Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.C(OC([NH:13][C:14]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16][CH2:15]1)=O)(C)(C)C.[CH3:21]O>>[NH2:13][C:14]1([C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1(N)CCC1
Temperature: 0 °C
Yield: 75 %

Procedure:
Concentrated H2SO4 (10 ml) was added at 0° C. to a solution of 1-(tert-butoxy-carbonylamino)-cyclobutane-1-carboxylic acid (9.29 mmol, 1 equiv.) in MeOH (30 ml), and the reaction was refluxed for 2 hours at 0° C. The solvent was removed under reduced pressure. The residue was taken up in distilled water, adjusted to pH 8-9 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with distilled water (2×150 ml) and saturated NaCl solution (2×50 ml) and dried over sodium sulfate. The solvent was concentrated under reduced pressure to yield the desired product in the form of a white solid. Yield: 75%
Reaction SMILES: Cl[C:2]1N=C2C(N=CN2C2CC(N3C=C(CC)N=N3)C(O)C2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:47]1([CH:53]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:54][NH:55][C:56]2[N:64]=[C:63]([NH:65]CCN3CCCCC3)[N:62]=[C:61]3[C:57]=2[N:58]=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3[CH:83]=[C:82](CO)[CH:81]=[N:80]3)[C@@H:76]([OH:86])[C@H:75]2[OH:87])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[CH2:94]([N:96]1[CH:100]=[C:99]([CH2:101][CH2:102]N)[N:98]=[CH:97]1)[CH3:95]>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:88]1([CH:53]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:54][NH:55][C:56]2[N:64]=[C:63]([NH:65][CH2:102][CH2:101][C:99]3[N:98]=[CH:97][N:96]([CH2:94][CH3:95])[CH:100]=3)[N:62]=[C:61]3[C:57]=2[N:58]=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3[N:80]=[C:81]([CH2:82][CH3:83])[CH:2]=[N:3]3)[C@@H:76]([OH:86])[C@H:75]2[OH:87])[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1
Reactant: CCc1cn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)nn1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CCn1cnc(CCN)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCc5cn(CC)cn5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from 3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA9) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 461 by replacing 1-(2-amino-ethyl)piperidine with 2-(1-ethyl-1H-imidazol-4-yl)-ethylamine (intermediate CD). MS (ES+) m/e 648.42 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]([CH3:35])([CH3:34])[S:30][CH2:29]1.CN(C)C=O>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[C:32](=[O:33])[C:31]([CH3:34])([CH3:35])[S:30][CH2:29]4)[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: CC1(C)SCN(CCCCBr)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)SCN(CCCCN2CCN(c3n[nH]c4cc(F)ccc34)CC2)C1=O
Yield: 34.6 %

Procedure:
To a stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (4.4 g), K2CO3 (2.8 g), 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (6.6 g) and dimethylformamide (75 ml) was heated at 75° for 4 hours. The reaction was poured into H2O, and the aqueous mixture extracted with ethyl acetate. The ethyl acetate was washed (H2O), dried (MgSO4) and the solvent concentrated to afford an oil. Upon standing the oil crystallized, and when the mass was triturated with ether, 3.3 g of a solid was collected. The compound was recrystallized from toluene-hexane to yield 2.8 g of 3-(4-(1-[6-fluoro-1H-indazol-3-yl]-4-piperazinyl)-butyl)-5,5-dimethyl-4-thiazolidinone, m.p. 123°-125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]2[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[O:31]=[C:28]([NH:1][C:2]1[CH:27]=[CH:26][C:5]2[O:6][C:7]3[CH:25]=[CH:24][CH:23]=[CH:22][C:8]=3[C@@H:9]3[C@H:14]([NH:15][C:16](=[O:21])[C:17]([F:19])([F:20])[F:18])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1)[CH2:29][CH3:30]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc2c(c1)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc2c(c1)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.9 %

Procedure:
To a solution of trans-N-(7-amino-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido-[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (50 mg, 0.13 mmol) in CH2Cl2 (2 mL) was added propionyl chloride (11 μl, 0.13 mmol) and triethylamine (20 μl, 0.14 mmol). The reaction mixture was stirred for 1.5 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 (aq) and extracted with CH2Cl2. The organic layer was dried and evaporated. The crude product was purified on silica and by HPLC to afford the title compound (27 mg, 48%). Data (m/z)=434 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Li+].[OH-].Cl>CO.C1COCC1.O>[F:10][C:8]1[CH:7]=[CH:6][C:5]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH:9]=1)[C:3]([OH:31])=[O:2]
Reactant: COC(=O)c1cc(F)ccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)ccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of 5-fluoro-2-tritylsulfanyl-benzoic acid methyl ester (4.74 g, 11.2 mmol) and LiOH (1.74 g, 41.4 mmol) in 80 mL of MeOH/THF/H2O (1/2/1) was stirred at rt overnight. The reaction mixture was acidified to pH 4 using 1 N HCl. The precipitate was collected by filtration, rinsed with water and dried in vacuo to provide 5-fluoro-2-tritylsulfanyl-benzoic acid (4.16 g). MS ESI(+) m/e: 415.13 (M+1).
Reaction SMILES: Cl.NC[C:4]1[CH:5]=[C:6]([OH:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9].[C:15]([O:19][C:20]([O:22]C(OC(C)(C)C)=O)=O)([CH3:18])([CH3:17])[CH3:16].[CH2:30]([N:32](CC)CC)C>CO>[C:15]([O:19][C:20]([NH:32][CH2:30][O:14][C:6]1[C:7](=[CH:12][CH:13]=[CH:4][CH:5]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:22])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(CN)cc1O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccccc1OCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
Methyl 4-aminomethylsalicylate hydrochloride (10.9 g, 50 mmoles) was suspended in anhydrous methanol (200 mL) and di-tert-butyldicarbonate (10.9 g, 50 mmoles) and triethylamine (7.0 mL, 50 mmoles) were added. The solid rapidly dissolved with the slow evolution of gas. The reaction mixture was stirred at room temperature for 18 hours under dry nitrogen, then evaporated to dryness to afford a white amorphous mass. This mass was partitioned between ethyl acetate (200 mL) and water (100 mL). The layers were separated, and the ethyl acetate solution was dried over anhydrous sodium sulfate. The solution was filtered and evaporated to a white solid. This solid was crystallized from ethyl acetate/hexanes, filtered, and dried in vacuo to afford 13.7 g (97% yield) of methyl N-tert-butoxycarbonylaminomethyl-salicylate (m.p. 95°-96° C., open capillary, uncorrected).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCOc1ccc(Br)cc1
Temperature: 52.5 °C
Reaction time: 5 h
Yield: 76.4 %

Procedure:
In a flask equipped with a stirrer and a thermometer, 4.29 g (24.8 mmol) of 4-bromophenol was dissolved in 40 ml of dry dimethylformamide (abbreviated as DMF hereinbelow) under a nitrogen atmosphere, and 5.0 g (29.9 mmol) of 5-bromopentanol and 4.14 g (29.9 mmol) of potassium carbonate were added at room temperature, followed by stirring at 50 to 55° C. for 5 hours under incubation. After the completion of the reaction, water was added, and the mixture was subjected to extraction with ethyl acetate. The resulting organic phase was washed with NaCl saturated water, dried over anhydrous sodium sulfate, filtered, and concentrated, to thereby obtain 7.8 g of a crude product in the form of a yellow oil. The crude product was then purified by silica gel column chromatography using hexane/ethyl acetate as an eluting solvent to obtain 4.91 g of 5-(4-bromophenoxy)pentanol in the form of a light yellow oil in a 76% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]#[N:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N+:9]2[O-])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.C(O)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]#[N:18])=[C:15]3[C:10]([CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([CH:19]4[CH2:21][CH2:20]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2[n+]([O-])n1-c1ccc(Br)cc1
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N#Cc1c2cc(C3CC3)c([N+](=O)[O-])cc2nn1-c1ccc(Br)cc1
Temperature: 60 °C
Yield: 86.1 %

Procedure:
To a stirred solution of compound (v) (4.1 g, 0.010 mol) in chloroform (40 mL) was added phosphorus trichloride (4.1 mL, 0.047 mol) and the reaction mixture was heated to 60° C. for 1 h (monitored by TLC and LCMS). The reaction mixture was quenched in ice water and the product was extracted into DCM (2×80 mL). Concentration of solvent gave the crude product, to which was added ethanol and filtered to give 2-(4-bromophenyl)-5-cyclopropyl-6-nitro-2H-indazole-3-carbonitrile (vi) (3.3 g, 84%).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([O:19][CH3:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[O:9])[C:4](=[O:21])O1.[CH2:23]=O.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CO>[CH3:20][O:19][N:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[C:8]([C:7]1[CH2:23][N:25]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:4](=[O:21])[C:5]=1[OH:6])=[O:9]
Reactant: CON(Cc1ccc(C)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: C=O
Reactant: NCCN1CCOCC1
Solvent: CO
Product: CON(Cc1ccc(C)cc1)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Yield: 45 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(4-methylbenzyl)-acetamide (0.30 g, 0.98 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.17 g (45% yield) of the title compound as a solid. 1HNMR 400 MHz (CDCl3) δ (ppm); 2.35 (3H, s, CH3), 2.47 (4H, m, 2×NCH2), 2.56 (2H, t, J=6.2 Hz, NCH2), 3.62 (2H, t, J=6.2 Hz, NCH2), 3.66 (4H, m, 2×OCH2), 3.71 (3H, s, OCH3), 4.27 (2H, s, NCH2), 4.85 (2H, s, NCH2), 7.14–7.24 (4H, m, aromatics). HRMS (FAB+) calculated for C20H28N3O5: [M+H]+: 390.202896. found: 390.203567.
Reaction SMILES: C=O.[CH3:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]([NH2:34])=[O:33])=[N:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[N:8][CH:9]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:3][C:4]1[C:5]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:32]([NH2:34])=[O:33])=[N:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:35])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)=[N:8][CH:9]=1
Reactant: Cc1cnc(Nc2ccc(C3CCNCC3)nc2)nc1CCc1ccccc1CC(N)=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(Nc2ccc(C3CCN(C)CC3)nc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Formaldehyde (37% wt. in H2O; 0.017 mL, 0.22 mmol) was added to a solution of 2-(2-(2-(5-methyl-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetamide (4) (32 mg, 0.07 mmol) in MeOH (4 mL) under an atmosphere of nitrogen. The resulting solution was stirred for 15 minutes at room temperature then sodium triacetoxyborohydride (63 mg, 0.30 mmol) was added in one portion. After stirring at room temperature for 18 hours a further portion of formaldehyde (37 wt. % in H2O; 0.017 mL, 0.22 mmol) was added and after 15 minutes sodium triacetoxyborohydride (63 mg, 0.30 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 20 hours then the volatiles were removed in vacuo and the residue partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over Na2SO4. The volatiles were removed under reduced pressure to give the title compound 5 as an off white solid (20 mg, 61%); 1H NMR (400 MHz, d4-MeOH) δ 8.79 (d, J=2.2 Hz, 1H), 8.15 (dd, J=8.6, 2.7 Hz, 1H), 8.12 (d, J=0.6 Hz, 1H), 7.27-7.23 (m, 2H), 7.20-7.15 (m, 3H), 3.64 (s, 2H), 3.16-3.06 (m, 4H), 2.98 (dd, J=9.2, 6.0 Hz, 2H), 2.72 (tt, J=12.0, 3.9 Hz, 1H), 2.40 (s, 3H), 2.32 (td, J=12.0, 2.4 Hz, 2H), 2.11 (s, 3H), 1.97 (d, J=11.9 Hz, 2H), 1.92-1.80 (m, 2H). LCMS-A: rt 4.237 min; m/z 445 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>ClCCl>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[S:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[C:6]([NH2:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(C(N)=O)cc1Sc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
A mixture of 4-amino-3-(2,4-difluorophenylthio)benzamide (0.82 g), methanesulfonyl chloride (0.64 g) and triethylamine (0.6 g) in dichloromethane (10 ml) was stirred for 2 hours at room temperature. The reaction mixture was evaporated. To the residue were added methanol (10 ml) and potassium hydroxide (0.6 g). The mixture was kept overnight and evporated. The residue was treated with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue obtained was recrystallized from ethanol to give 3-(2,4-difluorophenylthio)-4-(methanesulfonamido)benzamide (0.54 g).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].Cl[C:8](Cl)([O:10]C(=O)OC(Cl)(Cl)Cl)Cl.[CH:19]([NH:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:21])[CH3:20].O>C(Cl)Cl>[CH:19]([N:22]([C:8](=[O:10])[NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[NH:23][C:24]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:30])([CH3:21])[CH3:20]
Reactant: NCC(F)(F)F
Reactant: CC(C)NNC(=O)OC(C)(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)N(NC(=O)OC(C)(C)C)C(=O)NCC(F)(F)F

Procedure:
2,2,2-Trifluoroethanamine (284 mg, 2.87 mmol), TEA (0.8 ml, 5.74 mmol)) in CH2Cl2 (6 mL) were added to the solution of triphosgene (298 mg, 1 mmol) in CH2Cl2 (8 mL) at −40° C. and the reaction mixture was stirred for 30 min tert-Butyl N-(isopropylamino)carbamate (JOC, 2013, 78, 3541-3552.) (500 mg, 2.87 mmol) in CH2Cl2 (4 mL) was then added to the reaction mixture at −40° C. and stirred at ambient temperature—overnight. Water was added to the reaction mixture and it was extracted with CH2Cl2. The organic layer wad washed with brine, dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (580 mg, crude): mp 90-94° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.70 (bs, 1H), 6.81 (t, J=6.3, 1H), 3.89-3.80 (m, 2H), 3.11-3.08 (m, 1H), 1.40 (s, 9H), 0.97 (d, J=6.0 Hz, 6H); ESIMS m/z 241.9 ([M-tert-Butyl]+).
Reaction SMILES: CC[O:3][CH2:4][CH3:5].[OH-:6].[K+].[N+:8]([C:11]1C=[CH:15][CH:14]=[CH:13][C:12]=1C)([O-:10])=[O:9].O>CO>[N+:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=1[C:4]([OH:3])=[O:6])([O-:10])=[O:9]
Reactant: CCOCC
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 24 %

Procedure:
A catalytic amount of a metal catalyst (0.01 g metal porfin or 0.005 g metal (AcAc)2 +0.01 g crown-ether) was added to a 33% methanolic KOH-solution, (34 g KOH in 100 ml methanol). The reaction mixture was cooled to 25° C., 2-nitrotoluene (13.7 g, 0.1 mol) was added and air was passed through the reaction mixture, the temperature of the reaction mixture being kept at 25° C. After 12 hours the passsing through of air was interrupted and 150 ml water and 50 ml methanol was added. The reaction mixture was filtered. The filter layer was dissolved in boiling toluene (benzene), was filtered when hot, was cooled and was filtered again. Recrystallisation from ethanol gave a product with m.p. 120°-121° C. Yield 24-27%. As a by-product o-nitrobenzoic acid was formed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:16](=[O:19])[CH2:17]Br>C(N(CC)CC)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:16](=[O:19])[CH2:17][N:10]([CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:11])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CNCc1cccc(OC)c1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: COc1cccc(CN(C)CC(=O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
1-(3-Methoxyphenyl)-N-methylmethanamine is reacted with 3,4-dichlorophenacyl bromide in the presence of triethylamine to give 1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanone. Reduction of this ketone by sodium borohydride yields 1-(3,4-dichlorophenyl)-2-(3-methoxybenzyl)(methyl)amino)ethanol, which undergoes acid mediated cyclization to give 4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline. This racemic tetraisoquinoline derivative can be separated via chiral HPLC or supercritical fluid chromatography (SFC) to give the single enantiomers. Alternatively, the chiral separation can be achieved by recrystallization using chiral acids such as di-p-toluoyl-D-tartaric acid or di-p-toluoyl-L-tartaric acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].C(N(CC)CC)C.C(O[CH2:18][C:19]1[S:23][C:22]([NH:24][C:25]([C:27]2[CH:28]=[C:29]([Cl:44])[C:30]([N:33]3[CH2:38][CH2:37][CH:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:35][CH2:34]3)=[N:31][CH:32]=2)=[O:26])=[N:21][C:20]=1[C:45]1[S:46][CH:47]=[C:48]([Cl:50])[CH:49]=1)(=O)C>CN(C)C1C=CN=CC=1.CCO>[Cl:44][C:29]1[C:30]([N:33]2[CH2:34][CH2:35][CH:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:37][CH2:38]2)=[N:31][CH:32]=[C:27]([C:25](=[O:26])[NH:24][C:22]2[S:23][C:19]([CH2:18][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])=[C:20]([C:45]3[S:46][CH:47]=[C:48]([Cl:50])[CH:49]=3)[N:21]=2)[CH:28]=1
Reactant: CNCCOC
Reactant: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(COC(C)=O)s3)cc2Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CN(C)CCOC)s3)cc2Cl)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
39 μl of N-(2-methoxyethyl)methylamine, 51 μl of triethylamine and 23 mg of 4-(dimethylamino)pyridine were added to a 6 ml EtOH suspension of 107 mg of ethyl 1-(5-{[5-[(acetoxy)methyl]-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidine-4-carboxylate, and the mixture was stirred at 50° C. for 2 hours. After the solvent was distilled off, a saturated sodium hydrogencarbonate aqueous solution was added, and the mixture was extracted with EtOAc, and washed with water and with brine(saturated sodium chloride aqueous solution). The resulting product was dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using a hexane:EtOAc (10:1 to 3.5:1) as an elution solvent to obtain 90 mg of ethyl 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](N)=[O:8])=[CH:5][CH:4]=1)#[N:2].N([O-])=[O:13].[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:13])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
p-Cyanobenzamide (1.46 g) and acetic acid (20 ml) were mixed and stirred vigorously at room temperature. To the mixture, sodium nitrite (2.07 g), and immediately thereafter, 95 wt. % sulfuric acid (3 g) was added and stirred vigorously for one hour. The acetic acid was removed under reduced pressure, and water (40 ml) was added to the residue. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 1.26 g of p-cyanobenzoic acid (yield 86%). The p-cyanobenzoic acid obtained had a purity of 95%.
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[C:11]([O:14][CH2:15][C:16]1[CH2:23][S:22][CH:21]2[N:18]([C:19](=[O:28])[CH:20]2[NH:24][C:25]([NH2:27])=[S:26])[C:17]=1[C:29]([O:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])(=[O:13])[CH3:12]>ClCCl>[C:11]([O:14][CH2:15][C:16]1[CH2:23][S:22][C@H:21]2[N:18]([C:19](=[O:28])[C@H:20]2[NH:24][C:25]([N:27]=[CH:4][N:5]([CH3:7])[CH3:6])=[S:26])[C:17]=1[C:29]([O:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])(=[O:13])[CH3:12]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(N)=S)C2SC1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=S)N=CN(C)C)[C@H]2SC1
Reaction time: 0.33 h

Procedure:
A 650 mg portion of N,N-dimethylformamide diethylacetal in 10 ml of dichloromethane was added dropwise to a solution of 2 g of (6R-trans)-3-[(acetyloxy)methyl-7-[(aminothioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester in 35 ml of dichloromethane. The mixture was stirred for 20 minutes, then filtered, evaporated and the residue purified by flash chromatography using the system ethyl acetate:petroleum ether (1:1) and giving 1.08 g of the desired product.
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: F[B-]1(F)n2cccc2C=C2C=CC=[N+]21
Reactant: [N-]=[N+]=NBr
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).