide was added to the mixture, and the mixture was stirred at 34° C. for 4.5 hours. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 5:1 by volume mixture of ethyl acetate and hexane) to afford 4.35 g of the title compound as an oil.
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C:15]1[C:16]([CH3:22])=[CH:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>>[CH3:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[NH:14][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C)c(N)c1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Product: Cc1ccc(C)c(Nc2c(C(=O)O)cccc2[N+](=O)[O-])c1
Yield: 65 %

Procedure:
Reaction of 2-bromo-3-nitrobenzoic acid and 2,5-xylidine gave 2-(2,5-dimethyl phenylamino)-3-nitro benzoic acid (65%): mp (benzene/acetone) 215-217° C. 1H NMR [(CD3)2SO] δ 2.10 (s, 3 H, CH3), 2.23 (s, 3 H, CH3), 6.53 (s, 1H, H-6'), 6.79 (d, J=7.4 Hz, 1 H, H-4'), 7.02 (t, J=8.0 Hz, 1 H, H-5), 7.11 (d, J=7.7 Hz, 1 H, H-3'), 8.03 (dd, J=8.1, 1.4 Hz, 1 H, H-6), 8.22 (dd, J=7.7, 1.5 Hz, 1 H, H-4), 9.84 (br s, 1 H, NH), 13.8 (br s, 1 H, CO2H). Anal. (C15H14N2O4) C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:19][CH:20]\2O)[N:11]=[N:10]1)=[O:5])[CH3:2].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:57]([OH:60])(=[S:59])[CH3:58].O>CN(C)C=O.C(OCC)(=O)C>[C:57]([S:59][CH:20]1[CH2:19][CH2:18][N:17]([C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:16]/[C:15]/1=[CH:14]\[C:12]1[N:11]=[N:10][N:9]([CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:13]=1)(=[O:60])[CH3:58]
Reactant: CC(O)=S
Reactant: CCOC(=O)CCCn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)nn1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)nn1
Temperature: 25 °C

Procedure:
To a solution of (E)-3-({1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-4-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (13.7 g) in N,N-dimethylformamide (50 ml) were added N,N-dimethylformamide dineopentyl acetal (14.2 ml) and thioacetic acid (3.4 ml) with stirring at room temperature. The resulting mixture was stirred at room temperature for 0.5 hours and then water and ethyl acetate were added to separate the layers. After the organic layer was washed with a saturated aqueous sodium chloride solution, it was dried over anhydrous magnesium sulfate. After evaporation of the under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate, hexane, and dichloromethane (2:1:1 to 1:1:1) as the eluent to afford an approximately 1:2 mixture (12.8 g) of (E)-4-(acetylsulfanyl)-3-({1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-4-yl}methylidene)-1-(triphenylmethyl)piperidine and 5-((acetylsulfanyl){1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-4-yl}methyl)-1-(triphenylmethyl)-1,2,3-tetrahydropyridine. Furthermore, this mixture contained a small amount of (Z)-4-(acetylsulfanyl)-3-({1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-4-yl}methylidene)-1-(triphenylmethyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.86 (s, br, 1H), 7.62–6.72 (m, 12H) 5.12–5.02 (m, 1H), 3.68–3.52 (m, br, 2H), 3.02–2.82 (br, 2H), 2.82–2.56 (m, br, 4H), 2.56–2.40 (m, br, 2H), 2.06–1.80 (m, br, 6H), 1.64–1.40 (m, br, 2H), 1.25 (d, 6H, J=6.8 Hz). Anal. Calc. for. C32H39Cl3N2O2.1.3MeOH: C, 63.25; H, 7.07; N, 4.42; Found: C, 63.41; H, 6.99; N, 4.17. ESMS m/e: 553.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[F:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[F:9]
Reactant: Fc1ccc(F)c(Cl)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a stirred solution of 1-chloro-2,5-difluorobenzene (0.770 g, 5.18 mmol) in concd H2SO4 (8.0 mL) at 0° C., KNO3 (0.525 g, 5.19 mmol) was added in one lot. The resulting yellow solution was allowed to warm to room temperature and stirred overnight at room temperature. It was then poured into ice (80 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum and the residue was dried further under vacuum to afford 0.845 g (85%) of title compound as a yellow liquid; 1H NMR (CDCl3) δ7.43 (dd, 1H, J1 =9.6 Hz, J2 =6.0 Hz), 7.93 (t, 1H, J=7.2 Hz).
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H-].[Na+].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25]Br.[Na+].[I-]>CN(C=O)C.O>[F:21][C:22]1[CH:23]=[C:24]([CH2:25][O:18][C:15]2[CH:14]=[CH:13][C:12]([C:2]([OH:1])([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6])=[CH:17][CH:16]=2)[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(OCc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Yield: 140.3 %

Procedure:
Into a 100 mL-3 neck flask fitted with a stirrer and thermometer, 200 mg of [2-hydroxy-2-(4-hydroxyphenyl)propyl][(methylethyl)sulfonyl]amine in DMF (5 mL) was added dropwise to 35 mg of NaH in DMF (20 mL) while stirring at room temperature under a nitrogen atmosphere. After stirring at this temperature for 30 minutes, 153 mg of 3,5-difluorobenzyl bromide in DMF (5 mL) was added dropwise followed by the addition of 92 mg of NaI portion wise. The reaction was then heated at 100° C. for 2 hours. The mixture was cooled to room temperature and poured into H2O and the desired product was extracted with ethyl acetate. This organic layer was washed with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 410 mg of a brown oil. This two spot material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 1:1. Collection of the bottom spot provided the intermediate title compound (70 mg, 24%) as an oil. Ion spray M.S. 398.1 (M*−1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1.[CH2:20]([NH2:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[CH3:22][C:21]([CH3:24])([CH3:23])[CH2:20][NH:25][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:14][CH3:15])=[O:13])[CH:3]=1
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(Cl)ncn2)c1
Reactant: CC(C)(C)CN
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(C)c(Nc2cc(NCC(C)(C)C)ncn2)c1
Temperature: 110 °C
Yield: 95.4 %

Procedure:
To a solution of 3-(6-chloro-pyrimidin-4-ylamino)-4,N-dimethyl-benzamide (0.4 g, 1.44 mmol) in DMSO (3 mL), neopentylamine (0.4 mL, 3.39 mmol) was added. The resulting solution was heated at 110° C. for 4 days. The product was purified by silica gel column chromatography using ethyl acetate as eluent to afford the product (0.45 g, yield 99%). MS (m/z): 328 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>C(O)CC>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11])([O-:10])=[O:9]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccccc1Br
Solvent: CCCO
Product: CN(C)CCNc1ccccc1[N+](=O)[O-]
Yield: 91.7 %

Procedure:
To a solution of 2-bromonitrobenzene (10.23 g) in 1-propanol (100 ml) was added N,N-dimethylethylenediamine (13.41 g) and the mixture was refluxed for 3 days. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=50:1) to give 9.72 g of N-(2-nitrophenyl)-N',N'-dimethylethylenediamine.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH2:4]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[N:10]=1)=[O:8])[CH3:5]>C(O)C.O>[CH2:4]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:3][CH2:1][CH3:2])[N:10]=1)=[O:8])[CH3:5]
Reactant: CCNC(=O)c1cccc(Br)n1
Reactant: CCN
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1cccc(NCC)n1

Procedure:
prepared by reaction of ethylamine with 6-bromo-pyridine-2-carboxylic acid ethylamide; in contrast to the general procedure the reaction was carried out by heating a solution of the starting materials in ethanol/water for 72 h at 100° C. in an autoclave