Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:18][CH:17]=1>CN(C)C=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:9]2[CH2:10][CH2:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[O:12])=[CH:18][CH:17]=1
Reactant: O=C1NCCN1c1ccccc1
Reactant: BrCCCCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCOc2ccc(Br)cc2)CCN1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-phenyl-2-imidazolidinone (0.10 g, 0.62 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 27.0 mg, 0.68 mmol). The mixture was stirred at room temperature for 30 minutes; then cooled in ice bath. 1-Bromo-4-[(5-bromopentyl)oxy] benzene (0.20 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvents were pumped off. Saturated aqueous NH4Cl and dichloromethane (15 mL) were added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 9) as a yellow solid (0.19 g, 77%).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](F)=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH:26]([CH3:28])[CH3:27])[N:18]=1)[CH:14]=[C:13]([C:29]([OH:31])=[O:30])[C:12]2=[O:32].Cl.Cl.[NH2:37][CH:38]1[CH2:41][NH:40][CH2:39]1.CN1CCCC1>C(O)C>[NH2:37][CH:38]1[CH2:41][N:40]([C:8]2[C:7]([Cl:6])=[C:16]3[C:11]([C:12](=[O:32])[C:13]([C:29]([OH:31])=[O:30])=[CH:14][N:15]3[C:17]3[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH:26]([CH3:27])[CH3:28])[N:18]=3)=[CH:10][C:9]=2[F:33])[CH2:39]1
Reactant: CC(C)Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To 160 mg of N,N-dimethylformamide were added 55 mg of 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-isopropylamino-pyridine-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 35 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 80° C. for 30 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 51 mg of the title compound as a colorless powder.
Reaction SMILES: C(O[CH2:5][C@H:6]1[C@H:10]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][C:7]1=[O:16])(=O)C.C([NH:20][C@H:21]([C:24]([OH:26])=[O:25])[CH2:22][SH:23])(=O)C.[OH-].[Na+].CO.[CH3:31][C:32](C)=[O:33]>>[C:13]([O:12][CH2:11][C@@H:10]1[CH2:9][CH2:8][C:7](=[O:16])[C@H:6]1[CH2:5][S:23][CH2:22][C:21]([NH2:20])([C:32](=[O:33])[CH3:31])[C:24]([OH:26])=[O:25])(=[O:15])[CH3:14]
Reactant: CC(=O)OC[C@@H]1CCC(=O)[C@H]1COC(C)=O
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)OC[C@@H]1CCC(=O)[C@H]1CSCC(N)(C(C)=O)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
A solution of trans-2,3-bis(acetoxymethyl)-cyclopentanone [Compound (a)] (205 mg, 0.899 mmol) in acetone (7.2 ml) was added to N-acetyl-L-cysteine (147 mg, 0.899 mmol), and then added IN-sodium hydroxide (1.8 ml), stirred at room temperature for 15 minutes. The reaction solution was concentrated. The residue was purified by Sephadex LH-20 (11.80% aqueous methanol) to obtain the compound (II) (276 mg, yield 86.9%).
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:33]([C:30]3[CH:29]=[CH:28][C:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)=[CH:32][CH:31]=3)=[O:34])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)ccc3o2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30.4 %

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.700 g, 2.69 mmol), 4′-fluoro-biphenyl-4-carboxylic acid (0.872 g, 4.03 mmol), HATU (1.43 g, 3.76 mmol), polystyrene-bound diisopropylamine (7.53 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (15 mL). Shake the mixture overnight at room temperature. Filter the mixture and wash the polystyrene resin with 1:1 CH2Cl2/MeOH. Subject the mixture to flash column chromatography on an ISCO Companion (120 g column, eluting with 20% 2M NH3 in MeOH/CH2Cl2) to yield a mixture of products. Subject the mixture to flash column chromatography (3×40 g, eluting with 20% 2M NH3 in MeOH/CH2Cl2) to yield a mixture of products. Concentrate the fractions and suspend the residue in anhydrous diethyl ether. Stir at room temperature for 3 d. Filter the mixture to yield the product as a white solid (0.375 g, 30%). Submit the racemic mixture to chiral chromatography to yield the product (0.187 g) as the second eluting enantiomer; mass spectrum (m/e): 459.2 (M+1), 457.3 (M−1). 1H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 8.07-8.03 (m, 2H), 7.85-7.79 (m, 4H), 7.73 (d, J=2.0 Hz, 1H), 7.40-7.31 (m, 4H), 3.50 (d, J=7.6 Hz, 2H), 3.13 (s, 3H), 2.65-2.56 (m, 1H), 2.54-2.47 (m, 2H), 2.43-2.36 (m, 1H), 2.29-2.24 (m, 1H), 2.23 (s, 3H), 1.93-1.84 (m, 1H), 1.49-1.40 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:12][C:13]1[NH:17][N:16]=[CH:15][C:14]=1[C:18]#[N:19].[CH:20]1([N+:25]#[C-:26])[CH2:24][CH2:23][CH2:22][CH2:21]1.Cl(O)(=O)(=O)=O>CO>[CH:20]1([NH:25][C:26]2[N:17]3[N:16]=[CH:15][C:14]([C:18]#[N:19])=[C:13]3[NH:12][C:4]=2[C:3]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=2[F:1])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: [C-]#[N+]C1CCCC1
Reactant: N#Cc1cn[nH]c1N
Reactant: COc1ccc(C=O)c(F)c1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: COc1ccc(-c2[nH]c3c(C#N)cnn3c2NC2CCCC2)c(F)c1
Reaction time: 15 h
Yield: 11.5 %

Procedure:
To a clear light yellow solution of 2-fluoro-4-methoxybenzaldehyde (802 mg, 5.2 mmol) and 5-amino-1H-pyrazole-4-carbonitrile (562 mg, 5.2 mmol) in methanol (20 mL) were added a neat cyclopentyl isonitrile (500 mg, 5.2 mmol) and perchloric acid (104 mg, 93.3 μL, 1.04 mmol) at RT under nitrogen atmosphere. Lots of brown solids were precipitated within 1 h and the resulting suspension was stirred for 15 h. After 15 h, it became a dark brown solution without any solids. Then, the solvent was removed under vacuum and the residue was purified using an ISCO (120 g) column chromatography eluting with 0-50% EA in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 203 mg (11.5% yield) of 3-(cyclopentylamino)-2-(2-fluoro-4-methoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile as an yellow solid. LC/MS calcd. for C18H18FN5O (m/e) 339.37, obsd. 340.2 (M+H, ES+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: CC(C)(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 109.8 %

Procedure:
To a solution of 4-bromo-1-fluoro-2-nitrobenzen (25 g, 0.1 mol) in THF (100 mL) is added t-butylamine (18 mL, 0.17 mol). The solution is heated at 60° C. for 16 hours. The solvent is removed in vacuum. The residue is suspended in methanol (20 mL). The precipitate is collected by filtration and washed with methanol to give (4-bromo-2-nitro-phenyl)-tert-butyl-amine as an orange solid (30 g, 97%).
Reaction SMILES: [CH:1]([OH:3])=[O:2].O.CCO[CH2:8][CH3:9].[CH:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:1]([O:3][CH2:14][CH2:15][CH2:10][CH2:11][CH2:12][CH2:13][CH2:10][CH2:15]/[CH:14]=[CH:13]\[CH2:12][CH2:11][CH2:8][CH3:9])=[O:2]
Reactant: c1ccccc1
Reactant: O=CO
Reactant: CCOCC
Solvent: O
Product: CCCC/C=C\CCCCCCCCOC=O
Reaction time: 6 h
Yield: 78 %

Procedure:
A mixture of 11 g of compound VI and 11 g of 97% formic acid in 50 ml of dry benzene was relfuxed for 6 hours, continuously removing the water formed with a Dean-Stark trap. The cooled solution was treated with 100 ml each of H2O and ether, and the organic layer was washed several times with cold H2O, 10% NaHCO3 solution, and saturated with NaCl solution, then dried with Na2SO4. Evaporation of solvent and distillation gave 9.7 g (78%) of compound I as a colorless liquid boiling at 103°-108° (0.2 mm), ND25 1.4464.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[Cl:19]N1C(=O)CCC1=O.CN(C)C=O>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2
Reactant: CCOC(=O)c1cc2cccc(N)c2n1COC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(Cl)ccc(N)c2n1COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of ethyl 7-amino-1-(methoxymethyl)-1H-indole-2-carboxylate (3.18 g), N-chlorosuccinimide (1.74 g) and N,N-dimethylformamide (20 ml) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was-subjected to silica gel column chromatography to give the title compound (0.91 g, yield 25%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.I[C:22]1[NH:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28].C(Cl)Cl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:22]1[NH:26][C:25]([CH3:27])=[N:24][C:23]=1[CH3:28]
Reactant: Cc1nc(C)c(I)[nH]1
Reactant: COC(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(-c2[nH]c(C)nc2C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
To methyl 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 50.2, 600 mg, 2.02 mmol) in dioxane (20 mL) was added 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5, 538 mg, 2.42 mmol) and Pd(dppf)Cl2.DCM (165 mg, 0.20 mmol). The mixture was degassed with argon and stirred for 10 minutes at room temperature, then an aqueous potassium carbonate solution (1M, 10 mL) was added and the mixture was stirred at 90° C. for 18 h. The mixture was cooled and diluted with EtOAc, then filtered through Celite®. The filtrate was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-100% EtOAc in hexanes) to yield 270 mg (50%) of the title compound as a foam. m/z (ES+) 265 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J=2.2 Hz, 1H), 7.90 (dd, J=8.4, 2.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 3.91 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:14][CH:13]=[CH2:12])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(Br)ccc1O
Reaction time: 72 h
Yield: 90.7 %

Procedure:
A mixture of 5-bromosalicylic acid (10 g, 46 mmol), allyl bromide (6.12 g, 51 mmol) and sodium bicarbonate (4.65 g, 55 mmol) in 50 ml of DMF was stirred under a drying tube for 72 hr. The reaction mixture was poured into water, extracted with ethyl acetate. and the organic layer dried over MgSO4. Concentration under vacuum gave 10.73 g (91%) of product (1-Scheme 2) with the expected NMR.
Reaction SMILES: CC(C)([O-])C.[K+].C[C:8]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:13])[N:11](NC2C=CC=CC=2)[C:10]([S:21][CH3:22])=[N:9]1.CI.O>O1CCCC1>[CH3:22][S:21][C:10]1[NH:11][C:12](=[O:13])[CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]=1
Reactant: CSC1=NC(C)(c2ccccc2)C(=O)N1Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: CSC1=NC(c2ccccc2)C(=O)N1
Temperature: 0 °C
Yield: 110.6 %

Procedure:
0.4 g (3.5 mmol) of potassium tert-butoxide is added to a solution of 4-methyl-1-phenylamino-2-methylthio-4-phenyl-2-imidazolin-5-one (Compound 9) (1 g, 3.2 mmol) in anhydrous tetrahydrofuran (30 ml), cooled beforehand to 0° C. The mixture is left to react for 0.5 hour at 0° C. 0.5 g (3.5 mnol) of methyl iodide is then added and then the mixture is left to react for 0.5 hour at room temperature. The reaction mixture is poured into 100 ml of water and the product is extracted with 100 ml of diethyl ether. The ethereal solution is dried over magnesium sulfate and then concentrated. The product crystallizes when triturated in 10 ml of diisopropyl ether. It is filtered and then dried under vacuum. 0.73 g (yield: 70%) of Compound 22 is thus obtained in the form of a pale-yellow powder melting at 124° C.
Reaction SMILES: Cl[C:2]1[CH:3]=C(C=C[CH:11]=1)C(OO)=O.[CH2:12]([NH:14][C:15]([CH:17]1[CH2:21][CH:20]([N:22]2[C:26]3[N:27]=[C:28]([S:41]CCC)[N:29]=[C:30]([NH:31][CH:32]4[CH2:34][CH:33]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:25]=3[N:24]=[N:23]2)[CH:19]([OH:45])[CH:18]1[OH:46])=[O:16])[CH3:13].ClCCl>C(O)C>[CH2:12]([NH:14][C:15]([CH:17]1[CH2:21][CH:20]([N:22]2[C:26]3[N:27]=[C:28]([S:41][CH:2]([CH3:3])[CH3:11])[N:29]=[C:30]([NH:31][CH:32]4[CH2:34][CH:33]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:25]=3[N:24]=[N:23]2)[CH:19]([OH:45])[CH:18]1[OH:46])=[O:16])[CH3:13]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: ClCCl
Product: CCNC(=O)C1CC(n2nnc3c(NC4CC4c4ccccc4)nc(SC(C)C)nc32)C(O)C1O

Procedure:
3-Chloroperoxybenzoic acid (50%, 9.0 g) was added to a suspension of the product of example 1, step e) (4.1 g) in ethanol (200 ml) and dichloromethane (50 ml) and the resulting solution stirred at room temperature for 18 hours. The reaction mixture was concentrated and the residue taken up in ethyl acetate (500 ml) , washed with 10% aqueous sodium metabisulfite solution (2×100 ml) and 10% aqueous sodium bicarbonate solution (2×100 ml) then dried and concentrated. Purification (SiO2, ethyl acetate as eluant) gave the subtitle compound (2.4 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]2[CH3:18])[N:5]=[C:4](O)[CH:3]=1.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:36])=O>>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]2[CH3:18])[N:5]=[C:4]([Cl:36])[CH:3]=1
Reactant: Cc1cc(O)nc(N2CCc3ccccc3C2C)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Cl)nc(N2CCc3ccccc3C2C)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture solution of 6-methyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-hydroxypyrimidine(7.0 g, 27.4 mmol) prepared in the above Step 2, phosphorous oxychloride(30 ml) and N,N-dimethylaniline(2. 3 ml) was stirred at 90° C. for 2 hours and cooled. The reaction mixture was added to ice water and basified with sodium bicarbonate and then was extracted with ethyl ether. The ethyl ether layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4.5 g of titled compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1Br)(=[O:3])[CH3:2].N[C:26](=N)[SH:27].IC[CH2:31][C:32]([OH:34])=[O:33]>CC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[S:27][CH2:26][CH2:31][C:32]([OH:34])=[O:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: N=C(N)S
Reactant: O=C(O)CCI
Agent: NC(N)=S
Solvent: CC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](SCCC(=O)O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
Synthesis of Carbohydrate Containing CAP Reagents (Tetrafluorophenyl 3-(2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranosyl)propionate (4a)). Tetra-O-acetyl-D-galactosyl bromide (Sigma) was converted to the thiopseudourea (TPU) derivative by treatment with thiourea in acetone according to the literature procedure (Stowell, C. P., and Lee, Y. C. (1982) Preparation of neoglycoproteins using 2-imino-2-methoxyethyl 1-thioglycosides. Methods in Enzymology, 83, 278). This TPU derivative was reacted with 3-iodopropionic acid (Aldrich) according to the literature procedure (Ponpimom, M. M., et al (1981) Cell-Specific Ligands For Selective Drug Delivery To Tissues And Organs, J. Med. Chem., 24, 1388) to give 2-carboxyethyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside. The crude material was purified by flash chromatography (3.5×30 cm silica) using a gradient of methanol in methylene chloride. The product eluted with 10% methanol. Removal of solvent gave 135 mg (20% yield) of the carboxylic acid as a yellow syrup. The tetrafluorophenyl ester (4a) was prepared from 0.13 g (0.35 mmol) of the carboxylic acid by treatment with 1.5 equivalents of tetrafluorophenyl trifluoroacetate in CH2Cl2 in the presence 2 equivalents of triethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1(B(O)O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:17]2[C:18]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1cccc2ccccc12
Product: Brc1cccc(-c2cccc3ccccc23)c1

Procedure:
1-(3-Bromophenyl)naphthalene was synthesized by the same method, except that in Synthetic Example 1, 3-bromoiodobenzene was used in place of 4-bromoiodobenzene and that 1-naphthaleneboronic acid was used in place of 2-naphthaleneboronic acid.
Reaction SMILES: C1(C)C=CC(S(OC[CH:12]=[CH:13][C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.[F:19][C:20]([F:31])([F:30])[CH2:21][CH2:22][S:23]([CH:26]([CH3:29])[C:27]#[N:28])(=[O:25])=[O:24].[H-].[Na+].Cl.O1CCC[CH2:36]1>>[F:15][C:14]([F:17])([F:16])[CH:13]=[CH:12][CH2:29][C:26]([CH3:36])([S:23]([CH2:22][CH2:21][C:20]([F:19])([F:30])[F:31])(=[O:24])=[O:25])[C:27]#[N:28]
Reactant: Cc1ccc(S(=O)(=O)OCC=CC(F)(F)F)cc1
Reactant: C1CCOC1
Reactant: CC(C#N)S(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CC(C#N)(CC=CC(F)(F)F)S(=O)(=O)CCC(F)(F)F
Reaction time: 48 h

Procedure:
To a solution of 1.5 g of 4,4,4-trifluoro-2-butenyl p-toluenesulfonate and 1.2 g of 2-(3,3,3-trifluoropropylsulfonyl)propionitrile in 30 ml of tetrahydrofuran was added 0.2 g of sodium hydride (60% in oil) at room temperature. The reaction mixture was stirred at the same temperature for 2 days. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.80 g of 6,6,6-trifluoro-2-methyl-2-(3,3,3-trifluoropropylsulfonyl)-4-hexenenitrile (hereinafter referred to as the present compound (34)).
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: BrCCCCCCCCCCBr
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCCCCCCCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,10-dibromodecane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,10-dibromodecane. The crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a pale yellow solid. Yield: 1.32 g (65%). 1H-NMR (400 MHz, d6-DMSO) δ=1.16-1.40 (m, 14H), 1.76 (tt, J=7.0, 7.0 Hz, 2H), 3.50 (t, J=6.6 Hz, 2H), 3.79 (t, J=7.0 Hz, 2H), 6.61 (d, J=9.0 Hz 2H), 7.70 (d, J=9.0 Hz, 2H), 8.95 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][O:10][C:11]1[CH:32]=[CH:31][C:14]([O:15]C2C=C(N3CCC4(NCCC4)C3)C=NC=2)=[CH:13][CH:12]=1.COC1C=CC([O-])=CC=1.[Na+]>CN(C)C=O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:15][C:14]2[CH:31]=[CH:32][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COc1ccc(Oc2cncc(N3CCC4(CCCN4)C3)c2)cc1
Reactant: Brc1cncc(Br)c1
Agent: COc1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cncc(Br)c2)cc1

Procedure:
In an alternative approach to the synthesis of pyridine-substituted pyridyl diazaspiroalkanes, 3,5-dibromopyridine can be converted into the corresponding 5-alkoxy-3-bromo- and 5-aryloxy-3-bromopyridines by the action of sodium alkoxides or sodium aryloxides. Procedures such as those described by Comins et al., J. Org. Chem. 55: 69 (1990) and Hertog et al., Recueil Trav. Chim. Pays-Bas 74: 1171 (1955) are used. This is exemplified by the preparation 7-(5-(4-methoxyphenoxy)-3-pyridyl)-1,7-diazaspiro[4.4]nonane. Reaction of 3,5-dibromopyridine with sodium 4-methoxyphenoxide in N,N-dimethylformamide gives 3-bromo-5-(4-methoxyphenoxy)pyridine. Coupling of 3-bromo-5-(4-methoxyphenoxy)pyridine with 1-benzyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane in the presence of sodium tert-butoxide, and a catalytic amount of tris(dibenzylideneacetone)dipalladium(0) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, in toluene, followed by hydrogenolysis of the benzyl protecting group, will provide 7-(5-(4-methoxyphenoxy)-3-pyridyl)-1,7-diazaspiro[4.4]nonane.