Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH3:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]([CH3:20])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[S:30][CH:31]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:28]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1
Yield: 31.2 %

Procedure:
A solution of 2,2,2-trichloroethyl {4-[acetyl(methyl)amino]phenyl}carbamate (200 mg, 0.589 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (144 mg, 0.589 mmol), diisopropylethylamine (0.103 ml, 0.589 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (80.0 mg, 31.3%) as a solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([NH:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[H-].[Na+].[O:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>C1COCC1>[C:16]1([C:9]([NH:8][C:3]2([CH2:2][O:1][CH2:43][C:42]3[CH:45]=[CH:46][C:39]([C:31]4[O:30][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=5[N:32]=4)=[CH:40][CH:41]=3)[CH2:7][CH2:6][CH2:5][CH2:4]2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OCC1(NC(c2ccccc2)(c2ccccc2)c2ccccc2)CCCC1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(C(NC2(COCc3ccc(-c4nc5ccccc5o4)cc3)CCCC2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a mixture of 1-hydroxymethyl-1-triphenylmethylaminocyclopentane (2.95 g; 8.25 mmol) in 100 ml of THF is added sodium hydride (60%; 0.495 g; 12.38 mmol) and allowed to stir for 1 hr. To this mixture is then added 4-(benzoxazol -2-yl)benzyl bromide (1.90 g; 6.60 mmol) and heated to reflux for 48 hrs. The reaction mixture is quenched with H2O, concentrated in vacuo and flash chromatographed using 7:1; hexane:EtOAc to obtain 1-triphenylmethylamino(4-[benzoxazol-2-yl]benzyloxymethyl)cyclopentane which is used directly in the next step.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH:18]1[C:19]2[C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[O:8][C:9]=2[CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1ccc(OC2CCCCC2=O)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc2oc3c(c2c1)CCCC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
262.3 g (1 mol) of ethyl p-(2-oxocyclohexyloxy)-benzoate are cooled to 10° and 250 ml of concentrated sulfuric acid are added dropwise in the course of about 2 hours. During this addition, the temperature is kept at between 10° and 20° with an ice-water bath. When the addition has ended, the mixture is stirred at room temperature for a further 3 hours and then poured onto a 2:1 mixture of saturated aqueous sodium carbonate solution and ice. The aqueous phase is extracted once with about 1,000 ml of ether and then a further three times with 300 ml of ether each time and the combined organic phases are washed four times with 300 ml of 2 N sodium hydroxide solution each time, dried over sodium sulfate and evaporated under a waterpump vacuum. The oily residue is purified by filtration over a layer of silica gel, chloroform being used as the solvent and eluting agent. After evaporating off the chloroform, ethyl 6,7,8,9-tetrahydro-2-dibenzofurancarboxylate is obtained as a yellowish oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]([O:16]CC)=[O:15])[C:5]1=[O:19].Cl>[OH-].[Na+]>[OH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]1=[O:19]
Reactant: CCOC(=O)c1nc2ccccc2n(CCO)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nc2ccccc2n(CCO)c1=O

Procedure:
3,4-Dihydro-4(2-hydroxyethyl)-3-oxo-2- quinoxalinecarboxyic acid, ethyl ester (10 g) in aqueous sodium hydroxide (100 ml., 2N) was warmed at 80°-100° for 5 minutes. The yellow solution was acidified with hydrochloric acid (2N) and the solid that crystallised was collected and dried. It had m.p. 195° (d).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)C>[N:30]([CH2:12][CH:13]1[CH2:22][CH2:21][C:20]2[C:15](=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[CH:17]=[CH:18][CH:19]=2)[O:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cccc(-c4ccccc4Cl)c3O2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: [N-]=[N+]=NCC1CCc2cccc(-c3ccccc3Cl)c2O1
Temperature: 70 °C
Yield: 82 %

Procedure:
A solution of [8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate, prepared in Example 1, step 7 (0.25 g, 0.58 mmol) and sodium azide (0.15 g, 2.3 mmol) in anhydrous dimethyl sulfoxide (9.5 mL) was heated to 70° C. under nitrogen for 16 hours. The cooled reaction mixture was then diluted with diethyl ether (50 mL), washed with water (5×25 mL) and saturated brine (25 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 0.14 g (82%) of 2-azidomethyl-8-(2-chloro-phenyl)-chroman as a colorless oil that was used without further purification.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:9]=[C:10]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:11]([NH2:14])=[N:12][CH:13]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>O1CCOCC1>[CH3:22][O:21][C:18]1[N:17]=[CH:16][C:15]([C:10]2[C:11]([NH2:14])=[N:12][CH:13]=[C:8]([C:30]3[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=3)[CH:9]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(-c2cc(Br)cnc2N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(-c3ccc(S(C)(=O)=O)cc3)cnc2N)cn1
Temperature: 120 °C
Reaction time: 14 h
Yield: 105.1 %

Procedure:
K2CO3 aqueous solution (1 M, 5.4 mL) was added to a suspension of 5-bromo-3-(6-methoxypyridin-3-yl)pyridin-2-amine (1.44 g, 5.14 mmol), 4-(methylsulfonyl)phenyl boronic acid (1.08 g, 5.40 mmol, 1.05 equiv.), and Pd(PPh)3 (300 mg, 5 mol %) in dioxane (15 mL) under N2. The reaction mixture was stirred at 120° C. for 14 h, poured onto H2O (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/EtOAc, 2/8) providing 3-(6-methoxypyridin-3-yl)-5-(4-methylsulfonylphenyl)pyridin-2-amine (1) (1.92 g, 65%) as a pale yellow solid. IR (thin film/cm−1): νmax 3378, 1594, 1301, 1148. H1 NMR (400 MHz, CDCl3): δ 8.34 (d, 1H, J=2.0 Hz), 8.26 (d, 1H, J=2.0 Hz), 7.97 (d, 2H, J=8.4 Hz), 7.70 (d, 2H, J=8.4 Hz), 7.69 (d, 1H, J=8.4 Hz), 7.58 (d, 1H, J=2.0 ), 6.86 (d, 1H, J=8.4 Hz), 4.80 (bs, 2H), 3.98 (s, 3H) and 3.06 (s, 3H). C13 NMR (100 MHz, CDCl3): δ 164.16, 156.30, 146.94, 146.82, 145.57, 143.34, 139.02, 138.86, 136.92, 128.17, 126.84, 125.84, 118.88, 111.49, 53.67 and 44.62.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[CH3:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1>>[CH2:23]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:28][CH:29]=1)[CH2:22][CH2:21][CH3:20]
Reactant: CCCCc1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Product: CCCCc1ccc(OCC#Cc2ccc(C[C@H](OC)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 4-n-butylphenol in a manner analogous to that described for Example 5, Step B. MS(ES) for C23H26O4 [M−H]−: 365.2
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O>N1C=CC=CC=1>[CH2:7]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-octylbenzenesulfonyl chloride (6.06 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.83 g, 10.8 mmol, 55% yield) as a solid, mp 123-124° C.; 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=7 Hz), 1.36 (m, 10H), 1.59 (m, 2H), 2.63 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.82 (d, 2H, J=8 Hz), 8.23 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 29.2, 29.3, 29.4, 31.1, 31.8, 35.9, 126.5, 129.0, 138.1, 142.6, 148.7, 167.3; MS (Q-TOF) Calcd for C16H24N3O2S2 354.1310, found 354.1211 (M+H)+; Calcd for C16H23N3NaO2S2 376.1129, found 376.1154 (M+Na)+.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=2)[CH2:19]1.[C:30]([C:32]1[CH:33]=[C:34]([C:38]2[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][CH:39]=2)[CH:35]=[CH:36][CH:37]=1)#[N:31].ON1C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:30]([C:32]1[CH:33]=[C:34]([C:38]2[CH:39]=[CH:40][C:41]([C:42]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=4)[CH2:19]3)=[O:43])=[CH:45][CH:46]=2)[CH:35]=[CH:36][CH:37]=1)#[N:31]
Reactant: N#Cc1cccc(-c2ccc(C(=O)O)cc2)c1
Reactant: COc1ccc2c(c1)CN(CCCCN)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1ccc2c(c1)CN(CCCCNC(=O)c1ccc(-c3cccc(C#N)c3)cc1)CC2
Reaction time: 1 h
Yield: 60.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.41 g, 2.14 mmol) was added to a solution of 2-(4-aminobutyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline (0.5 g, 2.14 mmol), 4-(3-cyanophenyl)benzoic acid (0.368 g, 2.14 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) in dichloromethane (8 ml). The resultant mixture was shaken for 18 h. before saturated aqueous potassium carbonate (5 ml) was added and shaking continued 1 hr. The organic layer was chromatographed on silica gel using 10-100% ethyl acetate-hexane gradient elution to afford the title compound as a yellow gum (0.57 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:10]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:9]1.[NH2:30][C:31]1[C:32]([C:39](O)=[O:40])=[N:33][C:34]([Br:38])=[C:35]([F:37])[CH:36]=1>>[NH2:30][C:31]1[C:32]([C:39]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C@H:10]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:9]2)=[O:40])=[N:33][C:34]([Br:38])=[C:35]([F:37])[CH:36]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccncc2N)C[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccncc2NC(=O)c2nc(Br)c(F)cc2N)C[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Following Method 11 of Example 305, trans-(+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-3-(tert-butyldimethylsilyloxy)piperidin-4-ylcarbamate and 3-amino-6-bromo-5-fluoropicolinic acid was reacted yielding trans-(+/−)-tert-butyl 1-(3-(3-amino-6-bromo-5-fluoropicolinamido)pyridin-4-yl)-3-(tert-butyldimethylsilyloxy)piperidin-4-yl-carbamate. LCMS (m/z): 641.2 (MH+); LC Rt=4.73 min.
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.Cl>C(OCC)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:18])=[CH2:4])=[CH:13][CH:12]=1
Reactant: CCOCC
Reactant: COc1ccc(C(C)=O)cc1
Agent: C[Mg]Br
Agent: Cl
Product: C=C(C)c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
To a 1000 mL three-necked flask equipped with a mechanical stirrer, methyl magnesium bromide/diethyl ether solution (200 mL, 3.0 mol) is added. A solution of 85.3 g of 4′-methoxyacetophenone dissolved in 80 mL of anhydrous diethyl ether is charged to the Grignard reagent over 90 minutes at ambient temperature. Diethyl ether (200 mL) and 250 mL of 3N hydrochloric acid are added slowly to the reaction mixture. The solution is stirred for another 30 minutes. The aqueous layer is separated and washed twice with 100 mL of diethyl ether. The ethereal layers are combined and vacuum distilled. The desired product is obtained in a yield of 91.7 g as a yellow oil whose structure is verified by 1Hnmr and mass spectroscopy.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[OH:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.O>CS(C)=O>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([O:12][CH3:13])[CH:7]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: COc1cc(C(O)C2CC2)ccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cc(C(=O)C2CC2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of cyclopropyl(2-methoxypyridin-4-yl)methanol (5.30 g) and triethylamine (41.2 mL) in DMSO (120 mL) was added sulfur trioxide pyridine complex (18.8 g), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give a crude product of the title compound (4.42 g) as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:21][OH:22].C(N(CC)C(C)C)(C)C.NO.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.CCOC(C)=O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:19][C@@H:20]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]=3[CH2:11]2)=[N:13][CH:14]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: N[C@H](CO)c1ccc(C(F)(F)F)cc1
Agent: NO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CO)c4ccc(C(F)(F)F)cc4)c3C2)nc1
Reaction time: 2 h

Procedure:
A reaction mixture of 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (150 mg, 0.58 mmol) and (S)-2-amino-2-(4-(trifluoromethyl)phenyl)ethanol (180 mg, 0.86 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (0.20 mL, 1.2 mmol) was run in a microwave reactor at 180° C. for 2 h. LC-MS indicated amino alcohol was consumed and about 50% conversion of the chloride. Additional (S)-2-amino-2-(4-(trifluoromethyl)phenyl)ethanol (100 mg) was added and the mixture was run microwave reaction at 160° C. for another 2 h. The reaction mixture was treated with aq. Na2CO3 and EtOAc (150 mL). The organic layer was separated and washed with brine, dried (Na2SO4), and concentrated. The residue was purified by semi-prep HPLC to give a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[S:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[C:39](Cl)=[O:40].O>C(Cl)Cl>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:39](=[O:40])[C:38]3[CH:37]=[C:36]([O:35][CH3:34])[C:44]([O:45][CH3:46])=[C:43]([O:47][CH3:48])[CH:42]=3)[CH2:15][CH2:14]2)=[S:12])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=CC(=S)N2CCNCC2)c2ccc(OC)cc2)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=CC(=S)N2CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 357.2 %

Procedure:
1.049 g of 1-[3,3-bis(4-methoxyphenyl)thioacryloyl)piperazine [prepared as described in step (b) above] and 0.29 ml of triethylamine were dissolved in 30 ml of methylene chloride, and 0.157 g of 3,4,5-trimethoxybenzoyl chloride were added, whilst ice-cooling, to the resulting solution. The reaction mixture was then stirred for 1 hour at room temperature, after which it was poured into water and extracted twice with methylene chloride. The combined extracts were washed with 10% w/v aqueous hydrochloric acid, with a saturated aqueous solution of sodium bicarbonate and with water, in that order, after which they were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography through 40 g of silica gel and by medium pressure liquid chromatography using a Lobar B column using mixtures of methylene chloride and ethyl acetate ranging from 9:1 to 4:1 by volume as eluent, to give 1.368 g of the title compound as a yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][NH2:11].Cl[C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][NH:11][C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: Clc1nc2ccccc2s1
Reactant: NCCC#Cc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C(#Cc1ccccn1)CCNc1nc2ccccc2s1
Temperature: 120 °C
Yield: 94.7 %

Procedure:
4-(pyridin-2-yl)but-3-yn-1-amine (640 mg, 4.40 mmol), 2-chlorobenzo[d]thiazole (373 mg, 2.2 mmol) and DIEA (452 μL, 2.64 mmol) were poured into DMF (2.2 mL) and the resulting solution was heated two days at 120° C. The solvent was removed under reduce pressure and the crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 70/30 as eluent) to afford 582 mg of N-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazol-2-amine (Yield: 95%) as a brownish oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=2[N+:13]([O-])=O)[CH2:3][CH2:2]1>C(OC(=O)C)C.[Pd]>[CH:1]1([NH:4][C:5]2[C:6]([NH2:13])=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(NC2CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(NC2CC2)c(N)c1

Procedure:
A stirred solution of cyclopropyl-(4-methoxy-2-nitro-phenyl)-amine (0.8 g, 0.0038 mol) in ethylacetate (25 ml) was hydrogenated using 10% Pd/C for 6 h at room temperature. The reaction was filtered through CELITE® and the filter bed was thoroughly washed with EtOAc. The resulting solution was concentrated to provide N1-cyclopropyl-4-methoxy-benzene-1,2-diamine as a brown liquid. C10H14N2O; Crude 1H NMR (400 MHz, DMSO-d6), δ: 6.66 (d, J=8.8 Hz, 1H), 6.18-6.15 (m, 1H), 6.08 (d, J=6.0 Hz, 1H), 4.03 (d, J=6.8 Hz, 1H), 3.75-3.68 (m, 2H), 3.58 (s, 3H), 0.63 (d, J=6.0 Hz, 2H), 0.40 (s, 2H). MS (M+1): 179.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:3][CH2:2]1.C=O.[C:21](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:21][N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([NH2:18])=[N:13][CH:12]=[CH:11]3)[CH2:3][CH2:2]1
Reactant: Nc1nccc2cc(OC3CCNCC3)ccc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN1CCC(Oc2ccc3c(N)nccc3c2)CC1
Reaction time: 72 h
Yield: 52.7 %

Procedure:
Three drops of glacial acetic acid was added to a solution of 6-(piperidin-4-yloxy)-isoquinolin-1-ylamine (35 mg, 0.14 mmol) in N, N-dimethylformamide (1 ml), followed by addition of formaldehyde (37% aqueous solution, 200 mL). Sodium triacetoxyboro-hydride (150 mg) was added to the mixture, which was shaken for 72 h. Saturated aqueous sodium hydrogen carbonate was added and then the mixture acidified with acetic acid. The mixture was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 6-(1-methylpiperidin-4-yloxy)-isoquinolin-1-ylamine (19 mg), EIMS: m/z=258.5 [M+H]+
Reaction SMILES: [B-]1(F)(F)[N+:9]2=[CH:10][CH:11]=[CH:12][C:8]2=[CH:7][C:6]2N1C=[CH:4][CH:5]=2.C=CC1C=CC=CC=1.Br[N:24]=[N+:25]=[N-]>[Cu]>[N:9]([CH:10]=[CH:11][C:12]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=NBr
Reactant: F[B-]1(F)n2cccc2C=C2C=CC=[N+]21
Agent: [Cu]
Solvent: C=Cc1ccccc1
Product: [N-]=[N+]=NC=Cc1ccccc1

Procedure:
In the copper binding embodiment of the invention, the chemosensor, (12), comprises 8-HQ moiety as a binding site and BODIPY as a reporting group. (10) was prepared from styrene by bromination, conversion to the bromoazide which was eliminated to give azidostyrene; on heating (10) was isolated. (11) was synthesized by (10)'s reaction with methoxytetralone in the presence of NaH. In a one-pot three-step conversion, 8-HQ-2-carbaldehyde was condensed with pyrrole (11) to afford the dipyromethane which was oxidized to the dipyrromethene and reaction with BF3-OEt2 gave chemosensor (12) (FIG. 12, Scheme 2).