Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([F:15])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[Br:14])=[O:4].[H-].[Na+].[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([F:15])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[N:9]=[C:8]2[Br:14])=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(Br)c2c1F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c(Br)nn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Reaction time: 0.42 h
Yield: 30.7 %

Procedure:
Under ice-cooling, to a solution of 2.99 g of 3-bromo-4-fluoro-1H-5-indazolecarboxylic acid methyl ester obtained in Production Example II-13-d in 30 ml tetrahydrofuran was added 526 mg of 60% sodium hydride, and the mixture was stirred for 25 minutes. Then, 3.21 g of triphenylmethyl chloride was added and the mixture was stirred at the same temperature for 15 minutes and further stirred at room temperature for 45 minutes. The reaction mixture was ice-cooled again, saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was sequentially washed with water (×2) and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:9), and the resulting crystals were recrystallized from diisopropyl ether, to give 1.73 g of the title compound as white needles.
Reaction SMILES: O.Cl.[C:3]([NH2:11])(=[NH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Na].[CH3:13][O:14][C:15](=[O:24])[C:16]([CH:19](OC)OC)=[CH:17]O.O>CN(C=O)C>[CH3:13][O:14][C:15]([C:16]1[CH:17]=[N:10][C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][CH:19]=1)=[O:24]
Reactant: COC(=O)C(=CO)C(OC)OC
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To a solution of benzamidine hydrochloride hydrate (2 mmol) in anhydrous DMF (4 mL) is added sodium salt of 2-dimethoxymethyl-3-hydroxy-acrylic acid methyl ester (0.46 g, 2.32 mmol) and the reaction mixture heated at 100° C. under N2 for 1 hour. The reaction is cooled to room temperature and water (15 mL) is added. After addition of water, immediate precipitation of the product is observed. The solids are collected by filtration, washed with water (2.5 mL) and vacuum dried to yield 2-phenyl-pyrimidine-5-carboxylic acid methyl ester (0.32 g, 74%). (see: P. Zhichkin, D. J. Fairfax, S. A. Eisenbeis, Synthesis, 2002, 720-722.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1.CN(C1C=[C:25]([CH:26]=[O:27])C(OC)=CC=1)S(C)(=O)=O.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl.[Cl-].[Na+].O>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:7]=1)(=[O:27])[CH3:25]
Reactant: COc1ccc(N)cc1C1OCCO1
Reactant: COc1ccc(N(C)S(C)(=O)=O)cc1C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(NC(C)=O)cc1C1OCCO1
Reaction time: 20 h
Yield: 100 %

Procedure:
To a solution of 2-(5-amino-2-methoxyphenyl)-1,3-dioxolane (an intermediate for the compound of Example 3, 17.3 g, 88.8 mmol) and triethylamine (27 ml, 195.4 mmol) in CH2Cl2 (30 ml) was added dropwise acetic anhydride (9.3 ml, 97.7 mmol) and then stirred for 20 hr. To the mixture was added brine and then extracted with CH2Cl2, dried over MgSO4 and concentrated in vacuo to give 2-(5-acetylamino-2-methoxyphenyl)-1,3-dioxolane (21.3 g, >100%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CN(C)C=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.5 %

Procedure:
A solution of 2,5-dichloronicotinic acid (25.0 g, 130 mmol) in methylene chloride (650 mL) was treated with oxalyl chloride (22 mL, 260 mmol) followed by N,N-dimethylformamide (1.0 mL) and stirred at room temperature for 18 hours. The gas evolution ceased and the reaction mixture was concentrated. The acid chloride intermediate was taken up in methylene chloride (300 mL), cooled to 0° C. and treated with methanol (26 mL). The reaction was stirred at 0° C. for 30 minutes, allowed to warm to room temperature and was concentrated in vacuo to give an oil. This oil was taken up in ethyl acetate, washed with water saturated potassium carbonate, brine, dried over magnesium sulfate and concentrated to give methyl 2,5-dichloronicotinate (24.5 g, 92%) as an oil. LCMS calculated for C7H6Cl2NO2(M+H)+: m/z=205.9, 207.9. found: 205.9, 207.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([CH2:29][NH2:30])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH2:14]([N:16]1[C:28]2[CH:27]=[CH:26][C:25]([CH2:29][NH:30][C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:13])=[CH:24][C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15]
Reactant: CCn1c2ccccc2c2cc(CN)ccc21
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(CNC(=O)C(C)NC(=O)OC(C)(C)C)ccc21
Yield: 77.3 %

Procedure:
A solution of 2-((tert-butoxycarbonyl)amino)propanoic acid (200 mg, 1.06 mmol), (9-ethyl-9H-carbazol-3-yl)methanamine (237 mg, 1.06 mmol), HATU (522 mg, 1.37 mmol) and TEA (0.442 mL, 3.17 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 60% ethyl acetate/hexane), and crystallized from ethyl acetate and hexane to give tert-butyl (1-(((9-ethyl-9H-carbazol-3-yl)methyl)amino)-1-oxopropan-2-yl)carbamate (324 mg, 0.819 mmol, 78%) as a white powder.
Reaction SMILES: [Br-:1].[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:17][N+:12]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[Br-:1].[C:18]([O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:17][N+:12]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH:10]=1)(=[O:20])[CH3:19]
Reactant: Oc1ccccc1-c1cc2cccc[n+]2o1
Reactant: CC(=O)OC(C)=O
Agent: [Br-]
Product: CC(=O)Oc1ccccc1-c1cc2cccc[n+]2o1
Yield: 73 %

Procedure:
2-(2-Hydroxyphenyl)isoxazolo[2,3-a]pyridinium bromide from Example 1 (5.0 g) is refluxed in acetic anhydride (40 ml) under nitrogen for 60-90 minutes. The solution is cooled, and the solvent is evaporated. The oily residue is diluted with ethyl acetate to crystallize the product. Recrystallization from isopropanol gives gray-white crystals (4.16 g, 73%), m.p. 198°-201° C.
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([C:22](O)=[O:23])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)[C:7]([CH3:25])=[N:6][N:5]=1)([CH3:3])[CH3:2].[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[CH:32]([NH2:34])[CH3:33]>>[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[CH:32]([NH:34][C:22]([C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:14]=[C:9]([N:8]2[C:7]([CH3:25])=[N:6][N:5]=[C:4]2[CH:1]([CH3:3])[CH3:2])[CH:10]=1)=[O:23])[CH3:33]
Reactant: CC(N)c1cnccn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3c(C)nnc3C(C)C)c2)cc1
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3cnccn3)cc(-n3c(C)nnc3C(C)C)c2)cc1

Procedure:
5-(3-Isopropyl-5-methyl-[1,2,4]triazol-4-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide was prepared from 5-(3-isopropyl-5-methyl-[1,2,4]triazol-4-yl)-4′-methyl-biphenyl-3-carboxylic acid and 1-pyrazin-2-yl-ethylamine using the procedure of step 4 of Example 6.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)(=O)CCCCC=CCCCCC>>[C:1]([OH:14])(=[O:13])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC=CCCCC(=O)O
Agent: CCCCCC=CCCCCC(=O)O
Product: CCCCCCCCCC=CC(=O)O

Procedure:
5-dodecenoic acid; 6-dodecenoic acid;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(I)c(OCc2ccccc2)c1
Temperature: 50 °C
Yield: 99.8 %

Procedure:
The mixture of 3-hydroxy-4-iodo-benzoic acid methyl ester (1.2 g, 4.3 mmol), potassium carbonate (1.78 g, 13 mmol), acetone (15.0 mL), benzyl bromide (1.5 g, 8.6 mmol), and TBAI (0.05 g) is heated to 50° C. overnight. The solvent is removed under reduced pressure. The residue is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as white solid (1.58 g, 99%). LC-ES/MS m/e 386.0 (M+18).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.COC1C=CC=CC=1[Li].[Cl:23][C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=1>CCOCC.O1CCCC1>[Cl:23][C:24]1[N:25]=[C:26]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[O:7][CH3:8])[CH:27]=[C:28]([CH3:30])[N:29]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: COc1ccccc1
Agent: [Li]CCCC
Agent: [Li]c1ccccc1OC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1-c1cc(C)nc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Part A: Anisole (2.16 g), n-butyllithium (2.5 M in hexanes, 4.0 mL), and dry ether (4.0 mL) were stirred 18 h at room temperature. Ether (5 mL) and tetrahydrofuran (SmL) were added to make a 0.47 M solution of 2-methoxyphenyllithium (21.12 mL), of which 0.47 mL was added to 2-chloro-4-methylpyrimidine (0.71 g, prepared as described by Strekowski et al (J. Heterocylic Chem. 27, 1393 (1990)) dissolved in dry ether (37 mL) and stirred 30 minutes at -30° C. and 2 hours at 0° C. The reaction was quenched with acetic acid (515 μL), water (36 μL) and tetrahydrofuran (5 mL). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.31 g) dissolved in tetrahydrofuran (5 mL) was added to the reaction which was then stirred 20 minutes. 1N Sodium hydroxide (aq.) (10 mL) was added at 0° C. and the reaction was washed with iN sodium hydroxide (3×10 mL). The organic layer was filtered through silica gel and concentrated to dryness to give 2-chloro-6-methyl-4-(2-methoxyphenyl)pyrimidine (0.72 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[N:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)c1ncc(Br)cn1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A cloudy solution of 1-(5-bromopyrimidin-2-yl)ethanone (300 mg, 1.49 mmol), 3-(trifluoromethyl)phenylboronic acid (567 mg, 2.98 mmol), K3PO4 (950 mg, 4.48 mmol), DavePhos ligand [2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl](59 mg, 0.15 mmol), and Pd(OAc)2 (17 mg, 0.075 mmol) in 6 mL toluene was heated at 100° C. for 1 h. The mixture was cooled to room temperature, and filtered through Celite. Filter cake was rinsed with 30 mL EtOAc. The filtrate was poured into 20 mL water. Layers were separated, and the aqueous was further extracted with EtOAc (20 mL). Combined organics were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated directly onto silica gel. Column chromatography (10-100% EtOAc/heptane) gave 0.26 g 1-(5-(3-(trifluoromethyl)phenyl)pyrimidin-2-yl)ethanone as tan solid. MS m/z 267.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 2H), 7.93-7.69 (m, 4H), 2.87 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:17]>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][C:14]2[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=2[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[O:17])=[O:9])=[CH:10][CH:11]=1
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(N(C)C)cc2)cc1
Yield: 91 %

Procedure:
Using the procedure described in Example 55, Part B, 4-dimethylaminobenzoic acid and 2-amino-N-(4-methoxyphenyl)benzamide (1.25 mmol), yielded 444 mg (91%) of the title compound as a white solid.
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([NH2:41])=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1.C(OCC)C>O1CCCC1>[O:4]1[CH2:5][CH2:6][O:2][CH:3]1[CH2:7][CH:8]=[C:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([NH2:41])=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1
Reactant: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: NC(=O)c1ccc(C2CCC(=O)CC2)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(=O)c1ccc(C2CCC(=CCC3OCCO3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
140.9 g of 2-(1,3-dioxolan-2-yl)ethyl-triphenylphosphonium bromide were suspended in 4.5 l of tetrahydrofuran while gassing with nitrogen and the suspension was treated at 0° C. within 5 minutes with 36.8 g of potassium tert.butylate. The orange suspension was stirred at room temperature for a further 1 hour and treated within 5 minutes with 46.1 g of 4-(4-oxocyclohexyl)benzamide. The reaction mixture was stirred at room temperature for a further 4.5 hours and then concentrated in a vacuum. The yellowish crystals obtained (212.5 g) were treated with 1.2 l of diethyl ether. The mixture was stirred at room temperature for 30 minutes and then suction filtered. The residue was washed with diethyl ether and then suspended in 700 ml of water. The mixture was stirred for 15 minutes and then suction filtered. The residue was washed with water and dissolved while heating in 600 ml of dioxan. The solution was left to cool to room temperature. The separated crystals were removed by filtration under suction, washed with a small amount of dioxan and hexane and dried at 60° C. in a vacuum, whereby there were obtained 39.2 g of crystalline 4-[4-[2-(1,3-dioxolan-2-yl)ethylidene]cyclohexyl]benzamide with m.p. 209°-212° C. Working-up of the mother liquor (72.6 g) gave a further 7.7 g of product and 64.2 g of a second mother liquor.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]#[N:11])=[CH:8][CH:9]=1)=O.[BH4-].[Na+].[NH4+].[Cl-]>C(O)C>[OH:2][CH2:3][C:5]1[O:6][C:7]([C:10]#[N:11])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C#N)o1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: N#Cc1ccc(CO)o1
Reaction time: 2 h

Procedure:
A solution of the ester from step 1 (0.098 g, 0.652 mmol), in ethanol (2.5 ml) at 0° C. was treated with sodium borohydride (0.11 g, 2.936 mmol) and the reaction was stirred for 2 hrs. Saturated NH4Cl solution (1 ml) was added and the aqueous extracted with diethylether. The combined extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed (silica gel, diethylether) to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:19]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:22])[CH:20]=[CH2:21]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)OCc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
153.2 g (1.0 mole) of 2-nitrobenzyl alcohol, 95.7 g (0.94 mole) of triethylamine and 12.9 g (0.11 mole) of 4-(dimethylamino)pyridine were dissolved in 600 ml of acetone and to the resulting solution, there was dropwise added a solution of 95.0 g (1.05 mole) of acryloyl chloride in 150 ml of acetone at 0° C. over one hour with stirring. Then the stirring was continued for additional one hour. After filtering off the resulting salt, the filtrate was concentrated and purified by column chromatography (packed material: silica gel: eluent: hexane/ethyl acetate=10/1). Thus, 141 g of an oily liquid was recovered.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([CH:16]3[CH2:21][NH:20][C:19](=[O:22])[CH2:18][CH2:17]3)=[C:11]([F:23])[CH:10]=2)[CH2:4]1.FC1C=C(N2C[C@H](CNC(=O)C)OC2=O)C=C(F)C=1I.CCN(CC)CC.Cl[CH:52](Cl)/[CH:53]=[N:54]/[NH:55]S(C1C=CC(C)=CC=1)(=O)=O>CO>[F:23][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][N:1]3[CH:52]=[CH:53][N:54]=[N:55]3)[O:7][C:6]2=[O:8])[CH:14]=[C:13]([F:15])[C:12]=1[CH:16]1[CH2:21][NH:20][C:19](=[O:22])[CH2:18][CH2:17]1
Reactant: NC[C@H]1CN(c2cc(F)c(C3CCC(=O)NC3)c(F)c2)C(=O)O1
Reactant: Cc1ccc(S(=O)(=O)N/N=C/C(Cl)Cl)cc1
Agent: CC(=O)NC[C@H]1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C1CCC(c2c(F)cc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CN1
Reaction time: 16 h

Procedure:
5-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,6-difluorophenyl}piperidin-2-one (0.1 g, 0.31 mmol) (prepared by the route described in Example 1, substituting N-{[(5S)-3-(3,5-difluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide) is dissolved in MeOH (2 mL). To this mixture is added Et3N (0.125 ml, 0.9 mmol) and N′-[(1E)-2,2-dichloroethylidene]-4-methylbenzenesulfonohydrazide (0.17 g, 0.6 mmol)(Prepared in Example 26 step 1). The reaction is stirred at 0° C. to RT for 16 hours. The mixture was concentrated to dryness, reconstituted in CH2Cl2 (125 mL) and extracted with H2O. The organic layer was dried (MgSO4), loaded onto a SIM and purified on a Biotage 12M column to yield (0.033 g, 30%). 1H-NMR (DMSO) δ: 8.17, 7.77, 7.61, 7.25, 5.16, 4.83, 4.21, 3.87, 3.28, 3.18, 2.29, 1.86
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:20](O)=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:30][NH:31][O:32][CH3:33].Cl.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C@H:2]([C:20]([N:31]([O:32][CH3:33])[CH3:30])=[O:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:19])[NH:8][S:9]([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:10])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
To a suspension of Boc-Arg(Tos)-OH (2 g, 4.7 mmol) in DMF (20 mL) at 0° C. was added MeNHOMe.HCl (1 g, 10.3 mmol), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol). The solution was stirred at 0° C. for 10 hours. DMF was evaporated by vacuum. The oily residue was dissolved in EtOAc (200 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3, water (20 mnL), 1 M HCl ( 10 mL) and sat. NaCl (2×20 mL). The organic layer was dried over MgSO4, filtered and evaporated to give a suspension. The suspension was filtered, and the solid was washed with cold EtOAc (10 mL) and dried to give Boc-Arg(Tos)-N(Me)OMe, shown above, (1.5 g, 70% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([CH3:10])[N:5]1[CH2:11][CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]1[O:23][C:24]2[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:15].I[CH:33]([CH3:35])[CH3:34]>CN(C)C=O>[CH3:10][C@H:6]1[CH2:7][CH2:8][CH2:9][C@@H:4]([CH3:3])[N:5]1[CH2:11][CH2:12][NH:13][C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[C:22]1[O:23][C:24]2[CH:30]=[C:29]([O:31][CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:27][C:25]=2[N:26]=1)=[O:15]
Reactant: CC(C)I
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2nc(N3CCCC[C@H]3C(=O)NCCN3[C@H](C)CCC[C@@H]3C)oc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydride as a 60% dispersion in oil (6 mg) was added to a solution of (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-(6-hydroxy-1,3-benzoxazol-2yl)-2-piperidinecarboxamide (54.5 mg) [see Preparation 39] in dimethylformamide (2 ml) at 0° C. After 5 minutes 2-iodopropane (0.014 ml) were added. The reaction mixture was stirred at room temperature for 4 hours, after which time sodium hydride (3 mg) followed by 2-idodpropane (0.007 ml) was added. The mixture was stirred for a further 18 hours, after which time the solvent was removed and the residue partitioned between water and diethyl ether. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 97:3.5:0.5, by volume, dichloromethane/methanol/0.88 aqueous ammonia solution to afford (2S)-N-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-(6-isopropoxy-1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (24 mg) as a brown solid.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH:9]=O)[CH2:2]1.[NH2:11][OH:12]>>[CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH:9]=[N:11][OH:12])[CH2:2]1
Reactant: NO
Reactant: O=CC1CCCCC12CC2
Product: ON=CC1CCCCC12CC2

Procedure:
Spiro[2.5]octane-4-carbaldehyde oxime (I-11I) was prepared by reaction of spiro[2.5]octane-4-carbaldehyde and hydroxylamine following the same procol as described for I-6c. MS m/z 154.1 (M+1).