Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[Br:9].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:9][C:3]1[C:4]([CH2:7][CH3:8])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: CCc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCc1noc(NS(=O)(=O)c2ccccc2)c1Br
Yield: 70 %

Procedure:
N-(4-Bromo-3-ethyl-5-isoxazolyl) benzenesulfonamide was prepared from 5-amino-4-bromo-3-ethylisoxazole and benzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give off-white crystals, m.p. 90-93° C., yield 70%.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])[C:27]([OH:29])=O)#[N:23].[F:37][C:38]1[C:46](/[C:47](/[NH:50]O)=[N:48]/[H])=[C:45]2[C:41]([C:42]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:43][NH:44]2)=[CH:40][CH:39]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:22]([C:24]1[CH:25]=[C:26]([C:27]2[O:29][N:48]=[C:47]([C:46]3[C:38]([F:37])=[CH:39][CH:40]=[C:41]4[C:45]=3[NH:44][CH:43]=[C:42]4[CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])[N:50]=2)[CH:30]=[CH:31][C:32]=1[O:33][CH:34]([CH3:36])[CH3:35])#[N:23]
Reactant: [H]/N=C(\NO)c1c(F)ccc2c(CCC(=O)OCC)c[nH]c12
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(F)ccc12
Reaction time: 1 h
Yield: 86.3 %

Procedure:
HOBT (672 mg) and EDCI (841 mg) were added to a solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (450 mg) in THF (10 mL). The resulting solution was stirred for 1 hour. Ethyl 3-{6-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D145) (836 mg) in THF (5 mL) was added, and the reaction mixture was stirred at RT for 2 hours. TBAF (2.02 g) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 2 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D148) (875 mg) as a yellow solid. MS (ES): C25H23FN4O4 requires 462; found 463.2 (M+H+).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.[CH:15](I)([CH3:17])[CH3:16].Cl>CN(C=O)C.O>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH:14][CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)I
Reactant: NS(=O)(=O)c1cccc(CO)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NS(=O)(=O)c1cccc(CO)c1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% oil dispersion, 0.177 g) was added to 3-hydroxymethylbenzenesulfonamide (0.77 g) with stirring in DMF (15 ml) under nitrogen at 21°. After 10 min, isopropyl iodide (0.45 ml) was added followed by a further 0.3 ml after 1 h. After an additional 2 h more isopropyl iodide (0.2 ml) was added. After 3 days more sodium hydride oil dispersion (0.08 g) was added. After another day, the solution was poured into water acidified with 2M hydrochloric acid and the product was extracted with ethyl acetate twice. The combined extracts were washed with brine and evaporated to an oil. This oil was loaded onto a column of silica gel (60 g) and the column was eluted successively with 30%, 50% and 70% ethyl acetate in 40-60 petroleum ether to give the title compound (0.527 g) LCMS RT=2.22 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=C(C#N)C=1.[OH:23]O>C[Re](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]2[CH2:14][O:23]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: OO
Agent: C[Re](=O)(=O)=O
Agent: N#Cc1cccnc1
Product: CC(C)(C)OC(=O)N1CC[C@H](C2CO2)C1

Procedure:
To (R)-3-vinylpyrrolidine-1-carboxylic acid t-butyl ester (6.1 g, 30.8 mmol, 1.0 eq.) was added 3-pyridinecarbonitrile (320 mg, 3.1 mmol, 0.1 eq.) and methyltrioxorhenium (VII) (192 mg, 769 mmol, 0.025 eq.). The mixture was stirred until homogeneous. 30% Hydrogen peroxide (33:77, hydrogen peroxide:H2O, 4.1 mL, 1.3 eq.) was added, and the mixture was placed in a ice water bath and stirred for 2 hours. Additional methyltrioxorhenium (VII) (50 mg) was added. The organic layer was collected and washed with a saturated sodium metabisulfite solution under an ice bath. The material was then washed with saturated aqueous NaCl. The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The peroxide layer was carefully quenched by adding ice followed by adding saturated sodium metabisulfite solution dropwise at 0° C. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to give (S)-3-oxiranylpyrrolidine-1-carboxylic acid t-butyl ester as a yellowish oil (4.2 g).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:14]([O:21][C:22]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:23]=1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>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.C(OCC)(=O)C.O.COCCOC>[CH2:14]([O:21][C:22]1[CH:37]=[CH:36][C:35]([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:34][C:23]=1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Brc1ncccn1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)c(C(=O)OCc3ccccc3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(OCc1ccccc1)c1cc(-c2ncccn2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Water (5.3 mL), 2-bromopyrimidine (0.95 g), sodium carbonate (1.3 g), and bis(triphenylphosphine)palladium(II) dichloride (0.14 g) were added to an ethylene glycol dimethyl ether (18 mL) solution of the obtained benzyl 2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.8 g), followed by heating to reflux under a nitrogen atmosphere for 4 hours. The reaction mixture was cooled to room temperature, an then bis(triphenylphosphine)palladium(II) dichloride (0.14 g) was added thereto, followed by heating to reflux under a nitrogen atmosphere for 5 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 80-50% hexane/ethyl acetate] to obtain 1.4 g of benzyl 2-(benzyloxy)-5-(pyrimidin-2-yl)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](OC)=[O:18])[CH:15]=3)[N:10]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=3)[N:10]([C:21]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)c(-c1cccc(F)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Under ice-cooling, a solution of 3.85 g of methyl 3-(3-fluorophenyl)-1-trityl-1H-5-indazolecarboxylate in 40 ml tetrahydrofuran was added 535 mg of lithium aluminium hydride, and the mixture was stirred at the same temperature for 5 minutes and at room temperature for further 30 minutes. The reaction mixture was ice-cooled, saturated aqueous sodium sulfate solution was added, aluminium hydroxide was precipitated, and the organic layer was decanted. To the residue was added 20 ml of tetrahydrofuran, stirred, and the organic layer was re-decanted twice. The solvent was evaporated from the collected organic layers. The residue was dissolved in 80 ml of ethyl acetate, and then the mixture was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude crystals were recrystallized from diisopropyl ether, to give 3.37 g of the title compound as white needles.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:30][C:31]1[CH:32]=[C:33]([S:37]([NH:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[OH:43][CH2:42][C:41]([NH:40][S:37]([C:33]1[CH:32]=[C:31]([NH:30][C:27]([C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:13])[F:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[O:28])[CH:36]=[CH:35][CH:34]=1)(=[O:39])=[O:38])([CH3:45])[CH3:44]
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC(C)(C)CO)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.11) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 646.4 [(M+H+]; mp 268° C.
Reaction SMILES: [C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([CH3:33])=[CH:28][C:27]=3[C@@H:34]([NH:37]C(=O)OCC3C=CC=CC=3)[CH2:35][CH3:36])[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([CH3:33])=[CH:28][C:27]=3[C@@H:34]([NH2:37])[CH2:35][CH3:36])[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](NC(=O)OCc1ccccc1)c1cc(C)c(C)cc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Agent: [Pd]
Solvent: CCO
Product: CC[C@H](N)c1cc(C)c(C)cc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1

Procedure:
A mixture of amine 112 (910 mg, 1.41 mmol) and 10% Pd on carbon (91 mg of “Degussa type”), in ethanol/glacial acetic acid (1:1, 20 mL) was hydrogenated at atmospheric pressure for approximately 3 h. The resulting mixture was filtered through a short column of Celite®, eluting copiously with ethanol. The filtrate was evaporated and the residue was partitioned between DCM and saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous phase was re-extracted twice with DCM. The combined organic extracts were washed with water, brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo to afford 113 as a colorless oil which was used in the next step without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[N:21](COCC[Si](C)(C)C)[C:22]([C:25]2[CH:26]=[N:27][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[NH:38][C:39]([C@@H:42]5[CH2:46][CH2:45][CH2:44][N:43]5C(OC(C)(C)C)=O)=[N:40][CH:41]=4)=[CH:33][CH:32]=3)=[N:29][CH:30]=2)=[CH:23][N:24]=1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]1[NH:21][C:22]([C:25]2[CH:26]=[N:27][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[NH:38][C:39]([C@@H:42]5[CH2:46][CH2:45][CH2:44][NH:43]5)=[N:40][CH:41]=4)=[CH:33][CH:32]=3)=[N:29][CH:30]=2)=[CH:23][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)n4COCC[Si](C)(C)C)cn3)cc2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(-c2cnc([C@@H]3CCCN3)[nH]2)ccc1-c1ncc(-c2cnc([C@@H]3CCCN3)[nH]2)cn1
Yield: 36.3 %

Procedure:
TFA (8 mL) was added in one portion to a stirred solution of (S)-2-[5-(2-{4-[2-((S)-1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.50 g, 1.98 mmol) in dry CH2Cl2 (30 mL) at room temperature. The flask was sealed and the mixture was stirred at room temperature for 16 h before the solvent(s) were removed in vacuo. The residue was taken up in methanol, filtered through a PVDF syringe filter (13 mm×0.45 μm), distributed to 8 pHPLC vials and chromatographed by HPLC (gradient elution from 10% B to 100% B over 13 min on a Phenomenex C18 column, 30×100 mm, 10 μm, where A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1% TFA). After concentration of the selected test tubes by speed vacuum evaporation, the product was dissolved in methanol and neutralized by passing the solution through an UCT CHQAX 110M75 anion exchange cartridge. There was isolated the title compound as a yellow mustard-colored solid (306.7 mg, 36% yield) upon concentration of the eluant.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:14]=[C:13]([CH3:15])[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1.CC1CCCO1.O.C([O-])([O-])=O.[Na+].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl>>[CH3:2][C:3]1[CH:14]=[C:13]([CH3:15])[C:6]2[N:7]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(C)c2c(c1)C(=O)CCCN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: Cc1cc(C)c2c(c1)C(=O)CCCN2C(=O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 50 h
Yield: 91.9 %

Procedure:
Charge a 22 L flask with an overhead stirrer, thermocouple, 3 L addition funnel, baffle, cooling bath and N2 purge and 7,9-dimethyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one hydrochloride (1,000 g, 4.43 moles). Add 2-methyltetrahydrofuran (6.44 kg, 7.5 L, 74.5 moles) and agitate the off-white slurry. Cool to 5-15° C. Add water 2.5 L, 138.8 moles and Na2CO3 (1.12 kg, 3 moles) to the addition funnel then slowly add to the reaction mixture at a fast drip over about 25 m. Charge a 2 L addition funnel with benzyl chloroformate (91.59 kg, 8.86 moles) add dropwise to the reaction, while maintaining the reaction mixture below about 15° C. Transfer the resulting mixture to a flask equipped with a condenser and heat to 25-25° C. and stir for about 50 h. Cool to about 15° C., add HCl (5 M, until the pH is about 5). Separate the layers. Extract the aqueous layer with methyltetrahydrofuran (4 L); combine the organic layers and wash with water (4 l). Concentrate the organic layer at about 40° C. Add IPA (4 L) and then concentrate to 2 L. Transfer to a 12 L flask equipped with an overhead stirrer, thermocouple, heating mantle condenser, 2 L addition funnel and N2 purge. Heat the flask contents to about 70-80° C. and add heptane (5 L). Slowly cool to RT overnight; seed the mixture if necessary to induce crystallization of the titled compound. Cool and collect the solid; rinse the solid with cold heptane and dry in a vacuum at 50° C. to provide 1,316 g of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccccc1Cl
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccccc2Cl)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2-chlorophenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2-chlorophenyl)-6-oxohexyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[CH:12][NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([S:8][C:9]1[N:13]=[CH:12][N:11]([C:16](=[O:17])[N:15]([CH3:19])[CH3:14])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: c1ccc(CSc2nc[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)n1cnc(SCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
A suspension of 3-benzylthio-1H-1,2,4-triazole (172 mg), dimethylcarbamoyl chloride (248 μl) and anhydrous potassium carbonate (621 mg) in dimethylformamide (4 ml) was stirred at room temperature for 80 minutes. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with water and subsequently once with saturated aqueous sodium chloride solution, and then dried over sodium sulfate. After filtration, the solvent was distilled from the filtrate under reduced pressure to obtain a clear oil. The resultant oil was purified by a column chromatography (ethyl acetate/hexane=1/5) to yield the titled compound (88 mg) as a clear oil.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([O:17][C:18](=[O:41])[NH:19][C@@H:20]([CH2:32][O:33]CC2C=CC=CC=2)[CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:7][C@H:8]([O:17][C:18](=[O:41])[NH:19][C@@H:20]([CH2:32][OH:33])[CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(N[C@@H](COCc1ccccc1)CN1CCc2cc(F)ccc21)O[C@@H](CC1CCCCC1)C(=O)N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@@H](CO)CN1CCc2cc(F)ccc21)O[C@@H](CC1CCCCC1)C(=O)N1CCOCC1
Yield: 71.4 %

Procedure:
The title compound of Example 10 (50 mg, 0.088 mmol) was dissolved in a minimum amount of methanol (approx. 1-2 mL) and a catalytic amount of 10% Pd/C was added. Air was purged from the reaction vessel and H2 gas was introduced via a balloon. The reaction mixture was stirred for several hours under a H2 atmosphere, after which point the starting material had disappeared by LCMS. The Pd/C was filtered and the crude material was purified by reverse-phase HPLC to afford the title compound (30 mg, 71% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[NH2:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1.CCOC(C)=O.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>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:14]2[CH:15]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH2:9])=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: Nc1cccc(B(O)O)c1
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1cccc(-c2ncc(Br)cn2)c1
Temperature: 100 °C
Yield: 96.2 %

Procedure:
A mixture of 5-Bromo-2-iodo-pyrimidine (9.0 g; 31.6 mmol; 1.0 eq.), 3-aminophenyl boronic acid (4.3 g; 31.6 mmol; 1.0 eq.), K2CO3 (17.5 g; 126.4 mmol; 4.0 eq.) and Pd(PPh3)4 (1.83 g; 1.58 mmol; 0.05 eq.) in water/dioxane (67:135 mL) was heated overnight at 100° C. The reaction mixture was then diluted with EtOAc and organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated to give the title compound as a beige solid (7.6 g; 96%). HPLC (Condition A): Rt 1.90 min (purity 78.0%). MS (ESI+): 250.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([C:25]([NH2:27])=O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][NH2:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2C(N)=O)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CN)cc1OC

Procedure:
In a manner similar to Preparation 2, react 4-(3-chlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-2-piperazinecarboxamide (6.0 g, 15 mmol) with lithium aluminum hydride (1.2 g, 31 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC.O>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:36]
Reactant: CCOC(=O)CCCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
A mixture of 0.7 g (1.95 mmol) of rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester, 0.45 g (2.14 mmol) of ethyl 5-bromovalerate, 0.75 g (5.4 mmol) of anhydrous, granular potassium carbonate, and 8 mL of dimethyl sulfoxide was stirred at room temperature for 24 hr. The resulting mixture was poured into water and worked-up with ether in the usual manner. The crude product was flash chromatographed on silica gel, eluting with 2:1 hexane-ethyl acetate, affording 0.86 g (90%) of rac-(E)-5-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenoxy]pentanoic acid ethyl ester as a colorless oil.