Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=C(S[C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])C=C(C(C)(C)C)C=1O)(C)C.C(OC1[O:43][C@H:42]([CH2:44][OH:45])[C@@H:41]([CH2:46]O)[O:40]1)C>>[C:32]([C:23]1[CH:22]=[C:21]([SH:20]([CH:17]([CH3:18])[CH3:19])[S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:33])([CH3:34])[CH3:35])[C:24]([OH:31])=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)[CH:26]=[C:25]([C:27]([CH3:30])([CH3:28])[CH3:29])[C:24]=1[O:31][CH2:46][C@@H:41]([OH:40])[C@H:42]([OH:43])[CH2:44][OH:45])([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCOC1O[C@H](CO)[C@@H](CO)O1
Product: CC(C)[SH](Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1cc(C(C)(C)C)c(OC[C@@H](O)[C@H](O)CO)c(C(C)(C)C)c1

Procedure:
The title compound was prepared using the same procedure as described in Ex-1 starting from probucol and 2-ethoxy-1,3-dioxolane-4(R),5(R)-dimethanol. White solid, mp 69–71° C. 1H-NMR (CDCl3) δ 7.56 (s, 2H, Ph-H), 7.45 (s, 2H, Ph-H), 5.38 (s, 1H, PhOH), 4.2{tilde over (5)}4.32 (m, 1H, PhOCH2CH), 3.96 (dd, J=9, 10, 1H, CH—O—), 3.7{tilde over (2)}3.86 (m, 4H, , CH—O—), 3.0{tilde over (0)}3.40 (m, 3H, OH), 1.46 (s, 6H, S,S′-isopropylidene), 1.45 (s, 18H, tert-butyls), 1.43 (s, 18H, tert-butyls). MS m/z: 643 ([M+Na]+, 100%). Anal. calcd. for C35H56O5S2.⅓H2O: C67.05, H9.11, S, 10.23; found: C67.03, H9.06, S10.01.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=2)[N:9]=[C:8]([C:26]([F:29])([F:28])[F:27])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])[CH2:44][CH:43]=1)(=O)=O>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([C:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)=[O:49])[CH2:44][CH:43]=3)[CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:26]([F:29])([F:28])[F:27])[CH:7]=1
Reactant: CC1(C)OB(c2cccc(-n3nc(C(F)(F)F)cc3-c3ccco3)c2)OC1(C)C
Reactant: O=C(OCc1ccccc1)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CC=C(c2cccc(-n3nc(C(F)(F)F)cc3-c3ccco3)c2)CC1
Temperature: 75 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a stirred solution of 63 (533 mg, 1.319 mmol) in DMF (6.6 mL) were added potassium carbonate (419 mg, 3.03 mmol) and benzyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1 (2H)-carboxylate (578 mg, 1.582 mmol) followed by 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (58 mg, 0.079 mmol). The resulting suspension was allowed to stir at 75° C. for 4 h. The mixture then was filtered through celite and washed with EtOAc. The organic phase was washed with brine and dried over Na2SO4. The solution was then evaporated to dryness. The residue was purified via silica gel flash chromatography (5% to 40% EtOAc/hexanes). The title product 64 (430 mg, 66% yield) was isolated as a colorless oil. LRMS (ESI): calc. 493.5; found 494.5 (MH)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OC(=O)C)(=O)C.[CH3:19][C:20]([CH3:22])=O>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[C:20](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])([CH3:22])[CH3:19]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C(=O)OCC)=C(C)C
Yield: 44.7 %

Procedure:
A reaction mixture of 200 g (1.25 mol) of diethyl malonate, 159.51 g (1.56 mol) of acetic anhydride, 108.9 g (1.87 mol) of acetone, and 25.5 g (0.187 mol) of zinc chloride placed in a 1000 ml round bottom flask was allowed to reflux for 20 hours. The reaction mixture was cooled, diluted with 200 ml of benzene, and the resulting mixture was washed with water (4×250 ml). The combined aqueous layer was extracted with benzene (2×50 ml) and the organic layers were combined. After removing benzene in vacuo, the mixture was distilled twice (Vigreux distilling column--10") to afford 111.8 g (44.7%--crude) of diethyl isopropylidenemalonate contains a trace of diethyl malonate), b.p. 80° C./0.5 mm.
Reaction SMILES: [CH:1]1([CH2:5][N:6]([CH2:20][CH2:21][CH3:22])[CH:7]2[CH2:19][CH2:18][C:10]3[C:11]4[CH:12]=[CH:13][NH:14][C:15]=4[CH:16]=[CH:17][C:9]=3[CH2:8]2)[CH2:4][CH2:3][CH2:2]1.[Cl:23]N1C(=O)CCC1=O>O1CCCC1>[Cl:23][C:12]1[C:11]2[C:10]3[CH2:18][CH2:19][CH:7]([N:6]([CH2:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:20][CH2:21][CH3:22])[CH2:8][C:9]=3[CH:17]=[CH:16][C:15]=2[NH:14][CH:13]=1
Reactant: CCCN(CC1CCC1)C1CCc2c(ccc3[nH]ccc23)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCCN(CC1CCC1)C1CCc2c(ccc3[nH]cc(Cl)c23)C1
Yield: 81.2 %

Procedure:
A solution of cyclobutylmethyl-propyl-(6,7,8,9-tetrahydro-3H-benzo[e]indol-7-yl)amine 48 mg, 0.16 mmol) and N-chlorosuccinimide (35 mg, 0.26 mmol) in tetrahydrofuran (5 mL) was stirred at room temperature for 1 day. After pouring the reaction mixture into water, extraction (diethyl ether), drying (magnesium sulfate), filtering, and evaporation yielded 43 mg (80%) of the desired compound.:
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:2]=[CH2:3].CC([O-])(C)C.[K+].[Si:19]([O:26][CH2:27][C@@H:28]1[CH:33]=[C:32]([CH2:34][O:35][CH3:36])[C@H:31](OS(C)(=O)=O)[CH2:30][N:29]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].ON>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]([C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[C@H:31]1[CH2:30][N:29]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C@H:28]([CH2:27][O:26][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:33]=[C:32]1[CH2:34][O:35][CH3:36])[CH:2]=[CH2:3]
Reactant: COCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1OS(C)(=O)=O
Reactant: C=CCONC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: NO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCON(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl allyloxycarbamate (7.39 g, 42.66 mmol) in DMF (150 mL) at rt, potassium 2-methylpropan-2-olate (42.66 mL, 42.66 mmol) was added and gave a purple solution. After 30 min at rt, the mixture was cooled to 0° C. and (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(methoxymethyl)-5-(methylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (crude, 16.55 g, 35.55 mmol) in 50.0 mL DMF was added. The mixture was then warmed up to rt for 1 h. It was then diluted with ethyl acetate (200 mL) and washed aqueous sat. NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated to give a residue which contains some starting material. The crude was purified on a silica gel column yielding a colorless oil. (19.3 g). 1HNMR shows still a mixture (with hydroxyamine starting material). It was used directly in TBS deprotection.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])[CH:15]=[C:14](OC)[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][CH:35]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:16]1[CH:17]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[O:39])=[CH:36][CH:35]=3)[N:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Reactant: COc1cc(Nc2nc(Cl)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CCCN1c1cccc(Nc2nc(-c3ccc(C(N)=O)cc3)nc3scnc23)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 20.8 %

Procedure:
The mixture of (S)-5-chloro-N-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.29 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (77 mg, 0.29 mmol), Pd2(dba)3 (33 mg, 0.058 mmol), X-Phos (55 mg, 0.116 mmol) and Na2CO3 (123 mg, 1.16 mmol) in dioxane (20 mL) and water (5 mL) was heated to 100° C. with stirring for 16 h under N2. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (DCM:MeOH=80:1) to afford (S)-4-(7-(3-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (26 mg, 21%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.02 (s, 1H), 9.39 (s, 1H), 8.46-8.44 (m, 2H), 8.10 (s, 1H), 8.00-7.97 (m, 2H), 7.48-7.39 (m, 2H), 7.29-7.15 (m, 2H), 6.35 (d, 1H, J=7.8 Hz), 3.91 (brs, 1H), 3.41-3.31 (m, 1H), 3.19-3.16 (m, 1H), 2.08-1.98 (m, 2H), 1.71 (brs, 1H), 1.15 (d, 3H, J=6.3 Hz). LC-MS: 431 [M+H]+, tR=1.57 min. HPLC: 95.67% at 214 nm, 95.15% at 254 nm, tR=3.14 min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].[C:22]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:23][C:24]([CH3:26])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]2)[N:1]=[C:24]([CH3:26])[C:23]=1[C:22]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCC(=O)N1CCC(COc2cccc(N)c2C#N)CC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCN(C(=O)CC)CC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-((1-propionylpiperidin-4-yl)methoxy)benzonitrile (Example 153b) and ethyl acetoacetate as an off-white solid (41%). MS 400 (MH+).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][C:19](=[O:21])[CH2:18][C@@H:17]1[C@H:22]1[O:26][C:25]([CH3:28])([CH3:27])[N:24]([C:29](=[O:31])[CH3:30])[C@H:23]1[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CCOCC.C(OCC)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:20][C@@:19]([OH:21])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:18][C@@H:17]1[C@H:22]1[O:26][C:25]([CH3:27])([CH3:28])[N:24]([C:29](=[O:31])[CH3:30])[C@H:23]1[CH2:32][C:33]1[CH:34]=[C:35]([F:40])[CH:36]=[C:37]([F:39])[CH:38]=1)=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2CC(=O)CN2C(=O)OC(C)(C)C)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@](O)(c3ccccc3)CN2C(=O)OC(C)(C)C)OC1(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
Add phenyl magnesium bromide (3.0 mL, 9 mmol, 3M in ether) dropwise to an ice cold solution of (R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (0.40 g, 0.89 mmol) in ether (20 mL). Stir 60 minutes and warm to 23° C. Dilute with ethyl acetate and wash with saturated aqueous ammonium chloride. Purify on silica gel with dichloromethane/ethyl acetate mixtures to give the desired compound as a foam (0.19 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6](B(O)O)[CH:7]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1>O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CCOc1ccc(Cl)cc1-c1ccc([C@@H](C)N)cc1
Temperature: 200 °C
Yield: 80 %

Procedure:
A suspension of 5-chloro-2-ethoxyphenylboronic acid (601 mg, 3.0 mmol), palladium (II) acetate (33 mg, 0.15 mmol) and (R)-1-(4-bromophenyl)ethylamine (295 mg, 1.5 mmol) in water (4 ml) was heated for 5 min at 200° C. in a Smithcreator microwave oven. The reaction mixture was diluted with dichloromethane and purified on a Strata™ 5 g/20 ml SCX column (eluted with 2M ammonia in methanol) to give (R)-1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (341 mg, 1.2 mmol, 82%). To a solution of 1-(5′-chloro-2′-ethoxy-biphenyl-4-yl)-ethylamine (30 mg, 0.1 mmol) in dichloromethane (0.75 ml) was added triethylamine (36 mg, 0.35 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (30 mg, 0.13 mmol) in dichloromethane (0.5 ml). The reaction mixture was then agitated at room temperature for 16 h and quenched with acetic acid (200 μl). Purification by preparatory LCMS and removal of solvent under reduced pressure gave the title compound (21 mg, 0.04 mmol, 40%): 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, 1H), 7.32-7.37 (m, 3H), 7.21-7.24 (m, 3H), 7.10 (d, 1H), 4.35 (m, 1H), 4.05 (m, 2H), 2.20 (s, 3H), 1.26-1.35 (m, 6H) ppm; MS (ESI) m/z: value [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:31]([O:33][C:34](=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38]Br)[CH3:32]>CN(C)C=O>[CH2:31]([O:33][C:34](=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38][N:7]1[C:8]2[C:13](=[CH:12][C:11]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:10][CH:9]=2)[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:32]
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1-c1ccccc1
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCn1c(C(=O)OCC)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc21
Reaction time: 0.5 h

Procedure:
An amount of 23.5 g (63.3 m mole) of 5-benzyloxy-3-phenyl-1H-2-indole-carboxylic acid ethylester in absolute dimethylformamide was mixed with 3.0 g (63.3 m mole) of 50% sodium hydride. After 30 minutes, 13.2 g (63.3 m mole) of 5-bromo-valeric acid ethylester were added, and the mixture was stirred for three days. After evaporation, the residue obtained was chromatographed on silicagel (solvent: toluene/acetone (20.1)).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:34]=[C:33]4[CH2:35][CH2:36][O:37][C:32]4=[CH:31][C:29]=3[N:30]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[N:16]1([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:34]=[C:33]4[CH2:35][CH2:36][O:37][C:32]4=[CH:31][C:29]=3[N+:30]=2[O-:4])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1nc(CCCN2CCOCC2)nc2cc3c(cc21)CCO3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1nc(CCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCO3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
H2O2 (70%, 0.31 mL, ca. 6.3 mmol) was added dropwise to a stirred solution of TFAA (0.88 mL, 6.3 mmol) in DCM (12 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. The solution was added to a solution of 1-oxide 215 (200 mg, 0.63 mmol) and TFA (0.10 mL, 1.4 mmol) in DCM (12 mL) at 0° C. and the solution was stirred at 20° C. for 2.5 h. Dilute aqueous NH3 solution was added until the mixture was basic and then the mixture was extracted with CHCl3 (3×20 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (1-5%) of MeOH/DCM, to give 1,4-dioxide 216 (88 mg, 43%) as a dark yellow solid: mp 150-154° C.; 1H NMR δ 8.28 (t, J=1.6 Hz, 1H, H-9), 7.68 (s, 1H, H-5), 4.87 (t, J=8.5 Hz, 2H, H-7), 3.48 (dt, J=8.5, 1.5 Hz, 2H, H-8), 3.44 (t, J=4.4 Hz, 4H, 2×CH2O), 3.22 (t, J=7.2 Hz, 2H, CH2), 2.49 (t, J=6.5 Hz, 2H, CH2), 2.38 (t, J=4.4 Hz, 4H, 2×CH2N), 2.06-2.13 (m, 2H, CH2); 13C NMR δ 166.7, 156.1, 141.7, 136.3, 130.2, 117.8, 96.1, 73.5, 67.0 (2), 58.0, 53.5 (2), 29.0, 28.8, 21.8. Anal. calcd for C16H20N4O4: C, 57.8; H, 6.1; N, 16.9. Found: C, 57.8; H, 6.1; N, 16.6%.
Reaction SMILES: S1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH2:8])=[NH:7].[CH3:9][C:10]1C=CN=C(C#N)[CH:11]=1>>[CH3:11][C:10]1[CH:5]=[CH:4][N:3]=[C:2]([C:6]([NH2:8])=[NH:7])[CH:9]=1
Reactant: Cc1ccnc(C#N)c1
Reactant: N=C(N)c1nccs1
Product: Cc1ccnc(C(=N)N)c1

Procedure:
4-Methyl-pyridine-2-carboxamidine (Compound A2) was prepared in analogy to compound thiazole-2-carboxamidine with the procedure shown in Scheme 5 by using 4-methyl-pyridine-2-carbonitrile instead of thiazole-2-carbonitrile. MS: calc'd (MH+) 136, measured (MH+) 136.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCNC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.079 mmol), 4-aminobutyric acid (653 mg, 6.34 mmol) and NaOMe solution (9.5 mL, 4.76 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 16 mg of the title compound. MS: (+) m/z 526.32 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH:19]([OH:29])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-])=O)[C:15]([O:17]C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O.[Fe]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH:19]([OH:29])[C:20]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:26][C:15]2=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C1CCN(Cc2ccccc2)CC1)C(O)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2ccccc2C(O)C1C1CCN(Cc2ccccc2)CC1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Methyl 2-(1-benzylpiperidin-4-yl)-3-hydroxy-3-(2-nitrophenyl)propanoate (2.4 mmol, 950 mg) was dissolved in acetic acid (20 mL). Iron (17.7 mmol, 1.0 g) was added to the mixture. Reaction was heated at 85° C. and held with stirring for 1.5 hours. Mixture was cooled to room temperature then diluted with water (30 mL). Solids were decanted off. The aqueous solution was concentrated in vacuo. Residue was treated with ethyl acetate (50 mL). The mixture was made basic with aqueous sodium hydroxide. Celite was added to the resulting suspension to create a slurry. Mixture was filtered. Filtrate layers were separated. Aqueous layer was extracted 1× ethyl acetate. Combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained without further purification as yellow oil in 69% yield. MS m/e (M+H)+=335.3.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:6][CH:5]=1.Br>O>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(Cc2ccccc2C2CCNCC2)cc1
Agent: Br
Agent: Cl
Solvent: O
Product: Oc1ccc(Cc2ccccc2C2CCNCC2)cc1
Temperature: 157 °C
Reaction time: 0.53 h

Procedure:
A mixture of 3 g of 4-[α-(4-methoxyphenyl)-2-tolyl]piperidine hydrochloride, Example 39, and 48 ml of 48% HBr is refluxed on an oil bath (157° C.) with stirring for 32 minutes, cooled and then poured onto 48 ml of cooled water. The resulting suspension is quenched with 48 ml of concentrated ammonium hydroxide, stirred thoroughly and the solid is collected by suction filtration. The filter cake is dried in vacuo at 40° C. over sodium hydroxide pellets and then dissolved in 500 ml of hot absolute ethanol. 32 ml of triethylamine is added to the hot ethanolic solution. The hot solution is diluted with chloroform and then washed twice with water. The organic phase is collected, dried and filtered and then the solvent evaporated off leaving a solid product which is recrystallized from absolute ethanol in the presence of activated charcoal to give yellowish crystals, mp 217°-221° C. of 4-[α-(4-hydroxyphenyl)-2-tolyl]piperidine.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[CH:17]=[O:18])[CH:20]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Reactant: OB(O)c1cccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 95 °C
Yield: 47 %

Procedure:
5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) (1.53 g, 4.30 mmol), pyridine-3-boronic acid (CXXXI) (0.58 g, 4.73 mmol), and potassium phosphate tribasic (1.37 g, 6.45 mmol) was dissolved in 1,4-dioxane (43.0 mL) and water (9.0 mL) Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.4301 mmol) was added, and the reaction was heated to 95° C. for 2.5 h. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic phase was separated and washed sequentially with water and brine. The material was dried (MgSO4), concentrated, and purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge (100% hexanes→1:1 EtOAc:hexanes) to afford 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXXXII) (0.62 g, 2.02 mmol, 47% yield) as a tan amorphous solid. 1H NMR (DMSO-d6) δ ppm 10.23 (s, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.61 (dd, J=4.8, 1.5 Hz, 1H), 8.39 (d, J=0.98 Hz, 1H), 8.17-8.14 (m, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.95-7.93 (m, 1H), 7.64-7.60 (m, 1H), 6.13 (dd, J=9.4, 2.4 Hz, 1H), 3.93-3.90 (m, 1H), 3.86-3.81 (m, 1H), 2.45-2.41 (m, 1H), 2.11-2.07 (m, 2H), 1.82-1.78 (m, 1H), 1.66-1.62 (m, 2H); ESIMS found for C18H17N3O2 m/z 308 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Product: CC(C)(C)C(=O)Nc1cccc(COCc2cccc(Cl)c2)n1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(6-hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.73 g) and 3-chlorobenzyl bromide as a yellow oil (0.75 g). MS (ESI): 332.2 (MH+).