Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:6]=1[CH2:19][N:20]([CH2:31][C:32]([O:34][CH3:35])=[O:33])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO.[Cl-].[Na+].O>[CH3:35][O:34][C:32]([C:31]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:19][N:20]=1)[N:7]([CH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:33]
Reactant: CCC(CC)Cn1c(CN(CC(=O)OC)S(=O)(=O)c2ccc(C)cc2)c(C(=O)OC)cc(Br)c1=O
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CCC(CC)Cn1c(=O)c(Br)cc2c(O)c(C(=O)OC)ncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
5-Bromo-1-(2-ethyl-butyl)-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (4.89 g, 8.6 mmol) was dissolved in 170 mL of MeOH and placed in ice bath. NaOMe solution (6 mL, 25.7 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, followed by addition of brine, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% EtOAc/CH2Cl2) to give 3.1 g of the title compound as an off-white solid. MS: (+) m/z 383.23, 385.18 (M+1, 79/81Br).
Reaction SMILES: I[CH3:2].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:15](=[S:28])[NH:14][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1.[OH-].[NH4+]>O.C(O)C.C(Cl)(Cl)Cl>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:15]([S:28][CH3:2])=[N:14][C:9]=3[CH:10]=[N:11][C:12]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(=S)[nH]c2cnc3cc(Br)ccc3c21
Reactant: CI
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CSc1nc2cnc3cc(Br)ccc3c2n1CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Iodomethane (0.89 mL, 14 mmol) was added to a suspension of tert-butyl 3-(7-bromo-2-thioxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (4 g, 9 mmol) in deionized water (25 mL), ethanol (25 mL), and ammonium hydroxide (5 mL), and the reaction was stirred for two hours at room temperature and then diluted with chloroform and water. The aqueous layer was separated and extracted four times with chloroform. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was dried under high vacuum to provide 2.7 g of tert-butyl 3-(7-bromo-2-(methylthio)-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate.
Reaction SMILES: O1CCCC1.C[Si](C)(C(C)(C)C)[O:8][CH2:9][C@@H:10]1[C@@H:18]2[C@@H:13]([S:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:16][CH2:17]2)[CH2:12][C@H:11]1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C(OCC)(=O)C>[OH:8][CH2:9][C@@H:10]1[C@@H:18]2[C@@H:13]([S:14][C@@H:15]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:16][CH2:17]2)[CH2:12][C@H:11]1[O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1
Reactant: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@@H]2S1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](CO)[C@H](OC3CCCCO3)C[C@@H]2S1
Reaction time: 3 h
Yield: 58 %

Procedure:
To a tetrahydrofuran (74 mL) solution of the compound 9 (7.3 g) was added a 1 M tetrabutylammonium fluoride/tetrahydrofuran solution (27 mL), and the mixture was stirred for 3 hours. The reaction liquid was diluted with ethyl acetate (380 mL), washed with water (740 mL) and a saturated saline (380 mL). Further the aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined, dried with anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). The resulting compound was purified again by silica gel column chromatography (dichloromethane:ethyl acetate=4:1→ethyl acetate) to obtain a titled compound (3.24 g) having the following physical property values.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:17]([O:19][C:20](=[O:25])[C@H:21]([CH2:23][SH:24])[NH2:22])[CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:24][CH2:23][CH:21]([C:20]([O:19][CH2:17][CH3:18])=[O:25])[N:22]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CSC(C2CCN(C(=O)OC(C)(C)C)CC2)=N1

Procedure:
4-formyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 eq, 13 mmol) was dissolved under inert conditions in 40 ml toluene. To this solution cystein ethylester hydrochloride (1.6 eq, 21 mmol) and triethylamine (1.6 eq, 21 mmol) were added. The mixture was refluxed for 14 h. The generated water was removed with a Dean & Stark trap.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)(=[O:3])[CH3:2].[CH2:15]([O:17][C:18](=[O:28])[CH:19]([N+:25]([O-:27])=[O:26])[CH:20](O)[CH2:21][O:22][CH3:23])[CH3:16]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:15]([O:17][C:18](=[O:28])[CH:19]([N+:25]([O-:27])=[O:26])[CH:20]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[CH2:5][O:4][C:1](=[O:3])[CH3:2])[NH:10][CH:9]=1)[CH2:21][O:22][CH3:23])[CH3:16]
Reactant: CCOC(=O)C(C(O)COC)[N+](=O)[O-]
Reactant: CC(=O)OCc1cccc2[nH]ccc12
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(COC)c1c[nH]c2cccc(COC(C)=O)c12)[N+](=O)[O-]

Procedure:
4-Acetoxymethylindole (189 g) is dissolved in a mixture of toluene (6 l) and acetic acid (0.7 l). To this solution is added 3-hydroxy-2-nitro-5-oxa-hexanoic acid ethyl ester (570 ml). The flask containing the mixture is evacuated by means of a water jet pump. Then balancing to normal pressure is brought about by argon. Evacuation and pressure balancing are repeated four times. Then the reaction mixture is refluxed for two hours in a water-free argon atmosphere. After concentrating to 2 l the solution is diluted with ethyl acetate and shaken out three times with a liter of 1N hydrochloric acid each. Then it is washed to neutrality with saturated hydrochloric acid solution. The solution, dried over sodium sulfate, is evaporated. The residue is chromatographed on silica gel with dicloromethane. 393 g of the title compound is obtained in oily form.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][CH2:6][CH2:5][NH:4]1.[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[F:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH:3]1[CH2:2][OH:1])=[O:13]
Reactant: OCC1COCCN1
Reactant: O=C(Cl)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1F)N1CCOCC1CO
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
To a solution of 3-(hydroxymethyl)morpholine (345 mg; 2.95 mmol) in dichloromethane (10 mL) was carefully added 2-fluorobenzoyl chloride (0.35 mL; 2.95 mmol) and triethylamine (0.62 mL; 4.42 mmol) and the reaction stirred for 0.5 h. The product was combined with 4 N NaOH (10 mL) to hydrolyse any ester and the organic layer extracted (dichloromethane, 3×). The combined organic layers were dried (Na2SO4) and the solvent evaporated to give an oil, which was purified by flash column chromatography on silica (gradient elution, dichloromethane-methanol 1:0 to 9:1) to give 4-(2-fluorobenzoyl)-3-(hydroxymethyl)morpholine (165 mg; 0.69 mmol), EIMS: m/z=240.2 (M+H)+. This product and caesium carbonate (0.544 g) were heated to 120° C. in dimethylformamide (10 ml) solution under nitrogen for 4 hours. The solvent was evaporated, and the residue taken up in water and extracted with dichloromethane (3×). The combined dichloromethane extracts were dried (Na2SO4) and the solvent evaporated to give a crude solid which was purified by flash column chromatography on silica, eluting with ether to give the title compound (77 mg). M.p. 105-107° C.; EIMS: m/z=220.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]2[C:7]3[C:12]([CH2:13][CH2:14][C:3]=12)=[CH:11][CH:10]=[CH:9][CH:8]=3.[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(Cl)Cl.CO>CN1CCCC1=O.C(Cl)(Cl)Cl.CCOC(C)=O>[OH:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[O:6][N:5]=[C:4]3[C:7]4[C:12]([CH2:13][CH2:14][C:3]=23)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:20][CH2:19]1
Reactant: OCCN1CCNCC1
Reactant: Clc1onc2c1CCc1ccccc1-2
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OCCN1CCN(c2onc3c2CCc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 3-chloro-4,5-dihydronaphth[1,2-c]isoxazole (3.0 g, 14.63 mmol), 1-(2-hydroxyethyl)-piperazine (17.95 ml, 146.3 mmol) and K2O3 (4.1 g, 29.3 mmol) in 18 ml of N-methlypyrrolidinone under N2 was lowered into an oil bath preheated to 150° C. The mixture was heated while stirring under N2 for 1 hour. At that time, TLC (CH2Cl2) showed no remaining starting material. The mixture was removed from the heating bath, allowed to cool to room temperature, and diluted with H2O. Upon the addition of heptane, a solid precipitated. The solid was collected, washed with heptane and H2O, and dried in vacuo (0.1 mm) at 85° C. overnight to provide pure product, mp of 137°-138° C., homogeneous by TLC [silica, 1:1 CH3OH:EtOAc, Rf=0.67]. The IR (CHCl3), NMR (CDCl3) and Mass Spectrum (M+ =299, EI, 70 eV) were consistent with the structure. The yield was 2.603 g (8.70 mmol, 59.47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.[I:17]I>C(O)C.C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:17][C:8]1[CH:7]=[C:6]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COC(=O)CC(C)(C)c1ccc(OC)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CC(C)(C)c1ccc(OC)c(I)c1
Temperature: 25 °C

Procedure:
Methyl 3-(4-methoxyphenyl)-3-methylbutanoate (475 mg, 2.137 mmol) was dissolved in ethanol (20 mL). Iodine (542 mg, 2.137 mmol) and silver sulfate (666 mg, 2.137 mmol) were added and the reaction was stirred vigorously at room temperature, protected from light, for 1 hr. The reaction was then diluted with ethyl acetate (40 mL) and filtered. The filtrate was washed with sodium bisulfite (2×50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 0 to 50% ethyl acetate/hexanes to afford methyl 3-(3-iodo-4-methoxyphenyl)-3-methylbutanoate. 1H NMR (CDCl3, 500 MHz) δ 7.73 (d, J=2.5 Hz, 1H), 7.29 (dd, J=8.6, 2.5 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 3.86 (s, 3H), 3.55 (s, 3H), 2.57 (s, 2H), 1.41 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][N:14]2[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=O)=[CH:4][CH:3]=1.O1CCOCC1.C([O-])(=O)C.[NH4+:44]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:44][C:11]([C@@H:13]3[CH2:21][C:16]4([O:17][CH2:18][CH2:19][O:20]4)[CH2:15][N:14]3[C:22](=[O:32])[C@@H:23]([NH:27][C:28](=[O:31])[O:29][CH3:30])[CH:24]([CH3:26])[CH3:25])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1)OCCO2)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Temperature: 110 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
In a 5 mL seal tube, methyl (S)-1-((S)-8-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (75 mg, 142 μmol) was combined with 1,4-dioxane (2 ml) to give a light yellow solution. Ammonium acetate (110 mg, 1.42 mmol) was added and it was stirred at 110° C. overnight. It was cooled and diluted with EtOAc(10 ml), filtered and concentrated in vacuo to afford methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a light brownish solid (70 mg, 96.8%). ESI-LRMS m/e calcd for C22H27BrN4O5 [M+] 507. found 508 [M+H+].
Reaction SMILES: O[CH2:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[C:3]1([CH:2]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=3[CH2:5][N:6]3[C:7](=[O:16])[C:8]4=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]4[C:10]3=[O:11])[CH2:26][CH2:27]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:4]=1
Reactant: CCN(CC)CC
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1CO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1CN1CCC(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.704 g (10.117 mM) of N-[2-(hydroxymethyl)benzyl]phthalimide and 1.69 ml (12.1 mM) of triethylamine in 50 ml of tetrahydrofuran was added 0.86 ml (11.1 mM) of methanesulfonyl chloride dropwise with ice-cooling and the mixture was stirred at 0° C. for 0.5 hour. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of N,N-dimethylformamide, followed by addition of 1.79 g (11.1 mM) of 4-phenylpiperidine and 2.80 g (20.2 mM) of potassium carbonate, and the mixture was stirred at 100° C. overnight. This reaction mixture was poured in water and extracted with 2 portions of ethyl acetate. The organic layers were combined and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.O1CCOCCOCCOCCOCC1.[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[C:46]([F:49])[C:47]=1F)[C:43]#[N:44].[H-].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:39][C:40]1[CH:41]=[C:42]([CH:45]=[C:46]([F:49])[C:47]=1[N:11]1[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=2[C:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:17]=2)=[N:10]1)[C:43]#[N:44]
Reactant: COc1nccc2[nH]nc(-c3ccc(N4CCOCC4)cc3)c12
Reactant: N#Cc1cc(F)c(F)c(F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cc(C#N)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 4-methoxy-3-(4-(morpholin-4-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (250 mg), 1,4,7,10,13-pentaoxacyclopentadecane (266 mg) and 3,4,5-trifluorobenzonitrile (152 mg) in DMF (5 ml) was added sodium hydride (60%, 48.03 mg) at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with, saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (250 mg).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([NH:19]C(=O)OC(C)(C)C)=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:3]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[NH2:19][C:11]1[CH:10]=[CH:9][C:8]([CH:4]2[CH2:3][CH:2]([OH:1])[CH:6]([OH:7])[CH2:5]2)=[C:16]2[C:12]=1[C:13](=[O:18])[N:14]([CH3:17])[CH2:15]2
Reactant: CN1Cc2c(C3CC(O)C(O)C3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(C3CC(O)C(O)C3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [7-(3,4-dihydroxycyclopentyl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 243B, 36 mg, 0.099 mmol) in DCM (2 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 30 min, then evaporated under reduced pressure to give the desired product. This TFA salt was directly used in next step. MS (ES+): m/z=263.09 [MH+]. HPLC: tR=0.78 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH3:15]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CO.C(Cl)Cl>[CH3:15][O:13][C:12](=[O:14])[CH2:11][O:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)COCCc1cccc(F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)COCCc1cccc(F)c1
Yield: 92.6 %

Procedure:
A solution of [2-(3-fluoro-phenyl)-ethoxy]-acetic acid (1.20 g, 6.05 mmol), EDCl (1.28 g, 6.66 mmol), HOBt (0.90 g, 6.66 mmol) and DIPEA (1.56 ml, 9.08 mmol) in methanol (4 ml) was stirred at 0° C. for 2 hours. The reaction mixture was brought to dryness, the residue was dissolved in CH2Cl2 and was washed twice with 1M NaOH and brine. The organic layers were dried over MgSO4, filtered, the solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc/heptane, 1:4) to yield the title compound (1.20 g, 5.6 mmol; 93%) as colorless liquid. MS: m/e=213.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[Cl:19][C:18]1[C:13]([CH3:12])=[C:14]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:22])=[O:21])[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc2cccnc12
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 64.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.7 mmol), 2-methyl-3-chlorobenzenesulfonyl chloride (180 mg, 0.8 mmol) and DMAP (cat.) gave the title compound (150 mg, 65%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [ClH:1].C1([C:8]2[CH:23]=[CH:22][C:11]([NH:12][N:13]=NNC3C=CC=CC=3)=[CH:10][CH:9]=2)C=CC=CC=1.C(O)C.[NH4+].[OH-].Cl.[NH:30]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]3[N:49]=[CH:48][NH:47][C:45]3=2)[N:40]=[C:39]([CH3:50])[CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO>[ClH:1].[C:11]1([N:12]=[N:13][C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[C:44]5[N:49]=[CH:48][NH:47][C:45]5=4)[N:40]=[C:39]([CH3:50])[CH:38]=3)=[CH:32][CH:33]=2)[CH:22]=[CH:23][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(NN=NNc2ccc(-c3ccccc3)cc2)cc1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Cc1cc(Nc2ccc(N=Nc3ccccc3)cc2)c2c(ccc3nc[nH]c32)n1

Procedure:
A solution of 11.7 g. (0.05 m.) of p-phenylazoaniline hydrochloride in 500 ml. of ethanol was adjusted to pH 7.0 with 28% NH4OH. After the addition of 11 g. (0.05 m.) of the compound of Example I, C., the mixture was refluxed overnight. It was chilled, filtered, washed with ether and airdried to give 22 g. The crude product was recrystalled from MeOH to yield 17 g.
Reaction SMILES: ClC1C2C=CN(C)C=2N=CN=1.[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:31]3CCCC3)[C:15]=2[N:16]=[CH:17][N:18]=1>>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH3:31])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Agent: Cn1ccc2c(Cl)ncnc21
Product: Cn1cc(C(=O)c2cccc(N)c2)c2c(N)ncnc21

Procedure:
The title compound was prepared from 4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin by procedures analogous to those described for the preparation of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone. MS: 268.1 (MH+); HPLC Rf: 3.17 min. (HPLC method 4); HPLC purity: 92%.
Reaction SMILES: P(O[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)(OCC)(OCC)=O.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:13]1[CH:12]=[C:11](/[CH:10]=[CH:28]/[CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=1
Reactant: O=CCc1ccccc1
Reactant: CCOP(=O)(OCC)OCc1cc(OC)cc(OC)c1
Product: COc1cc(/C=C/Cc2ccccc2)cc(OC)c1
Yield: 78 %

Procedure:
Use diethyl 3,5-dimethoxybenzyl phosphate and phenylacetaldehyde as materials, and follow the method described in Example 5 to obtain a pale yellow solid as the target product (78%). 1H NMR (400 MHz, DMSO-d6): 3.22 (d, J=7.6 Hz, 2H), 3.79 (s, 6H), 6.25 (s, 1H), 6.34 (d, J=16.0 Hz, 1H), 6.66 (m, 1H), 6.72 (s, 2H), 7.16 (m, 3H), 7.27 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([C:4]1[C:9]2[CH2:10][C@@H:11]3[C:21]([C:22](=[O:23])[C:8]=2[C:7]([OH:33])=[CH:6][CH:5]=1)=[C:20]([OH:24])[C@@:19]1([OH:25])[C@H:13]([C@H:14]([N:30]([CH3:32])[CH3:31])[C:15]([OH:29])=[C:16]([C:26]([NH2:28])=[O:27])[C:17]1=[O:18])[CH2:12]3)[CH3:3].[Cl-:34].[Cl-].[Ca+2].C[C@@H]1[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@@]2(O)O[C@H]([C@H](C(O)=O)[C@@H](O)C2)C[C@@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C=CC=CC=CC=CC=CC=CC=C1.[OH-].[Na+]>[Mg+2].[Cl-].[Cl-]>[CH3:3][N:2]([C:4]1[C:9]2[CH2:10][C@@H:11]3[C:21]([C:22](=[O:23])[C:8]=2[C:7]([OH:33])=[CH:6][CH:5]=1)=[C:20]([OH:24])[C@@:19]1([OH:25])[C@H:13]([C@H:14]([N:30]([CH3:32])[CH3:31])[C:15]([OH:29])=[C:16]([C:26]([NH2:28])=[O:27])[C:17]1=[O:18])[CH2:12]3)[CH3:1].[ClH:34]
Reactant: [Cl-]
Agent: CN(C)c1ccc(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Agent: C[C@@H]1[C@H](O)[C@@H](C)/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Agent: C[C@@H]1[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](N)[C@@H]2O)C[C@@H]2O[C@](O)(C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@H]1C)C[C@H](O)[C@H]2C(=O)O
Product: Cl
Reaction time: 0.06 h

Procedure:
In vitro hemolysis of rabbit red blood cells (RBCs) after exposure to minocycline formulated in MgCl2 or CaCl2 was compared to in vitro hemolysis of RBCs after exposure to minocycline in saline, or exposure to amphotericin B. Minocycline HCl (LKT laboratories) stock solutions were prepared with MgCl2 in saline, saline, or lactated ringer, and the pH was adjusted with NaOH. Rabbit and sheep red blood cells (RBCs) were obtained from Innovative Research laboratory (Michigan, USA). Immediately before use, RBCs were washed three times in 0.9% saline and adjusted to a density of 5% in saline. 200 μl RBCs was added to 800 μl minocycline solution, and mixed by gentle inversion for 2-5 seconds. Samples were incubated at 37° C. or 30 minutes or at 25° C. for 2-5 minutes. Incubated samples were centrifuged at 12000×g for 4 minutes and the supernatants were removed and the hemoglobin absorbance was read at 540 nm. Samples were tested in triplicate. Amphotericin B (MP Biomedicals) and distilled H2O, or Triton-x and distilled H2O were used as positive controls; saline was used as a negative control. Percent hemolysis was calculated according to the following formula: