Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[C:22](Cl)=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[C:22]([NH:11][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:9])=[O:10])=[N:21][C:20]2[C:15]([N:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1cccc(F)c1
Temperature: 135 °C
Yield: 84.6 %

Procedure:
3-fluorobenzenesulfonamide (250 mg, 1.4 mmol), 2,3-dichloroquinoxaline (284.1 mg, 1.4 mmol) and dry K2CO3 (198.4 mg, 1.4 mmol) are dissolved in dry DMF (0.8 ml) and heated up to 135° C. in a sealed tube for 2.5 h. When TLC confirms the completion of the reaction, the reaction mixture is cooled down to rt and quenched by addition of water (4 ml) and AcOH (0.03 ml). The residue obtained is triturated and the resulting solid is filtered and washed with water until neutral pH then dried under vacuum to afford 400 mg (83%) of the title compound as an off white solid. 1H NMR (DMSO-d6) δ 12.8-10.9 (br s, 1H), 8.05-7.62 (m, 7H), 7.54 (td, J=2.0, 8.5 Hz, 1H). HPLC (max plot) 94%; Rt 3.79 min. LC/MS: (ES+): 338.1, (ES−): 336.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C(OCC)C>[C:22]1([CH2:28][CH2:29][C:30]([N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10]2)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C2CCCNC2)c1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cccc(C2CCCN(C(=O)CCc3ccccc3)C2)c1
Temperature: 25 °C
Yield: 148.9 %

Procedure:
To a stirred solution of 9.4 g (49.2 mmole) of 3-(3-methoxyphenyl)piperidine and 10.2 ml (73.8 mmole) of triethylamine in 120 ml of toluene, at 0° C., under nitrogen, was added dropwise, a solution of 12.4 g (73.8 mmole) of 3-phenylpropionyl chloride in 45 ml of toluene. The mixture was allowed to warm to room temperature, and then it was diluted with an equal volume of diethyl ether. The solid was removed by filtration and the filtrate was evaporated in vacuo to give 23.7 g of 1-(3-phenylpropionyl)-3-(3-methoxyphenyl)-piperidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([Br:32])[C:28](=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:40])[CH3:39])=O)(C)(C)C.[Cl:41]CCl>Cl>[ClH:41].[Br:32][C:29]1[C:28](=[O:33])[N:27]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:12][CH2:13][NH:8][C:9]([CH3:40])([CH3:39])[CH2:10]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)ncc12
Reactant: ClCCl
Agent: Cl
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCNC(C)(C)C4)cn3)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.051 g, 0.083 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl (2 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. This mixture was concentrated and allowed to sit for 10 days, it was then dissolved in 2 N HCl (2 mL) and stirred at room temperature for 5 hours. The solvent was removed to give 6-bromo-8-cyclopentyl-2-[5-(3,3-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.035 g, 71.4%). 1H NMR δ (400 MHz, DMSO-d6) 9.32 (s, 2H), 8.98 (s, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.26 (m, 1H), 5.89 (m, 1H), 3.34 (m, 2H), 3.23 (m, 4H), 2.58 (s, 3H), 2.14 (m, 2H), 1.91 (m, 2H), 1.77 (m, 2H), 1.57 (m, 2H), 1.38 (s, 6H).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[OH:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[C:39]=1[C:48](=O)[CH3:49].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:48]([C:39]2[C:40]([O:46][CH3:47])=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:38]=2[OH:37])[CH:49]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(O)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c(OC)c1
Yield: 65 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with -(2-hydroxy-4,6-dimethoxy-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (85 mg, 65% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][O:17][C:11]=3[CH:10]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.O>[CH3:25][S:26]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][O:17][C:11]=3[CH:10]=2)[CH2:3]1)(=[O:28])=[O:27]
Reactant: O[C@H]1CCN(CCc2ccc3c(c2)OCO3)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CCN(CCc2ccc3c(c2)OCO3)C1

Procedure:
(S)-3-Hydroxy-1-(3,4-methylenedioxyphenethyl)pyrrolidine (281 mg, 1.19 mmol) was dissolved in dichloromethane (8 ml). Triethylamine (162 mg, 1.60 mmol) and methanesulfonyl chloride (183 mg, 1.60 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred at 0° C. for 1 hour. The reaction liquid was distributed in dichloromethane and water. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a solvent mixture of dichloromethane and methanol (50:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-(3,4-methylenedioxyphenethyl) pyrrolidine in the form of a light yellow oil (359 mg, 97%).
Reaction SMILES: C([Mg]Br)C.CCOCC.[CH:10]1([C:13]#[CH:14])[CH2:12][CH2:11]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@:25]23[C:31]([CH3:33])([CH3:32])[C@@:28]([CH3:34])([CH2:29][CH2:30]2)[C:27](=[O:35])[O:26]3)=[O:24])=[C:18]([C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])[CH:17]=1>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@:25]23[C:31]([CH3:32])([CH3:33])[C@@:28]([CH3:34])([CH2:29][CH2:30]2)[C:27](=[O:35])[O:26]3)=[O:24])=[C:18]([C@@:36]([OH:41])([C:14]#[C:13][CH:10]2[CH2:12][CH2:11]2)[C:37]([F:38])([F:39])[F:40])[CH:17]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)OC2=O
Reactant: C#CC1CC1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Ethylmagnesium bromide 3M in ether (5.98 mL, 17.95 mmol) was added slowly to a solution of cyclopropyl acetylene (1.19 g, 17.95 mmol) in tetrahydrofuran (18 mL) in an ice-bath under argon and the mixture was stirred at 40° C. for 3 hours. Then (1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (9, 1.45 g, 3.59 mmol) was added in portions while the flask was in an ice-bath. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NH4Cl, and the mixture was extracted with ethyl acetate and two layers were separated. The organic layer was evaporated to dryness to give 1.67 g of the compound as a crude oil. It was further crystallized with petroleum ether and ethyl acetate to furnish (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut 3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxa mide (10) as a white or off-white solid. This solid was shown to be 98.8% de by HPLC.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1([CH2:19][NH:20][S:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][C:32](Cl)=[O:33])[CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:32](=[O:33])[CH:31]=[CH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([S:21](=[O:23])(=[O:22])[NH:20][CH2:19][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:25]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)NCc2cccc3ccccc23)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.30 g, 4.35 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-(3-[(naphthalen-1-ylmethyl)-sulfamoyl]-phenyl}-acryloyl chloride (16a) (0.33 g) in tetrahydrofuran (4 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate-acetonitrile affording the title compound (0.13 g, 40%) as a lightly pink crystals. M.p. 177° C. 1H NMR (DMSO-d6, HMDSO) δ: 4.45 (2H, d, J=6.0 Hz); 6.58 (1H, d, J=16.0 Hz); 7.29–8.38 (13H, m); 9.12 (1H, br s); 10.83 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 1.5% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 40:60; sample concentration 0.25 mg/ml; flow rate 1.2 ml/min; detector UV 220 nm). Anal. Calcd for C20H18N2O4S, %: C, 62.54; H, 4.70; N, 7.21. Found, %: C, 62.81; H, 4.74; N, 7.32.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:14]=1[O:36][CH3:37])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.CC(O)=O.CS(C)=O>CC(O)=O>[CH3:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:17]2[C:18]3[S:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:12][C:13]=3[C:14]([O:36][CH3:37])=[CH:15][CH:16]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1NC(=S)NC(=O)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)c2sc(NC(=O)c3ccccc3)nc12

Procedure:
From 1-benzoyl-3-{5-[bis-(4-methyl-benzyl)-amino]-2-methoxy-phenyl}-thiourea with HBr—AcOH (2 equiv.) and DMSO (1.1 equiv.) in AcOH. ES-MS m/e (%): 508 (M+H+, 100).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:7]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH2:6][CH2:5][CH2:4][N:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[H-].[Na+].I[CH3:27]>C1COCC1.CCOC(C)=O.O>[CH3:1][C@@H:2]1[C@H:7]([N:8]2[CH2:12][CH2:11][N:10]([CH3:27])[C:9]2=[O:13])[CH2:6][CH2:5][CH2:4][N:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: C[C@@H]1[C@H](N2CCNC2=O)CCCN1C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](N2CCN(C)C2=O)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
Compound 354 (490 mg, 1.55 mmol) was dissolved in 15 mL dry THF. It was treated with NaH (60% in mineral oil, 125 mg, 3.1 mmol) for 15 min at RT. To the mixture was then added iodomethane (200 μL, 3.1 mmol). The mixture was stirred at RT for 1.5 hour, diluted with 150 mL EtOAc and 50 water. The organic phase was separated, washed with water, dried, concentrated, and subjected to silica flash column using 0 to 4% MeOH in DCM to isolate (2R,3R)-benzyl 2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (355, 470 mg, 92%). It was dissolved in 100 mL iPrOH. To it was added 10% Pd/C (0.5 g), and the mixture was hydrogenated at 40 psi on a Parr shaker for overnight. The mixture was filtered through celite and concentrated in vacuo to give 1-methyl-3-((2R,3R)-2-methylpiperidin-3-yl)imidazolidin-2-one (356) as a white solid in quantitative yield.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:21][N:22]([CH3:25])C=O>C(O)C.CNCC1C=CC=CC=1>[CH2:21]([N:22]([CH3:25])[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:7]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Reactant: CN(C)C=O
Agent: CNCc1ccccc1
Solvent: CCO
Product: CN(Cc1ccccc1)C[C@@H](O)COc1cccc(-c2noc3ncccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and N-methylbenzylamine in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=390.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=O)#[N:33].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:37](=[O:39])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([C:32]#[N:33])[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)N2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)c1
Yield: 116.2 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 69 mg (0.514 mmol) of 3-cyanobenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (250 mg, 96%) is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.53, FD-MS: M+ =556.
Reaction SMILES: OC1C=CC=C(O)C=1.ClC[Si](CCl)(C)O[Si](C)(C)C.C([O-])([O-])=O.[K+].[K+].[N+]([C:29]1[CH:30]=[C:31]([C:37]#[N:38])[C:32](=[CH:35][CH:36]=1)[C:33]#[N:34])([O-])=O.Cl>O.CS(C)=O>[C:37](#[N:38])[C:31]1[C:32](=[CH:35][CH:36]=[CH:29][CH:30]=1)[C:33]#[N:34]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: C[Si](C)(C)O[Si](C)(CCl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccccc1C#N
Temperature: 90 °C

Procedure:
To a 2000 mL, three-necked flask fitted with a thermometer and a nitrogen inlet were added 1,3-dihydroxybenzene (48.2 g, 0.438 mol), bis(chloromethyl)tetramethyl disiloxane (50.1 g, 0.217 mol), powdered anhydrous K2CO3 (150 g, 1.09 mol), and dimethylsulfoxide (DMSO) (1000 mL). The resulting mixture was degassed with nitrogen at ambient temperature and heated at 90° C. under a nitrogen atmosphere for 8-16 hr. The mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (76.1 g, 0.440 mol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 hr. The mixture was allowed to cool to ambient temperature and poured into 1000 mL of distilled water. The mixture was made acidic by the addition of 6 M aqueous HCl and the resin was extracted out of the water layer by toluene (200 mL). The toluene extracts were washed 3 times with 500 mL of distilled water and the toluene extracts were dried using magnesium sulfate. Removal of the toluene resulted in an amber oil, which was dried at 80° C. under vacuum. The 2:1 oligomeric phthalonitrile was isolated as an amber glassy solid (131 g, 95%). 1H-NMR [CDCl3]: λ 7.70 (m, aromatic-HR), 7.69 (m, aromatic-HR), 7.35 (m, aromatic-HR), 7.10 (m, aromatic-HR), 6.98 (m, aromatic-HR), 6.88 (m, aromatic-HR), 3.73 (m, aliphatic-HR), 3.46 (m, aliphatic-HR), 0.22 (s, Si—CH3), 0.06 (s, Si—CH3).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=2)[CH2:3][CH2:2]1.[I-:15].[Na+].II.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[I:15])[CH2:3][CH2:2]1
Reactant: [I-]
Reactant: c1ccc(-c2cc(C3CC3)[nH]n2)cc1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Ic1c(-c2ccccc2)n[nH]c1C1CC1
Temperature: 100 °C

Procedure:
To a solution of 5-cyclopropyl-3-phenyl-1H-pyrazole (3.0 g, 16.28 mmol) in THF (20 mL) and water (20 mL) were added sodium iodide (2.441 g, 16.28 mmol), iodine (6.20 g, 24.43 mmol), and potassium carbonate (3.38 g, 24.43 mmol) at room temperature. The reaction was refluxed for 2 h (100° C.). The reaction was cooled to room temperature and quenched with 10% aqueous Na2SO3. The organic solvent was removed under reduced pressure and the aqueous phase was extracted with EtOAc, washed with NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (2.7 g). LCMS m/z=310.8 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.75-0.81 (m, 2H), 0.83-0.88 (m, 2H), 2.46-2.56 (m, 1H), 7.33-7.47 (m, 3H), 7.62-7.71 (m, 2H), 12.91 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([S:26][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: SCc1ccccc1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1cccnc1SCc1ccccc1
Yield: 78.5 %

Procedure:
10 g of 2,3-dichloropyridine, 11.2 g of anhydrous potassium carbonate and 100 ml of dimethylsulfoxide were mixed to obtain a suspension. To this suspension, 10 ml of a dimethylsulfoxide solution of 10.1 g of benzyl mercaptan was dropwise added over a period of about 20 minutes at 110° C. Then, the mixture was reacted at a temperature of from 120 to 130° C. for about 1.5 hours. Thereafter, the reaction product was put into water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate. Then, methylene chloride was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 12.5 g of oily 2-benzylthio-3-chloropyridine.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Br[C:30]1[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:30]4[CH:31]=[CH:32][C:33](=[O:37])[N:34]([CH3:36])[CH:35]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Cn1cc(Br)ccc1=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2ccc(=O)n(C)c2)C3)cc1

Procedure:
The compound was prepared following the general procedure in Example 289, substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea and substituting 2-Bromo-6-benzyloxypyridine for 5-bromo-1-methylpyridin-2(1H)-one: LC-MS m/z=490 (M+H).
Reaction SMILES: [F-:1].[Cs+].C(O)(CC)(C)C.[F-].C[O-].[Na+].[OH:13][CH2:14][C:15]1([O:23][C@H:22]([CH2:24]O)[C@@H:20]([OH:21])[C@@H:18]1[OH:19])[O:16]C>>[F:1][CH2:24][C@@H:22]([OH:23])[C@@H:20]([OH:21])[C@H:18]([OH:19])[C:15](=[O:16])[CH2:14][OH:13]
Reactant: [F-]
Reactant: COC1(CO)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: C[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CCC(C)(C)O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CF

Procedure:
As a starting material, D-fructose is inexpensive and readily available. Briefly, treatment of fructose with acidic methanol affords a mixture of methyl α/β-D-fructofuranosides (II, III) which may be separated using standard silica gel chromatography or, alternatively, carried on as a mixture (FIG. 1). Selective protection of the primary C-6 hydroxyl with tert-butyldimethylchlorosilane (TBDMSCl) in pyridine, followed by global acetylation produces intermediate (V) in moderate yield over the two steps. The silyl protecting group is removed by treatment with aqueous trifluoroacetic acid in dichloromethane to provide intermediate (VI) in 91% (Tatibouet et al., 2000). Compound (VI) is then fluorinated via triflation under standard conditions and immediate treatment with three equivalents of cesium fluoride in refluxing tert-amyl alcohol (Kim et al., 2006). The quick and clean fluoride displacement reaction is useful for installation of [18F] for imaging experiments. Standard deprotection of the acetates using sodium methoxide followed by acidic hydrolysis of the methyl fructofuranoside provides 6-deoxy-6-fluoro-D-fructose (IX) as a white solid in 62% (two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:12]1[C:20]([OH:21])=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)[C:5](=[O:11])[NH:6]2.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:12]1[C:20]([OH:21])=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)[C:5](=[O:11])[NH:6]2
Reactant: O=C1Nc2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2cccc(Cl)c2C1c1cc2c(cc1O)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a solution of 4-chloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (6.00 g, 18.8 mmol) in anhydrous dichloromethane (70.0 mL) was added trifluoroacetic acid (30.7 g, 269 mmol) and triethylsilane (18.0 mL, 13.1 g, 113 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with water (100.0 mL) and the solid was filtered. The solid was triturated with diethyl ether to afford 4-chloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (4.71 g, 83%) as a colourless solid: mp 210-225° C. (dec.); MS (ES+) m/z 304.1 (M+1), 302.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)CC
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(OC)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-fluorophenoxy)acetic acid methyl ester and 2-(4-methoxybenzyl)-3-oxopentanoic acid ethyl ester.