Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH3:15][C:10]1([CH3:16])[CH:11]([OH:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: CC1(C)CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CNCCC1O

Procedure:
A mixture of 1-benzyl-3,3-dimethyl-4-hydroxypiperidine (5.0 g, 22.0 mmole) and 20% palladium hydroxide (1.5 g) in methanol (100 ml) was stirred at 50-55° C. in hydrogen atmosphere (1 atm.) for 20 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,3-dimethyl-4-hydroxypiperidine as oil. Yield 2.9 g (94%), C7H15NO, m/z 130 (M+1), PMR (CDCl3): 0.83 (3H, s, CH3), 1.13 (3H, s, CH3), 1.29 (1H, m, H5), 1.45-1.9 (2H, m, H5& H6), 2.4 (1H, d, H2, j=12 Hz), 2.68 (1H, d, H2, j=12 Hz), 3.08 (1H, m, H6), 3.4 (1H, dd, H4, j=6 Hz & 12 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](I)=[C:9]([NH2:12])[N:8]=[C:7]([Cl:13])[N:6]=1)=[O:4].[CH:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15]>ClCCCl.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:14]=[CH2:15])=[C:9]([NH2:12])[N:8]=[C:7]([Cl:13])[N:6]=1)=[O:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)nc(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1c(N)nc(Cl)nc1C(=O)OC
Yield: 65.8 %

Procedure:
6-Amino-2-chloro-5-iodopyrimidine-4-carboxylic acid methyl ester (10 g, 32 mmol) was dissolved in 1,2-dichloroethane (100 mL), treated with vinyltributylstannane (11.6 mL, 12.6 g, 40 mmol) and sparged with a nitrogen stream for 10 min. Bis(triphenylphosphine)palladium(II) dichloride (1.1 g, 1.6 mmol, 5 mole %) was added and the mixture was heated at reflux under a nitrogen atmosphere for 3 h. The mixture was cooled, stirred with 10% aqueous KHF2 for 30 min, and filtered through diatomaceous earth to remove solids. The filter cake was washed with more 1,2-dichloroethane and ethyl acetate. The combined filtrates were washed with water, washed with saturated NaHCO3, washed with brine, dried, and evaporated. The crude material was chromatographed on silica (5-20% ethyl acetate/dichloromethane containing 2% acetic acid) to give the title compound (4.5 g, 70% yield). This material contained approximately 5% PPh3, but was used without further purification. MS: m/z=213. 1H NMR (CDCl3) δ 6.77 (dd, 1H), 6.4 (br, 2H), 5.70 (d, 1H), 5.61 (d, 1H).
Reaction SMILES: [OH:1][C@:2]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][C:4]([CH2:8][OH:9])([CH3:7])[C:3]1([CH3:11])[CH3:10].[CH3:15]OCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:7][C:4]12[C:3]([CH3:11])([CH3:10])[C@@:2]([C:12]([OH:14])=[O:13])([CH2:6][CH2:5]1)[O:1][CH2:15][O:9][CH2:8]2
Reactant: CC1(CO)CC[C@](O)(C(=O)O)C1(C)C
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC12CC[C@@](C(=O)O)(OCOC1)C2(C)C
Reaction time: 24 h

Procedure:
A mixture of Example 222A (131.6 mg), dimethoxymethane (0.575 mL) and para-toluenesulfonic acid monohydrate (catalytic) in benzene (15 mL) was stirred and heated to reflux with a Dean-Stark trap overnight. An additional 0.5 mL dimethoxymethane was added and heating continued 24 hours. The reaction mixture was evaporated to dryness and flash chromatographed over silica gel eluting with 10% methanol/CH2Cl2 to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 0.88 (s, 3H), 0.94 (s, 3H), 1.15 (s, 3H), 1.88-2.05 (m, 3H), 2.7-2.85 (m, 1H), 3.59 (s, 2H), 5.00 (AB q, J=26.3, 7.9 Hz, 2H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)(=[O:17])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C>CCOC(C)=O>[ClH:1].[N:12]1([S:15]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(O)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cccc(O)c1)N1CCNCC1
Reaction time: 0.17 h

Procedure:
HCl gas was bubbled into a solution of 4-(3-hydroxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (2.3 g, 9.5 mmol) in EtOAc (100 mL) at −20° C. with stirring for 10 min. The solution was stoppered, stirred for 1 h, purged with Ar for 15 min, then concentrated in vacuo to the title compound as a white solid. 1H NMR (d6-DMSO) δ 8.97, br s, 1H), 7.50 (t, 1H, J=8 Hz), 7.12-7.19 (m, 2H), 3.175 (d, 2H, J=5 Hz), 3.12 (t, 2H, J=5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=S)[C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[CH:17]=1
Reactant: C1CCNCC1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(=S)NC2
Solvent: O
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(N1CCCCC1)=NC2
Yield: 57 %

Procedure:
A stirred solution of 8-chloro-4,5-dihydro-1-methyl-6H-s-triazolo[4,3-a][1,4]benzodiazepine-6-thione (VIIIa) (2.65 g., 0.01 mole) and piperidine (25 ml.) was refluxed for 18 hours, under nitrogen. The solution was mixed with cold water and extracted with methylene chloride. The extract was washed with water, then brine, dried (Na2SO4) and concentrated in vacuo. The solid residue was mixed with ethyl acetate and collected by filtration; it was recrystallized from a methylene chloride/methanol/ethyl acetate mixture to give 1.39 g., melting point 238°-243° (soften 235) and 0.40 g., melting point 225°-232° (soften 220) of the titled compound (Ia) (57% yield). The analytical sample had: melting point 248°-249.5° (soften 235°), uv (EtOH) λ max 214 mμ (ε34,850), 235 (sh, 13,200), 287 (sh, 2950), 293 (3050). The ir and nmr spectra support the proposed structure.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16])=[O:4].[N:19]([CH2:22][C@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33]C(C(O)=O)=[C:31]([F:38])[CH:30]=2)[CH2:24]1)=[N+:20]=[N-:21].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[N:19]([CH2:22][C@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:2]([C:3]([O:5][C:6]3[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=3[F:16])=[O:4])=[C:31]([F:38])[CH:30]=2)[CH2:24]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.1 %

Procedure:
Pentafluorophenyl trifluoroacetate (2.2 ml, 12.9 mmol) was added dropwise with stirring to a solution of 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one (3.0 g, 10.7 mmol; prepared as described in Example 3) and pyridine (3.5 ml, 42.8 mmol) in DMF (10 ml). The mixture was stirred at r.t. for 2.5 h, and ethyl acetate with 3% aq. citric acid added. Organic layer was washed twice with 3% citric acid, brine, and dried (Na2SO4). The crude material was washed with ether-hexanes to afford a white crystalline product (4.3 g, 90%). HPLC Rt=7.1. MS (m/z): [M+H]+=447.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([F:16])=[C:6]([C:10]([F:15])=[C:11]([Cl:14])[C:12]=1[F:13])[C:7](F)=[O:8].O.Cl>O1CCOCC1>[Cl:3][C:4]1[C:5]([F:16])=[C:6]([C:10]([F:15])=[C:11]([Cl:14])[C:12]=1[F:13])[CH2:7][OH:8]
Reactant: O=C(F)c1c(F)c(Cl)c(F)c(Cl)c1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1c(F)c(Cl)c(F)c(Cl)c1F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
400 ml of dry dioxane and 55 g of sodium borohydride are initially introduced into a 2 l three-necked flask with a stirrer, reflux condenser and dropping funnel at 20° C., and 247 g of 3,5-dichloro-2,4,6-trifluorobenzoyl fluoride, dissolved in 250 ml of dry dioxane, are then added dropwise at this temperature. When the addition has ended, the mixture is stirred at 20° C. for a further 2 hours and then warmed to the reflux temperature for 1 hour. The solution is cooled to room temperature, a total of 50 ml of water are then added dropwise and the mixture is subsequently rendered acid with dilute hydrochloric acid. The reaction mixture is extracted three times with methylene chloride and, after drying the organic phase over sodium sulphate, the solvent is distilled off. 196.5 g (85% of the theoretical yield) of 3,5-dichloro-2,4,6-trifluorobenzyl alcohol of boiling point 134° to 135° C./20 mbars and melting point 67° to 68° C. are obtained from the residue by further distillation.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>ClCCl>[CH2:9]([O:8][P:4]([CH2:3][CH2:2][NH:1][C:20]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:27])([O:5][CH2:6][CH3:7])=[O:11])[CH3:10]
Reactant: CCOP(=O)(CCN)OCC
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CCNC(=O)c1cccnc1)OCC
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
To a mixture of diethyl 2-aminoethylphosphonate (8.1 g), triethylamine (9.1 g) and dichloromethane (100 ml) at 5° C. was added nicotinic acid chloride hydrochloride (10.4 g) in small portions over a period of 15 minutes. After being stirred for additional 1.5 hours, the reaction mixture was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10% methanol in chloroform) to give 11.2 g of N-(2-diethoxyphosphoryl-ethyl)-3-pyridinecarboxamide as an oil.
Reaction SMILES: CN([CH:4]([CH3:15])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14])=O)C.[NH2:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[F:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[CH:4]=[CH:15][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH3:24])[N:16]=1
Reactant: CC(C(=O)c1cccc(F)c1F)N(C)C
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)c1ccc(-c2cccc(F)c2F)nc1C

Procedure:
The title compound was prepared from dimethylamino-(2,3-difluorophenyl)-propan-1-one and ethyl 3-aminocrotonate using the general procedure outlined in D18. 1H NMR (250 MHz, CDCl3) δ (ppm): 8.28 (d, 1H), 7.83 (m, 1H), 7.70 (dd, 1H), 7.22 (m, 2H), 4.41 (q, 2H), 2.91 (s, 3H), 1.42 (t, 3H).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][N:8]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH:1]1([CH:7]2[CH2:12][C:11]([OH:13])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH2:9][N:8]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(C2CCCCC2)C1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Benzyl 2-cyclohexyl-4-oxopiperidine-1-carboxylate in THF (155 ml) was cooled to 0° C. and added phenylmagnesium bromide (22.08 ml, 61.8 mmol). The ice bath was removed and the solution stirred at room temperature for 14 hours. Quenched the reaction with 1N HCl and concentrated. Extracted three times with EtOAc and washed twice with water. The organics were dried, concentrated, and purified on silica gel 30% EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:7](=[O:14])[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:4]=2[CH:3]=1.[O:23]=[S:24]1(=[O:40])[C:28]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=2[C:26](=[O:34])[N:25]1[CH2:35][CH2:36][CH2:37][CH2:38]Br.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[O:40]=[S:24]1(=[O:23])[C:28]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=2[C:26](=[O:34])[N:25]1[CH2:35][CH2:36][CH2:37][CH2:38][N:18]1[CH2:19][CH2:20][CH:15]([N:6]2[C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][C:4]=3[N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[C:7]2=[O:14])[CH2:16][CH2:17]1
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Reactant: O=c1n(CC(F)(F)F)c2cc(F)ccc2n1C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCN1CCC(n2c(=O)n(CC(F)(F)F)c3cc(F)ccc32)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The 4-(5-fluoro-3-(2,2,2-trifluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine (~10 mmol.) above was dissolved in anhydrous DMF (25 mL) followed by the addition of 1,1 -dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (3.54 g, 10 mmol.) and triethylamine (1.4 mL, 10 mmol.) and allowed to stir at 50° C. under an inert atmosphere for three hours or until reaction was complete. The cooled solution was diluted with EtOAc and washed with NaHCO3 /Na2CO3 solutions, water (3×), and the organic layer dried (Na2SO4), filtered and the solvent evaporated to give 1,1-dioxido-2-(4-(4-(5-fluoro-3-(2,2,2-trifluoroethyl)-2-oxo-1-benzimidazolinyl)piperidin-1-yl)butyl)-5-chloro-1,2-benzisothiazol-3(2H)-one as a viscous oil. This material was dissolved in EtOAc (50 mL) and excess HCl gas/EtOAc was added to give an immediate copious white precipitate which was gently digested in the warmed EtOAc to give the crystalline HCl salt of Compound A, mp: 255-257 ° C. Analysis calculated for C25H25ClF4N4O4S.HCl: C, 48.00; H, 4.19; N, 8.96; found: C, 47.96; H, 4.17; N, 8.93. The NMR was consistent with structure.
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH3:44][C@H:45]([O:49][C:50]1[N:58]=[C:57]2[C:53]([N:54]=[C:55]([O:59][CH3:60])[NH:56]2)=[C:52]([NH2:61])[N:51]=1)[CH2:46][CH2:47][CH3:48].Br[CH2:63][CH2:64][CH:65]1[CH2:70][CH2:69][CH2:68][N:67]([C:71]([O:73][CH2:74][C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)=[O:72])[CH2:66]1>>[NH2:61][C:52]1[N:51]=[C:50]([O:49][C@@H:45]([CH3:44])[CH2:46][CH2:47][CH3:48])[N:58]=[C:57]2[C:53]=1[N:54]=[C:55]([O:59][CH3:60])[N:56]2[CH2:63][CH2:64][CH:65]1[CH2:70][CH2:69][CH2:68][N:67]([C:71]([O:73][CH2:74][C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)=[O:72])[CH2:66]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)[nH]c2n1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCBr)C1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9H-purin-6-amine trifluoroacetate salt and phenylmethyl 3-(2-bromoethyl)-1-piperidinecarboxylate.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>C(#N)C>[CH2:1]1[N:6]([CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12
Reactant: C1CCN2CCNCC2C1
Reactant: C=CC(=O)OCC
Solvent: CC#N
Product: CCOC(=O)CCN1CCN2CCCCC2C1

Procedure:
A solution of 7 g of octahydro-2H-pyrido[1,2-a]pyrazine and 15 ml of ethyl acrylate in 100 ml of acetonitrile is refluxed for 24 hours and then concentrated to dryness in vacuo to yield the expected product.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:5])C.Cl.[NH:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[NH2:19].C(N(CC)CC)C.O>ClCCl.CO>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:18]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:24][CH:25]=3)[N:19]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=NC(=O)c1ccc(OC)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reaction time: 8 h
Yield: 52.9 %

Procedure:
N-(1-ethoxy-ethylidene)-4-methoxy-benzamide 462 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(4-methoxy-phenyl)-3-mehtyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (381 mg, yield: 53%) was obtained as a solid phase.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[N:3]=1
Reactant: OCc1ccc(NCc2ccc(C(F)(F)F)nc2)nc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=Cc1ccc(NCc2ccc(C(F)(F)F)nc2)nc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
To 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanol (563, 1.20 g, 3.98 mmol) in dichloromethane (40.0 mL) was added Dess-Martin periodinane (1.86 g, 4.38 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into aqueous sodium thiosulfate and potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (564, 0.28 g, 23.5%).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH2:24][C:25](=[O:34])[N:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:27]=3)=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:10]=1[O:11]COC.Cl>CO>[OH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH2:24][C:25](=[O:34])[N:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:27]=3)=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: COCOc1ccc(C=Cc2ccc(C3=NN(c4ccccc4)C(=O)C3)cc2)cc1OCOC
Agent: Cl
Solvent: CO
Product: O=C1CC(c2ccc(C=Cc3ccc(O)c(O)c3)cc2)=NN1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-{4-[2-(3,4-bis-methoxymethoxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro-pyrazol-3-one (the cruce reaction product from Example 32) and conc. HCl in MeOH was stirred at room temperature for overnight. Evaporation of the solvent and purification by flash chromatography eluting with 10-15% MeOH in DCM, gave 5-{4-[2-(3,4-dihydroxy-phenyl)-vinyl]-phenyl}-2-phenyl-2,4-dihydro-pyrazol-3-one. 1H NMR (CD3OD+CDCl3, 300 MHz): 7.75-6.45(m, all aromatic peaks). 13C NMR (CD3OD+CDCl3, 75 MHz): 168.65, 148.27, 144.57, 144.36, 142.01, 132.16, 130.44, 129.07, 128.75, 126.94, 121.37, 120.82, 115.66, 115.08, 113.49. MS: 347 and 371 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:42][C:43]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:44]=1[NH2:45].C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:45][C:44]2[CH:46]=[C:47]([CH3:50])[CH:48]=[CH:49][C:43]=2[F:42])=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: O=C(O)c1cccc(Oc2ccnc(Br)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc(Br)c3)c2)c1

Procedure:
A mixture of 3-(2-bromo-pyridin-4-yloxy)-benzoic acid (200 mg, 0.68 mmol), HATU (312 mg, 0.82 mmol),) 2-fluoro-5-methylaniline (125 mg, 1.0 mmol) and N,N-diisopropylethylamine (193 mg, 1.5 mmol) in anhydrous DMF (10 ml) was stirred at 60° C. for 90 minutes. The mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 3-(2-bromo-pyridin-4-yloxy)-N-(2-fluoro-5-methyl-phenyl)-benzamide as off-white solid. Yield: 200 mg, 74%.
Reaction SMILES: C(N(CC)C(C)C)C.[CH2:9]([C@:16]1([CH3:22])[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[CH2:9]([C@:16]1([CH3:22])[CH2:21][N:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH3:27])=[O:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@]1(Cc2ccccc2)CNCCN1
Reactant: COC(=O)Cl
Agent: CCN(CC)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)OC)[C@](C)(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
Diethylisopropylamine (0.98 ml, 5.0 mmol) was added to a stirring solution of (R)-2-benzyl-2-methylpiperazine (0.38 g, 2.0 mmol) and methyl chloroformate (0.41 g, 0.35 ml, 2.8 mmol) in CH2Cl2 (20 ml). After stirring at ambient temperature for 2 h, the reaction was evaporated in vacuo and the residue purified by flash chromatography (SiO2, CH2Cl2 to 40% EtOAc in CH2Cl2) to afford pure product (0.28 g, 34% yield over the two steps). MS (ESI) 307 (M+H).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH:12]1[C:27]([OH:29])=O)=[O:10])C1C=CC=CC=1.B.C1COCC1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[O:10]=[C:9]1[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH:12]2[CH2:27][O:29]1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCN2C(=O)OCC2C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
1,4-Di((benzyloxy)carbonyl)piperazine-2-carboxylic acid (18.9 g, 47.4 mmol) was dissolved in THF (200 mL), and borane-THF complex (1.0 M solution in THF, 100 mL, 100 mmol) was added over about 15 min. Upon complete addition, the reaction mixture was heated to 50° C. After 3 h, the reaction mixture was allowed to cool to rt and was slowly quenched by the dropwise addition of MeOH. After gas evolution ceased, the reaction mixture was heated to 50° C. for 1 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The material was dissolved in EtOH (200 mL) and K2CO3 (6.9 g, 49.9 mmol) was added. The reaction mixture was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure, diluted with H2O (200 mL) and extracted with EtOAc (3×200 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (10 to 40% EtOAc in Hexanes gradient) to give 10.26 g (78%) of the desired product as a white solid. An additional 0.452 g (3%) of the desired product was isolated from impure chromatography fractions by recrystallization from methyl tert-butyl ether. LC-MS: RT=7.848 min; [M+Na]+=299.1.