Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:20](O)[CH2:21][OH:22].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1C=CC=CC=1>[CH3:18][C:17]1([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)=[CH:12][CH:13]=2)[O:22][CH2:21][CH2:20][O:19]1
Reactant: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Reactant: OCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: CC1(c2ccc(Oc3ccc([N+](=O)[O-])cn3)cc2)OCCO1
Reaction time: 3 h

Procedure:
380 mg of 1-{4-[(5-nitro-2-pyridinyl)oxy]phenyl}-1-ethanone was dissolved in 5 ml of benzene and, after adding 98 μl of ethylene glycol and 3 mg of (±)-10-camphorsulfonic acid, the mixture was heated at reflux. After 3 hours, the reaction solution was extracted with ethyl acetate. The organic layer was washed in turn with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: ethyl acetate/n-hexane (1:4)) to obtain the titled compound (280 mg).
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:28])=[C:6]([NH:12][C:13]2[N:18]=[C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)[C:16]3=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]3[N:14]=2)[CH:7]=[C:8]([C:10]#[N:11])[CH:9]=1)(=[O:3])[CH3:2].[CH3:29][Mg+].[Br-]>>[Cl:28][C:5]1[C:4]([C:1]([OH:3])([CH3:29])[CH3:2])=[CH:9][C:8]([C:10]#[N:11])=[CH:7][C:6]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:21][CH2:22]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1
Reactant: C[Mg+]
Reactant: CC(=O)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Agent: [Br-]
Product: CC(C)(O)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Temperature: 25 °C
Yield: 12.6 %

Procedure:
A solution of 2-((3-acetyl-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 675) (60 mg, 0.15 mmol) in TIIF (8 mL) was cooled in an ice bath and MeMgBr (3 M in THF, 0.26 mL, 0.76 mmol) was added and the reaction was allowed to warm to room temperature. It was quenched with sat. aq. NH4Cl solution and extracted twice with EtOAc. The organic extracts were washed with brine, dried with sodium sulfate, and the solvent removed. HPLC purification afforded 7.7 mg of the title compound,
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.C1COCC1>CO.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([S:31](=[O:33])(=[O:32])[NH2:34])=[CH:29][CH:30]=3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCc3ccc(S(N)(=O)=O)cc3)c(Br)c2)c(SC)s1

Procedure:
The reaction was conducted following the procedure for Example 156: step a, using. 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2: step c), 4-aminomethyl-benzenesulfonamide (0.033 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL]. Chromatography of the residue (0%–5% MeOH/DCM) yielded the title compound. ESI-MS (m/z): Calcd. for C19H18BrN3O6S4: 592.53 (M+H); found 592.0, 593.9.
Reaction SMILES: [SH:1][C:2]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[O:10][C:9]=2[C:8]([C:16]([C:35]2[C:45]3[O:46][C:47]([CH3:50])([CH3:49])[O:48][C:44]=3[C:43]([SH:51])=[C:37]3[O:38][C:39]([CH3:42])([CH3:41])[O:40][C:36]=23)([C:18]2[C:28]3[O:29][C:30]([CH3:33])([CH3:32])[O:31][C:27]=3[C:26]([SH:34])=[C:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=23)[OH:17])=[C:7]2[C:3]=1[O:4][C:5]([CH3:53])([CH3:52])[O:6]2.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:13]([S:51][C:43]1[C:37]2[O:38][C:39]([CH3:41])([CH3:42])[O:40][C:36]=2[C:35]([C:16]([C:18]2[C:28]3[O:29][C:30]([CH3:32])([CH3:33])[O:31][C:27]=3[C:26]([S:34][CH2:9][C:8]#[CH:7])=[C:20]3[O:21][C:22]([CH3:24])([CH3:25])[O:23][C:19]=23)([C:8]2[C:7]3[O:6][C:5]([CH3:53])([CH3:52])[O:4][C:3]=3[C:2]([S:1][CH2:53][C:5]#[CH:52])=[C:13]3[O:12][C:11]([CH3:14])([CH3:15])[O:10][C:9]=23)[OH:17])=[C:45]2[C:44]=1[O:48][C:47]([CH3:50])([CH3:49])[O:46]2)[C:2]#[CH:3]
Reactant: CC1(C)Oc2c(S)c3c(c(C(O)(c4c5c(c(S)c6c4OC(C)(C)O6)OC(C)(C)O5)c4c5c(c(S)c6c4OC(C)(C)O6)OC(C)(C)O5)c2O1)OC(C)(C)O3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCSc1c2c(c(C(O)(c3c4c(c(SCC#C)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c4c(c(SCC#C)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2

Procedure:
Tris(8-mercapto-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']bis(1,3)dioxole-4-yl)methanol (0.400 g, 0.50761 mmol (Example 31)) was added to a solution consisting of CH3CN (50 mL), K2CO3 (5.0 g) and BrCH2CCH (2.389 g, 2.284 mmol) at -5° C. under argon. The cooling bath was removed and the temperature increased to +23° C. A 1H NMR control of a small sample 20 minutes after the removal showed conversion to be complete. Diethyl ether (50 mL) was added and the solution was filtered. The solvents were evaporated and the residual oil weighed 0.401 g (87%).
Reaction SMILES: C(C1C=C(S[C:12]([S:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([O:26][CH2:27][C@H:28]3[C@H:32]([CH2:33][O:34][CH3:35])[O:31]C(OCC)[O:29]3)=[C:18]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:17]=2)([CH3:14])[CH3:13])C=C(C(C)(C)C)C=1O)(C)(C)C.[C:48]([OH:51])(=O)[CH3:49]>CO.O>[C:39]([C:18]1[CH:17]=[C:16]([SH:15]([CH:12]([CH3:13])[CH3:14])[S:15][C:16]2[CH:21]=[C:49]([C:22]([CH3:20])([CH3:23])[CH3:24])[C:48]([OH:51])=[C:18]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:17]=2)[CH:21]=[C:20]([C:22]([CH3:24])([CH3:25])[CH3:23])[C:19]=1[O:26][CH2:27][C@H:28]([OH:29])[C@@H:32]([OH:31])[CH2:33][O:34][CH3:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC1O[C@@H](COC)[C@H](COc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Reactant: CC(=O)O
Solvent: CO
Solvent: O
Product: COC[C@H](O)[C@@H](O)COc1c(C(C)(C)C)cc([SH](Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
2,6-Di-tert-butyl-4-{1-[3,5-di-tert-butyl-4-(2-ethoxy-5(s)-methoxymethyl-[1,3]dioxolan-4(S)-ylmethoxy)-phenylsulfanyl]-1-methyl-ethylsulfanyl}-phenol (Ex-15A, 0.72 g, 1.1 mmol) was dissolved in methanol (3 mL). Acetic acid (0.14 mL) and water (0.14 mL) were added and the resultant mixture was stirred at reflux for 3 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate and concentrated to an off-white foam. The residue was dissolved in methanol (3 mL) and potassium carbonate (0.085 g) was added. The mixture was stirred at room temperature for 30 min and diluted with water (10 mL). The solution was extracted with dichloromethane (3×10 mL), dried over sodium sulfate, and concentrated to a white foam. Silica gel chromatography (3:1 ethyl acetate: hexanes) gave 0.18 g (99%) of 1-{2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxyphenylsulfanyl)-1-methylethylsulfanyl]phenoxy}-4-methoxybutane-2(S),3(S)-diol as a white solid, mp 62–64° C. 1H-NMR (CDCl3) δ 7.55 (s, 2H), 7.45 (s, 2H), 5.36 (s, 1H), 4.25–4.26 (m, 1H), 3.86–3.90 (m, 3H), 3.59–3.61 (m, 2H), 3.41 (s, 3H), 2.79 (d, 1H, J=4.8 Hz), 2.63 (d, 1H, J=4.8 Hz), 1.42–1.45 (m, 42H). HRMS (ESI) calcd for C36H58O5S2 (M+Na), 657.3624; Found, 657.3630. Anal. calcd. for C36H58O5S2: C, 68.10, H, 9.21, S, 10.10; Found: C, 68.47, H, 9.38, S, 9.85.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.Cl.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](=[NH:28])[NH2:27].CCN(C(C)C)C(C)C>>[O:8]=[C:6]1[C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[S:4][C:3]([NH:28][C:26]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[NH:27])=[N:7]1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: N=C(N)c1cccs1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NC1=NC(=O)C(=Cc2ccc3ncccc3c2)S1)c1cccs1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, thiophene-2-carboximidamide hydrochloride and DIEA to give N-(4-oxo-5-quinolin-6-ylmethylene-4,5-dihydro-thiazol-2-yl)-thiophene-2-carboxamidine. LC-MS m/e 365 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:51][CH:52]1[C@H:56]2[C@H:57](OC3CCCCO3)[N:58](C(OC(C)(C)C)=O)[C:59]3[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:60]=3[C:61](=[O:62])[N:55]2[CH2:54][CH2:53]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]1[C@H:24]2[C@H:25](OC3CCCCO3)[N:26](C(OC(C)(C)C)=O)[C:27]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=3[C:29](=[O:30])[N:23]2[CH2:22][CH2:21]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:18]([O:19][CH:20]1[C@@H:24]2[CH:25]=[N:26][C:27]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:28]=3[C:29](=[O:30])[N:23]2[CH2:22][CH2:21]1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:51][CH:52]1[C@@H:56]2[CH:57]=[N:58][C:59]3[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:60]=3[C:61](=[O:62])[N:55]2[CH2:54][CH2:53]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 80 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15i (210 mg, 0.20 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16i (105 mg, 0.16 mmol, 81%) as a solid: [α]20D=+623° (c=0.13, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.26-1.52 (m, 14H, 14-H, 14′-H, 15-H, 15′-H, 16-H, 16′-H, 17-H), 1.82-1.92 (m, 4H, 13-H, 13′-H), 1.99-2.12 (m, 4H, 2-H, 2′-H), 2.26-2.38 (m, 4H, 1-H, 1′-H), 3.55-3.64 (m, 2H, 3-H, 3′-H), 3.69-3.77 (m, 2H, 11a-H, 11a′-H), 3.78-3.91 (m, 2H, 3-H, 3′-H), 3.94 (s, 6H, 7-OMe, 7′-OMe), 4.99-4.24 (m, 9H, 12-H, 12′-H), 6.80 (s, 2H, 9-H, 9′-H), 7.51 (s, 2H, 6-H, 6′-H), 7.65 (d, 2H, J=4.4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 28.9, 29.3, 29.4, 29.6, 46.6, 53.7, 56.1, 69.1, 110.4, 111.5, 120.0, 140.6, 147.8, 150.9, 162.3, 164.6; IR (neat): 3321, 2927, 1599, 1505, 1455, 1431, 1382, 1261, 1216, 1092, 1022 cm−1; MS (FAB) m/z (relative intensity) 709 ([M+2×MeOH]+., 4), 677 ([M+MeOH]+., 11), 645 (M+., 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:18]1([C:2]2[CH:3]=[C:4]3[CH2:10][C:9]4([CH:15]5[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]5)[CH2:11]4)[O:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
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: CCO
Solvent: COCCOC
Product: c1ccc(-c2cnc3c(c2)CC2(CN4CCC2CC4)O3)cc1
Yield: 68.5 %

Procedure:
Under a nitrogen atmosphere, 5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (118 mg, 0.4 mmol), phenylboronic acid (54 mg, 0.443 mmol), and tetrakis(triphenylphosphine)palladium(0) (11 mg, 2.3 mol %) were stirred in a solution of 1,2-dimethoxyethane (3 mL) and ethanol (0.75 mL) containing 2M aqueous sodium carbonate (0.65 mL, 1.3 mmol). The mixture was heated under reflux for 18 hours. The reaction mixture was then evaporated under reduced pressure, the residue was dissolved in chloroform (15 mL), and the extract was washed with saturated aqueous sodium carbonate (5 mL). The aqueous layer was extracted with chloroform (2×15 mL), and the organic layers were combined, dried (MgSO4), filtered, and evaporated under reduced pressure. Purification by flash chromatography through silica gel, eluting with ammoniated chloroform/methanol (95:5 to 9:1), provided the title compound (80 mg, 0.274 mmol, 68%) as a tan solid: electrospray MS 293 ([MH]+, 100).
Reaction SMILES: [N:1]1([C:6]2[CH:29]=[CH:28][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:24]C(=O)C)[CH:16]=[C:17]([N:19]5[CH:23]=[CH:22][CH:21]=[N:20]5)[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+]>C(O)C>[N:1]1([C:6]2[CH:29]=[CH:28][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([CH:16]=[C:17]([N:19]5[CH:23]=[CH:22][CH:21]=[N:20]5)[CH:18]=4)[NH2:24])[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(=O)Nc1cc(-n2cccn2)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-n2cccn2)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Temperature: 90 °C
Yield: 73 %

Procedure:
To a solution of the compound of Example 122 (230 mg, 0.6 mmol) in ethanol (20 ml) was added aqueous solution of sodium hydroxide (192 mg, 4.8 mmol, 8.0 eq.) and the mixture was heated at 90° C. for 3 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 73% yield (150 mg).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][CH2:12][CH2:11][C:10]([CH3:24])([O:14][C:15]3[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=3)[C:9]2=[O:25])=CC=1.[N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:24][C:10]1([O:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)[CH2:11][CH2:12][CH2:13][NH:8][C:9]1=[O:25]
Reactant: COc1ccc(CN2CCCC(C)(Oc3cc(F)c(F)c(F)c3)C2=O)cc1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(Oc2cc(F)c(F)c(F)c2)CCCNC1=O
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a mixture of 1-(4-methoxybenzyl)-3-methyl-3-(3,4,5-trifluorophenoxy)piperidin-2-one (76.2 mg) in acetonitrile (1 mL) was added a mixture of cerium(IV) ammonium nitrate (275 mg) in water (1 mL) at room temperature, and the mixture was stirred overnight. Cerium(IV) ammonium nitrate (110 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the insoluble material was removed by filtration. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate) and silica gel column chromatography (ethyl acetate/hexane) to give the title compound (30.1 mg).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH:10]=O)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:14]=1[NH2:15].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:15]/[C:14]1[C:13]([Cl:12])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1ccncc1/C=N/c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Titanium tetrachloride (1M, 4.3 mL, 4.3 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (1.06 g, 7.2 mmol), 2,6-dichloroaniline (1.17 g, 7.2 mmol) and triethylamine (3.0 mL, 21.6 mmol) in DCM (24 mL) under nitrogen. The resultant mixture was stirred for 3 hours at 0° C. before warming to room temperature and stirring for a further 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was suspended in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:17][CH:18]=[CH2:19])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)=[O:21].[CH3:29][S:30](Cl)(=[O:32])=[O:31].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:17]([N:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:20](=[O:21])[C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)=[C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH:7]=1)[CH:18]=[CH2:19]
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(N)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(NS(C)(=O)=O)c1
Temperature: 25 °C

Procedure:
A solution of 0.9 g of [2-amino-4-[6-(allyl-methyl-amino)-hexyloxy]-phenyl]-(4-bromo-phenyl)-methanone (Ex. 36) is treated in 20 ml of methylene chloride at 0° C. with 0.17 ml of methanesulphonyl chloride in 0.8 ml of methylene chloride and with 24.4 mg of dimethylaminopyridine. The reaction mixture is left to warm to room temperature overnight and concentrated and the residue is taken up in methylene chloride/saturated sodium bicarbonate solution. The organic phase is dried and concentrated. Purification over silica gel with methylene chloride/methanol (95:5) as the eluent gives 0.57 g of N-[5-[6-(allyl-methyl-amino)-hexyloxy]-2-(4-bromo-benzoyl)-phenyl]-methanesulphonamide which is converted into the fumarate, MS: m/e 523 (M+H+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[OH-].[Na+].O.[Cl:11][CH2:12][C:13]([N:15]([CH2:24]Cl)[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23])=[O:14]>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:11][CH2:12][C:13]([N:15]([CH2:24][N:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:7]=[N:6]1)[C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23])=[O:14]
Reactant: Cc1cccc(C)c1N(CCl)C(=O)CCl
Reactant: COc1cn[nH]c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cnn(CN(C(=O)CCl)c2c(C)cccc2C)c1
Reaction time: 3 h

Procedure:
A solution of 10.8 parts by weight of 4-methoxypyrazole and 4.0 parts by weight of sodium hydroxide in 20 parts by volume of water was added dropwise at 10°-15° C., with vigorous stirring, to a solution of 24.6 parts by weight of 2-chloro-N-chloromethyl-2',6'-dimethylacetanilide and one part by weight of benzyltriethylammonium bromide in 70 parts by volume of toluene and the stirring was continued for 3 hours. The organic phase was washed with three times 40 parts by volume of water, dried over sodium sulfate and evaporated in vacuo at 80° C. to give 28.1 parts by weight of 2-chloro-2',6'-dimethyl-N-(4-methoxypyrazol-1-yl-methyl)acetanilide of melting point 115°-116° C. (melting point of a sample recrystallized from ethanol: 118° C.), which according to the 1H-NMR spectrum and thin layer chromatography carried out using a 3:7 mixture of ethyl acetate:toluene was more than 97% pure.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].Br[CH2:37][CH:38]([CH3:40])[CH3:39]>>[CH2:37]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])[CH:38]([CH3:40])[CH3:39]
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: CC(C)CBr
Product: COc1cc2c(cc1OC)C(Cc1ccc(OCC(C)C)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with 1-bromo-2-methyl-propane
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[CH3:13][C:14]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:15][C:16](OC)=[O:17].O>S(=O)(=O)(O)O>[CH3:13][C:14]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:15][C:16]([O:4][C:3]1[C:2]([O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]=1[OH:6])=[O:1])=[O:17]
Reactant: COC(=O)C=C(C)CCCC(C)CCCC(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=CC(=O)OC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.69 g (3.9 mmol) of ascorbic acid was dissolved in concentrated sulfuric acid (18 mL). After addition of 1.0 g (3.9 mmol) of methyl 3,7,11-trimethyldodec-2-enoate, the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into iced water, and extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:20][N:19]=3)=[O:16])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:30]#[C:31]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:31]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:9][CH:10]=3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)#[N:30]
Reactant: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCNCC4)cn3)cc2)ccn1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(N4CCN(C#N)CC4)cn3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-(2-methylpyridin-4-yl)phenyl)-N-(5-(piperazin-1-yl)pyridin-2-yl)acetamide 131-1 (39 mg, 0.10 mmol), Cyanogen Bromide (13 mg, 0.12 mmol) and Potassium Carbonate (28 mg, 0.20 mmol) in DMF (1 mL) was stirred at room temperature overnight. The mixture was poured into water (5 ml) and extracted with ethyl acetate (5 mL×3). The combined organic phases were dried over Na2SO4, and concentrated. The crude product was purified by reverse phase HPLC to give N-(5-(4-cyanopiperazin-1-yl)pyridin-2-yl)-2-(4-(2-methylpyridin-4-yl)phenyl)acetamide 176. MS m/z 413.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.39(d, 1 Hz), 7.96(s, 1H), 7.89(d, 1H),7.68(d, 2H), 7.58(s, 1H), 7.50(d, 1H), 7.46(d, 2H), 7.37(dd, 1H), 3.74(s, 2H), 3.35(t, 4H), 3.18(t, 4H),2.55(s, 3H).