Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[CH2:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[O:5]=[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[C:3](=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])=[O:1]
Reactant: O=C(CC(=O)Nc1ccccc1C(=O)O)Nc1ccccc1C(=O)O
Reactant: O=Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Yield: 54.6 %

Procedure:
2,2'-[(1,3-Dioxo-1,3-propanediyl)diimino]bisbenzoic acid (1.0 g) and benzaldehyde (0.46 g, 1.5 mol equivalent) were heated under reflux in dry pyridine (8 ml) for 16 hours. After removing pyridine, the mixture was treated with water, made alkaline with 10% aqueous ammonia under ice cooling, and the aqueous layer was washed with ether. The aqueous layer was made acidic (pH=2) with 1N HCl, and the precipitated crystals were collected by filtration. After washing with water, the resulting solid was purified by dissolving in tetrahydrofuran, adsorbing on the silica gel column and separating the desired compound using a developing solvent [ethyl acetate:benzene=1:1 (containing 1% acetic acid)]. After removing the initially eluted impurities, the solvent was removed from the effluent out liquid containing the desired compound. The residue was crystallized by adding water, collected on a filter, washed with water, and dried to give the title compound (0.686 g, yield, 51%), which was recrystallized from the mixed solvent of CH3OH-H2O system to obtain pale yellow crystals of monohydrate (Crystal a, 0.507 g) (Drying: 1 mm Hg, 100° C., 15 hours), m.p., 195°-196° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:20][CH:21]([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>ClCCl>[F:20][CH:21]([F:32])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([N:10]2[CH2:11][CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9]2)=[O:31])=[CH:27][CH:28]=1
Reactant: O=C=Nc1ccc(OC(F)F)cc1
Reactant: Fc1ccc(C2=NNCC2c2ccc(F)cc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)F)cc1)N1CC(c2ccc(F)cc2)C(c2ccc(F)cc2)=N1
Temperature: 25 °C

Procedure:
9.85 g (0.038 mol) 3,4-bis-(4-fluorophenyl)-4,5-dihydropyrazole in 80 ml dichloromethane was treated with 7.03 g (0.038 mol) 4-difluoromethoxyphenyl isocyanate, with stirring at room temperature and stirred for an hour at room temperature. The reaction mixture was filtered through silica gel and the filtrate was concentrated. The residue was treated with 100 ml diisopropyl ether. The precipitated crystals were separated and dried in vacuo (100 Torr).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.[CH:22]1([N:28]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH3:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH:22]1([N:28]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH:35][C:18]([C:14]3[CH2:15][CH2:16][O:17][C:11]4[CH:10]=[CH:9][C:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)=[CH:21][C:12]=4[CH:13]=3)=[O:19])=[CH:33][CH:32]=2)[CH3:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCCCC4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
To a solution of 7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.28 g), 4-(N-cyclohexyl-N-methylaminomethyl)aniline (0.24 g) and 1-hydroxybenzotriazole (0.15 g) in dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g) under ice-cooling. Under nitrogen atmosphere, the mixture was cooled to room temperature, and to the mixture were added 4-dimethylaminopyridine (3 mg) and triethylamine (0.42 ml). The mixture was stirred for 20 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was washed with ethyl acetate and dried to give N-(4-(N-cyclohexyl-N-methylaminomethyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.40 g).
Reaction SMILES: [PH2](=O)[O-].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[CH3:14][O:15][C:16]1[CH:57]=[CH:56][C:19]([C:20]([O:33][CH2:34][C@H:35]2[O:39][C@@H:38]([N:40]3[CH:47]=[C:46]([CH3:48])[C:44](=[O:45])[NH:43][C:41]3=[O:42])[C@H:37]([O:49][CH2:50][CH2:51][O:52][CH3:53])[C@@H:36]2[CH2:54]I)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>ClCCl.C1COCC1.CO.CCN(CC)CC>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:33][CH2:34][C@H:35]2[O:39][C@@H:38]([N:40]3[CH:47]=[C:46]([CH3:48])[C:44](=[O:45])[NH:43][C:41]3=[O:42])[C@H:37]([O:49][CH2:50][CH2:51][O:52][CH3:53])[C@@H:36]2[CH3:54])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:56][CH:57]=1
Reactant: COCCO[C@@H]1[C@H](CI)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=[PH2][O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCO[C@@H]1[C@H](C)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccc(OC)cc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 105 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A mixture of ammonium phosphinate (410 mg, 5.1 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (1.18 mL, 0.90 g, 5.59 mmol) was heated at 100-110° C. for 2 h under nitrogen atmosphere with condenser. The intermediate BTSP(bis[trimethylsilyl]phosphinate) was cooled to 0° C. and 5 mL of dichloromethane was injected. To this mixture was injected a solution of 3′-deoxy-5′-O-(4-methoxytrityl)-3′-(iodomethyl)-2′-O-(2-methoxyethyl)-5-methyluridine (0.78 g, 1.1 mmol) and diisopropylethylamine (0.39 mL, 287 mg, 2.23 mmol) in 7 mL of dichloromethane. After the reaction mixture was stirred at rt overnight, a mixture of THF-MeOH-NEt3 (3/6/0.3 mL) was added and continued to stir for 1 h. The reaction mixture was filtered through a pad of celite and washed with dichloromethane. The solvent was evaporated and the residue was purified by flash chromatography on a silica gel column using 2:1, 1:1, and then 1:2 hexanes-EtOAc as eluent providing 380 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][C:5]2[CH:7]=[CH:8][C:9]([Li])=[C:10]([O:11][CH3:12])[C:4]=2[O:3]1.[Cl:15]N1C(=O)CCC1=O.S(=O)(=O)(O)O>>[Cl:15][C:9]1[CH:8]=[CH:7][C:5]2[CH2:6][C:2]([CH3:14])([CH3:1])[O:3][C:4]=2[C:10]=1[O:11][CH3:12]
Reactant: [Li]c1ccc2c(c1OC)OC(C)(C)C2
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Product: COc1c(Cl)ccc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension containing 2,3-dihydro-2,2-dimethyl-6-lithio-7-methoxybenzofuran is prepared as described in Example 1. The suspension is cooled in an ice-water bath and 13.3 g of N-chlorosuccinimide is added. The suspension is stirred at room temperature for eight hours and then acidified with cold aqueous sulfuric acid. The organic phase is separated, washed with water saturated with sodium chloride, then dried over sodium sulfate. The solvent is evaporated to give crude 6-chloro-2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([F:21])=[CH:23][CH:24]=2)=[O:13])=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(F)cc1
Yield: 9.7 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.00 g, 2.92 mmol) in 20 mL of dichloromethane and 4-fluoroaniline (0.657 g, 5.91 mmol) in 5 mL of pyridine. The crude product was triturated with hot ethanol-ethyl acetate mixture, filtered, and recrystallized from ethanol-DMF to yield 0.14 g of the title compound, mp 242°-244° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=1[N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1>ClCCl.C(N(CC)CC)C>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[CH:15][CH:14]=2)=[CH:31][C:30]=1[N:36]1[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2ccc(C3CCCCC3)cc2)cc1N1CCN(C)CC1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
4-Cyclohexylbenzoic acid (300 mg, 1.5 mmol) was heated at reflux with thionyl chloride (2 ml) and toluene (40 ml) for 2 h, and then evaporated to dryness under reduced pressure. 4-Methoxy-3-(4-methyl-1-piperazinyl)phenylamine (325 mg, 1.5 mmol) in dry dichloromethane (40 ml) was added with triethylamine (2 ml) and the mixture stirred for 1 h. The solution was partitioned between dichloromethane (40 ml) and saturated aqueous potassium carbonate (40 ml), the organic solution dried (sodium sulphate) and evaporated to dryness under reduced pressure to afford an oil, which was purified by flash column chromatography (silica, chloroform/methanol 5%) to afford the title compound (561 mg, 92%) which was crystallised from methanol/diethyl ether as the oxalate salt m.p. 117°-119° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:12][C@@H:11]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:10]3[CH2:9]2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27](B2OC(C)(C)C(C)(C)O2)=[C:28]([OH:30])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O.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:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:12][C@@H:11]4[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:15][C@@H:10]4[CH2:9]3)=[CH:4][CH:3]=2)=[C:28]([OH:30])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc(Cl)nn3)C[C@@H]2C1
Reactant: CC1(C)OB(c2ccc(Cl)cc2O)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc(-c4ccc(Cl)cc4O)nn3)C[C@@H]2C1
Temperature: 90 °C
Yield: 43.2 %

Procedure:
The reaction mixture of (3aR,6aS)-tert-butyl 5-(6-chloropyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (325 mg, 1 mmol), 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (280 mg, 1.100 mmol), sodium carbonate (318 mg, 3.00 mmol) and PdCl2(dppf).CH2Cl2 (61.2 mg, 0.075 mmol) in dioxane (5 mL) and water (5.00 mL) was degassed by bubbling N2 for 10 minutes. After heating at 90° C. overnight, the reaction mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel chromatography (0-10% MeOH/DCM) to afford (3aR,6aS)-tert-butyl 5-(6-(4-chloro-2-hydroxyphenyl)pyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (180 mg, 0.432 mmol, 43.2% yield) MS (M+1)=417.0.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:20])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1.CO.C(Cl)(Cl)Cl.[NH3:27]>O1CCOCC1>[NH2:27][C:2]1[C:7]2[C:8](=[O:20])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH2:10][CH2:11][O:12][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=C1c2c(Cl)ncnc2OCCN1c1ccc(I)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Nc1ncnc2c1C(=O)N(c1ccc(I)cc1)CCO2

Procedure:
A solution of 4-chloro-6-(4-iodophenyl)-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-5(6H)-one (279 mg, 0.70 mmol) in 0.5 N ammonia in p-dioxane was stirred in a sealed tube for 18 hours. Concentration of the reaction mixture, followed by chromatography (10 g silica gel, 0-5% methanol: chloroform) afforded the title compound of Preparation 5 as a white solid, 122 mg. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.80 (d, 2H), 7.60 (br s, 2H), 7.19 (d, 2H), 4.60 (m, 2H), 3.96 (m, 2H). m/z=383.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:13]=[CH:12][NH:11][N:10]=1.Cl[CH2:15][C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:16]([CH2:15][N:11]1[CH:12]=[CH:13][C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:10]1)#[N:17]
Reactant: N#CCCl
Reactant: Fc1cccc(F)c1-c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCn1ccc(-c2c(F)cccc2F)n1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
3.0 g of 3-(2,6-difluorophenyl)pyrazole was dissolved in 20 ml of acetonitrile, and 2.52 g of chloroacetonitrile and 4.61 g of potassium carbonate were added thereto at room temperature, and heated under reflux for 5 hours. After acetonitrile was distilled off under reduced pressure, ethyl acetate was added to the residue, which was then washed with a small amount of water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was recrystallized from a mixed solvent of isopropylether and diethyl ether to obtain 1.74 g of l-cyanomethyl-3-(2,6-difluorophenyl)pyrazole. 2) A solution of 0.5 g of 1-cyanomethyl-3-(2,6-difluorophenyl)pyrazole dissolved in 10 ml of THF was dropwise added to a suspension of 0.15 g of 55% sodium hydride in 10 ml of THF, at; 50° C. After the resulting product was stirred for 30 minutes, a solution of 0.67 g of 1-(1-methyl-3,5-dichloropyrazole-4-carbonyl)pyrazole dissolved in 10 ml of THF was dropwise added thereto at 50° C. and then stirred overnight at room temperature. The reaction mixture was poured into water, then extracted with ethyl acetate and washed with a small amount of water. The resulting product was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was recrystallized from a mixed solvent of isopropyl ether/ethyl acetate=3/1 to obtain 0.52 g of 2-(3-(2,6-difluorophenyl)pyrazol-1-yl)-3-(1-methyl-3,5-dichloropyrazol-4-yl)-3-hydroxyacrylonitrile.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>CO>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(CO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
A solution of methyl 3-(hydroxymethyl)benzoate (845 mg, 5.09 mmol) in methanol (15 mL) was treated with 1 M NaOH (aq) (15.300 mL, 15.30 mmol), and the reaction was stirred for about 16 hours at room temperature. At the conclusion of this period, the methanol was removed under reduced pressure, and the remaining aqueous solution was washed 3× with 10 mL of diethyl ether. The aqueous phase was acidified to pH 1 with concentrated HCl, and then extracted 3× with 20 mL of ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield 3-(hydroxymethyl)benzoic acid (680 mg, 4.47 mmol, 88% yield) as a colorless powder. MS (ESI+)=153.10, (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1[OH:15])=[O:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1[O:15][S:24]([CH3:23])(=[O:26])=[O:25])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CCCC2(CCCC2)C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCCC2(CCCC2)C1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-hydroxy-spiro[4.5]decane-7-carboxylic acid methyl ester (10.1 g) obtained in Step 3 and triethylamine (19.9 mL) in chloroform (100 mL) was added dropwise methanesulfonyl chloride (5.2 mL) under ice-cooling, followed by stirring the reaction mixture at room temperature for 2 hours. Then, after addition of triethylamine (10 mL), the reaction mixture was stirred at room temperature for 30 minutes. After ice-cooling, ice-cold water (30 mL) and saturated aqueous sodium bicarbonate solution (50 mL) were added to the reaction mixture, followed by separation of the organic layer. The organic layer was washed with saturated brine, dried and concentrated to give a crude 6-methanesulfonyloxy-spiro[4.5]decane-7-carboxylic acid methyl ester (22 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11][C:10]=2[F:26])=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[F:26][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([NH:1][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=2)(=[O:35])=[O:34])=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)cn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(NC(=O)OCc4ccccc4)cc3F)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
To a solution of benzyl {4-[(6-aminopyridin-3-yl)oxy]-3-fluorophenyl}carbamate (28.2 g, 79.8 mmol) in pyridine (141 mL) was added p-toluenesulfonyl chloride (18.3 g, 98.5 mmol), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, water and saturated brine in this order, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate and collected by filtration to give the title compound (29.2 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: CCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Pan B) (0.040 g, 0.154 mmol), amylamine (0.0139 g, 0.154 mmol) and 3 Å molecular sieves in a vial. Add methanol (1.5 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load directly onto a 5 g SCX column. Wash with methanol (10 mL), then elute with 2.0 M NaBH3 in methanol. Purify by loading the product onto a 5 g loading cartridge and eluting through a 10 g ISCO® column with 50% ethyl acetate, 5% (2.0 M NH3 in methanol) and 45% hexanes to give the title compound (0.0387 g, 76.0%: TOF MS ES+ 332.2 (M+H)+. HRMS calcd for C18H23N3O2F 332.1774 (M+H)+, found 332.1765, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.9 min, 100% purity.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5](Cl)(=[O:9])[C:6]([CH3:8])=[CH2:7].C(N(CC)CC)C>O1CCCC1>[C:5]([O:4][CH2:3][CH2:2][Br:1])(=[O:9])[C:6]([CH3:8])=[CH2:7]
Reactant: C=C(C)C(=O)Cl
Reactant: OCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCBr
Yield: 89.6 %

Procedure:
A reactor was charged with 12.50 g (100 mmol) of 2-bromoethanol and 100 ml of tetrahydrofuran (THF) at 0° C. in a nitrogen atmosphere. After the dropwise addition of 10.45 g (100 mmol) of methacrylic chloride and 11.13 g (110 mmol) of triethylamine, the mixture was reacted at 25° C. for 30 minutes with stirring. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by distillation to obtain 17.30 g of 2-bromoethyl methacrylate shown by the following formula (M-20′) (yield: 90%).
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH2:23][CH2:22][CH2:21][CH2:20]1.[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([O-])=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Na+]>CN(C)C=O>[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25][CH2:24][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1OCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 273 mg of 2-(2-pyrrolidin-1-yl-ethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 2 hours, and then concentrated under reduced pressure.
Reaction SMILES: O1C2C=CC=CC=2N=C1.NC1C(O)=CC=CC=1C.C(OC1C=C(CO)C(OCCCCCC)=CC=1C=O)CCCCC.NC1C=C(C(C)(C)C)C=CC=1O.[CH3:55][C:56]1[C:61]2[N:62]=[C:63]([C:65]3[C:72]([O:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])=[CH:71][C:68]([CH:69]=[O:70])=[C:67]([O:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH:66]=3)[O:64][C:60]=2[CH:59]=[CH:58][CH:57]=1>>[CH3:55][C:56]1[C:61]2[N:62]=[C:63]([C:65]3[CH:66]=[C:67]([O:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[C:68]([CH2:69][OH:70])=[CH:71][C:72]=3[O:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH3:79])[O:64][C:60]=2[CH:59]=[CH:58][CH:57]=1
Reactant: CCCCCCOc1cc(-c2nc3c(C)cccc3o2)c(OCCCCCC)cc1C=O
Agent: CC(C)(C)c1ccc(O)c(N)c1
Agent: CCCCCCOc1cc(CO)c(OCCCCCC)cc1C=O
Agent: Cc1cccc(O)c1N
Product: CCCCCCOc1cc(-c2nc3c(C)cccc3o2)c(OCCCCCC)cc1CO
Yield: 71 %

Procedure:
The sensor Zinhbo-5 can be synthesized as shown in Scheme 1, which requires a sequential construction of two benzoxazole units. The first benzoxazole unit is constructed by reaction of 2-amino-m-cresol with 2,5-bis(hexyloxy)-4-(hydroxymethyl)benzaldehyde in three steps (in 71% yield). The second benzoxazole unit is synthesized by reaction of 2-amino-4-(tert-butyl)phenol with 4-(4-methylbenzoxazolyl)-2,5-bis(hexyloxy)benzaldehyde.