Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:6]=[N:5][NH:4]1)[CH3:2].[C:18]1([C:24]2[O:28][N:27]=[CH:26][C:25]=2[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:1]([N:3]1[CH:7]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:15][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][C:25]3[CH:26]=[N:27][O:28][C:24]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH:6]=[N:5][NH:4]1)[CH3:2]
Reactant: CCN1NN=CC1CCOc1ccc(N)cc1
Reactant: O=C(O)CCCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCN1NN=CC1CCOc1ccc(NC(=O)CCCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of 4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]aniline (0.51 g), 4-(5-phenyl-4-isoxazolyl)butanoic acid (0.51 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.40 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.50 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[4-[2-(3-ethyl-4H-triazol-4-yl)ethoxy]phenyl]-4-(5-phenyl-4-isoxazolyl)butaneamide (0.83 g, yield 84%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 125–126° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12.[CH3:19][CH:20]([NH2:22])[CH3:21].I[Si](C)(C)C>C1COCC1.CCOC(C)=O.C1S(=O)(=O)CCC1>[CH:20]([NH:22][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12)([CH3:21])[CH3:19]
Reactant: COc1ccc(-n2ncc3c(Cl)ncnc32)cc1
Reactant: CC(C)N
Agent: C[Si](C)(C)I
Solvent: O=S1(=O)CCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Nc1ncnc2c1cnn2-c1ccc(O)cc1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To a mixture of compound 44C (388 mg, 1.48 mmol) and propan-2-amine (0.14 mL, 1.63 mmol) in THF (10 mL) was added TEA (0.456 mL, 3.27 mmol). The resulting mixture was stirred at 30° C. overnight and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and dried. To the crude material was added iodotrimethylsilane (1.0 mL, 7.06 mmol) in tetramethylene sulfone (5 mL). The reaction mixture was heated at 80° C. overnight. The reaction was slowly poured into ice-water (5 mL). The precipitate was collected, washed with water, and purified by reverse phase HPLC (mobile phase: 0%-50% acetonitrile in 0.1% TFA aqueous solution during 40 minutes) to provide the title compound: 1H NMR (400 MHz, DMSO-D6) δ ppm 9.68 (1H, s, br), 8.55 (1H, s, br), 8.39 (1H, s), 8.35 (1H, s), 7.82 (2H, d), 6.88-6.94 (2H, m), 4.34-4.46 (1H, m), 1.28 (6H, d)
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[C:9]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:10]([C:15]([N:17]2[CH2:20][C:19](=O)[CH2:18]2)=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([C:15]([N:17]2[CH2:20][C:19](=[CH2:1])[CH2:18]2)=[O:16])[C:9]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30]
Reactant: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 15 h
Yield: 21.2 %

Procedure:
Methyl triphenylphosphonium bromide (508 mg, 1.42 mmol) was treated with potassium tert-butoxide (159 mg, 1.42 mmol) in tetrahydrofuran (5 mL) at 0° C. for 10 minutes. 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (270 mg, 0.605 mmol), prepared using procedures similar to those described in Example 6, was dissolved in tetrahydrofuran (2 mL) and was added to the mixture. The mixture was stirred at ambient for 15 h and then the mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ethyl acetate in hexanes) gave 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-methylideneazetidin-1-yl)carbonyl]aniline (57 mg, 0.128 mmol, 21% yield): 1H NMR (400 MHz, CDCl3): 8.56 (br s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7.18-7.12 (m, 1H), 6.86-6.76 (m, 1H), 6.62 (ddd, 1H), 5.14-5.00 (br, 2H), 4.74 (br d, 4H); MS (EI) for C17H2F3IN2O: 445 (MH+).
Reaction SMILES: Cl.[CH2:2]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][NH:14][CH2:13]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH:19]([C:21]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCN(CC)CC.CC(O)=O>ClCCCl>[CH3:27][C:24]1([CH3:28])[O:23][CH2:22][C:21]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([CH2:19][N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[C:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:11]=3)[CH2:15]2)[CH2:26][O:25]1
Reactant: CCCCCCCCc1ccc2c(c1)CNC2
Reactant: CC(C)(C)OC(=O)NC1(C=O)COC(C)(C)OC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc2c(c1)CN(CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1)C2
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of the product of Step E (0.03 g; 0.112 mmol), tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (0.037 g; 0.115 mmol) and NaBH(OAc)3 (0.035 g; 0.17 mmol) in 1,2 dichloroethane (3 ml), Et3N (0.016 ml; 0.112 mmol) was added at room temperature, followed by AcOH (0.064 ml; 0.112 mmol). The resulting mixture was stirred overnight under N2. After dilution to 10 ml with Et2O, the mixture was washed with 1.M NaOH (2×2 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was purified by FCC (SiO2; hexane/EtOAc 8:2) to give pure title compound (0.05 g; 92%) as colourless solid. 1H-NMR (CDCl3) 0.86 (tr, 3H, J=7 Hz); 1.25 (m, 10H); 1.41 (s, 3H); 1.44 (s, 9H); 1.47 (s, 3H); 1.57 (m, 2H); 2.56 (tr, 2H, J=7.92 Hz); 3.18 (s, 2H): 3.79 (d, 2H, J=11.7 Hz); 4.05 (s, 4H); 4.14 (d, 2H, J=11.7 Hz); 5.03 (s, 1H); 6.98 (s, 1H); 6.99 (d, 1H, J=8.14 Hz); 7.06 (d, 1H, J=8.14 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][NH2:11].[N:12]([O-])=O.[Na+]>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:5][N:12]=[N:11][N:10]=1
Reactant: NN
Reactant: N#Cc1ccccc1Cl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccccc1-c1nnn[nH]1
Reaction time: 5 h

Procedure:
First, 71.2 mmol of 2-chlorobenzonitrile was dissolved in 50 ml of methanol, and 356 mmol of hydrazine and 35.6 mmol of 28% methylate were added thereto, followed by keeping at the reflux temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in 50 ml of 50% hydrochloric acid, and 74.8 mmol of sodium nitrite was added thereto at 0° C. to cause reaction. The reaction mixture was extracted with ethyl acetate to give 5-(2-chlorophenyl)tetrazole. Yield, 70%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][N:25]([CH3:31])[C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:24][N:25]([CH3:31])[C@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:27]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: CN(C)[C@H]1CCNC1
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CN(C)[C@H]1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and (S)-N,N-dimethylpyrrolidin-3-amine (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 10-35% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (60 mg, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H) 2.20-2.37 (m, 1 H) 2.61-2.71 (m, 1 H) 2.90 (d, J=3.79 Hz, 6 H) 3.79-3.91 (m, 1 H) 4.02-4.19 (m, 2 H) 4.35 (d, J=6.57 Hz, 2 H) 6.26 (d, J=2.27 Hz, 1 H) 7.15 (s, 1 H) 7.60 (d, J=8.59 Hz, 2 H) 7.99 (d, J=8.59 Hz, 2 H) 8.04 (d, J=2.02 Hz, 1 H) 9.87 (br. s., 1 H) 10.77 (s, 1 H). ESI-MS: m/z 409.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]([O:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[O:35]=[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]([O:25][CH2:26][CH2:27][O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1)[C:3]([OH:36])=[O:2]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCCOc2ccccc2)cc1
Yield: 92.7 %

Procedure:
A mixture of alpha-oxo-4-[[2-[3-(2-phenoxyethoxy)-2-naphthalenyloxy]ethyl]oxy]benzeneacetic acid methyl ester (0.50 g) in hot methanol (10 mL) plus enough tetrahydrofuran to dissolve the solids, was treated with 1N sodium hydroxide (2 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from acetone-hexane provided 0.45 g of alpha-oxo-4-[[2-[3-(2-phenoxyethoxy)-2-naphthalenyloxy]ethyl]oxy]benzeneacetic acid as a colorless solid, mp 176°-177° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.I[C:10]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[F:19][C:17]1[CH:18]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[C:15]([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=1
Reactant: O=C(O)c1ccc(F)cc1I
Reactant: Fc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc(F)cc1Sc1ccc(F)cc1
Temperature: 0 °C

Procedure:
To a solution of 3.28 g. (0.0256 mol) of p-fluorothiophenol and 6.8 g. (0.0256 mol) of 2-iodo-4-fluorobenzoic acid in 40 ml. of pyridine is added 3.54 g. (0.0256 mol) of potassium carbonate at room temperature with stirring. Additional pyridine is added to dissolve the precipitate and then 1.54 g. of cuprous chloride is added. The mixture is refluxed overnight, cooled, poured into ice-water, stirred and filtered. The aqueous solution is acidified, filtered and the solid dissolved in 5% sodium bicarbonate solution, then extracted with ether. The aqueous solution is acidified, extracted with ether, and the dried extract is concentrated to give 4-fluoro-2-(4-fluorophenylthio)benzoic acid, m.p. 209°-218° C. The latter (3.0 g., 0.0113 mol) is cyclized by heating for one hour with 45 g. of concentrated sulfuric acid to obtain 2,6-difluorothioxanthone, m.p. 205°-210° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].C(N(CC)CC)C.[CH3:19][CH2:20][O:21]CC.C(Cl)(=O)C>O>[C:20]([O:11][C:3]1[C:2]([CH3:1])=[CH:8][C:6]([OH:7])=[C:5]([CH3:9])[C:4]=1[CH3:10])(=[O:21])[CH3:19]
Reactant: CCOCC
Reactant: Cc1cc(O)c(C)c(C)c1O
Solvent: O
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C)cc(O)c(C)c1C
Temperature: 25 °C

Procedure:
Stir a mixture of trimethylhydroquinone (15.2 g, 0.1 mol), triethylamine (25.3 g, 0.25 mol) and ether (500 mL) in an ice bath. Slowly add acetylchloride (19.6 g, 0.25 mol) with stirring, allow the reaction to warm to room temperature for an hour, then dilute with water and the separate the layers. Evaporate the ether layer to dryness. Dissolve the resulting diacetate in methanol (300 mL). Add strong ammonium hydroxide (11 mL) and stir the mixture at room temperature overnight. Distill off the solvents under reduced pressure and dissolve the residue in ether. Wash the ether layer with water and evaporate to dryness. Recrystallization from hexane-ether yields 4-acetoxy-2,3,5-trimethylphenol (16.7 g, m.p.=106-107° C.).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1[CH:28]=O.O>O1CCCC1>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cn1cc2c(C=O)c(Cl)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(Cl)ccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
To a suspension of sodium hydride (0.488 g, 12.2 mmol) in tetrahydrofuran (10 mL) was added a solution of ethyl diethylphosphonoacetate (2.44 mL, 12.2 mmol) in tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 5-chloro-2-methyl-2H-indazole-4-carbaldehyde (2.16 g, 11.1 mmol) in tetrahydrofuran (10.0 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (2.54 g, yield 86%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[OH:25])([CH3:14])([CH3:13])[CH3:12].C=O.[CH2:28](NCCCC)CCC>>[C:11]([C:15]1[C:16]([OH:25])=[C:17]([CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)[CH2:28][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[S:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: Sc1nc2ccccc2s1
Reactant: CCCCNCCCC
Agent: C=O
Product: CC(C)(C)c1cc(Cn2c(=S)sc3ccccc32)c(O)c(C(C)(C)C)c1

Procedure:
3-(3,5-di-tert.butyl-2-hydroxybenzyl)-benzothiazole-2-thione (compound 31) is prepared by heating 0.2 mol 2-mercaptobenzothiazole, 0.2 mol of 2,4-di-tert.butylphenol and 0.2 mol of paraformaldehyd in the presence of 1 ml of dibutylamine at 150° for 4 hours and crystallising the product from ethanol.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[O:2].[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>CN(C)C1C=CN=CC=1.C(#N)C.CCOC(C)=O>[C:12]([O:16][C:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1ccc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
5-Formylindole (1.45 g, 10.0 mmol) and 4-dimethylaminopyridine (1.47 g, 12.0 mmol) were dissolved in acetonitrile (20 mL) with stirring at ambient temperature. Once dissolution was complete, the reaction mixture was cooled to −10° C. with stirring. Di-t-butylcarbonate (2.18 g, 10.0 mmol) was added in one portion. Stirring was continued for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and the organic solution was washed successively with water (20 mL), a 1N HCl solution (10 mL), a saturated NaHCO3 solution (20 mL) and brine (20 mL). The organic solution was dried over MgSO4 and filtered. Solvent was removed in vacuo from the filtrate to provide a pale yellow oil (2.45 g, 100% yield): 1H NMR (CDCl3, 300 MHz): 10.1 (s, 1H), 8.31 (d, 1H, J=8), 8.12 (s, 1H), 7.87 (dd, 1H, J=8, 1), 7.70 (d, 1H, J=4), 6.71 (d, 1H, J=4), 1.71 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:52]([CH:55]2[CH2:57][CH2:56]2)(=[O:54])=[O:53])=[C:6]([CH2:8][N:9]([CH3:51])[C:10]([CH:12]([NH:25][C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[C:32]([N:36]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:31][CH:30]=[CH:29]3)[C:13]2[CH:18]=[CH:17][C:16]([C@H:19]([CH2:22][OH:23])[CH2:20][F:21])=[C:15]([CH3:24])[CH:14]=2)=[O:11])[CH:7]=1.[C:58](Cl)(Cl)=[O:59]>C(#N)C.ClCCl>[C:39]([O:38][C:37]([N:36]([C:32]1[C:33]2[C:28](=[CH:27][C:26]([NH:25][C@H:12]3[C:10](=[O:11])[N:9]([CH3:51])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:52]([CH:55]4[CH2:56][CH2:57]4)(=[O:53])=[O:54])[NH:1][C:58](=[O:59])[O:23][CH2:22][C@H:19]([CH2:20][F:21])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:24])=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1)[C:44](=[O:45])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@H](CO)CF
Reactant: O=C(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](CF)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
To a solution of 24E (0.1 g, 0.124 mmol) in acetonitrile (5 mL) and dichloromethane (2.5 mL) at 0° C., was added phosgene solution (20% in toluene, 0.072 mL, 0.136 mmol) dropwise. The mixture was stirred at 0° C. for 30 min. Extra phosgene was removed by bubbling Ar for 20 min. The crude was then added dropwise via syringe pump into a solution of TEA (0.138 mL, 0.993 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The solution was stirred at rt over night. Solvent was removed, and the crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give a mixture of diastereoisomers (0.1 g, 0.120 mmol, 97% yield). The diastereomers were separated by a prep chiral HPLC (R,R-Whelk-O column 21.1×250 mm) to give 24F (38 mg, 76% yield). MS (ESI) (m/z): 831.9 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:13])[CH2:7][NH:8][C:9](=[O:12])[CH2:10][NH2:11])(C)(C)C.C[CH2:15][C:16]([S:19]SC(O)=O)(C)C.C(O)(C(F)(F)F)=[O:25]>>[SH:19][CH2:16][C:15]([NH:11][CH2:10][C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:13])=[O:12])=[O:25]
Reactant: CCC(C)(C)SSC(=O)O
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CNC(=O)CN
Product: O=C(O)CNC(=O)CNC(=O)CS
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
26.32 g (75.09 mmol) Carboxy methyl-t-butyl disulfide glycyl glycine t-butyl ester were dissolved in 233 ml TFA under N2-atmosphere. The resulting solution was stirred for 20 min at room temperature. TFA was evaporated under reduced pressure (5-10×10−2 mbar) and the resulting oil was dried under stirring for additional 2 h (5-10×10−2 mbar). After addition of 250 ml Et2O a white powder precipitated and the suspension was stirred for 3 h. The material was filtered off and resuspended in 100 ml Et2O. The resulting suspension was stirred over night, the product was filtered off and the material was dried at room temperature under reduced pressure yielding 20.46 g (92.5%) as a white powder.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:37][CH2:38][CH3:39].O>CN(C)C=O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[N:15]([CH2:37][CH2:38][CH3:39])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCCI
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccc(OC(C)C)cc2)c1C
Reaction time: 8 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (50 mg) and cesium carbonate (0.20 g) in N,N-dimethylformamide (1 mL) was added iodopropane (0.036 mL) at 50° C., and the mixture was stirred overnight. Water was added to the reaction mixture, and the resulting mixture was purified by solid phase extraction on ODS (washing solvent:distilled water, eluent:methanol). The resulting semi-purified material was purified by column chromatography on silica gel (eluent:dichloromethane/methanol=8/1) to give 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1-propylpyrazole (28 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][OH:6].I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:8]([N:2]([CH2:3][CH2:4][CH2:5][OH:6])[CH3:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CNCCCO
Reactant: CCCCCCCCCCCCI
Product: CCCCCCCCCCCCN(C)CCCO
Yield: 96 %

Procedure:
A solution of 3-(methylamino)propanol (5.71 g, 64.0 mmol, S. Koepke, R. Kupper, and C. J. Michejda, J. Org. Chem., 44, 2718,1979)), and iodododecane (7.58 g, 25.6 mmol) was reacted as described in example 1 to give 6.33 g (96%) of the title material as an oil, b.p. 100-105° C./0.04 torr.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)Cl.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:10][C:4]=2[CH:3]=1
Reactant: C1CNCCN1
Reactant: O=C1Nc2cc(Cl)ccc2Sc2ccccc21
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Clc1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1S2
Temperature: 100 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
To a mixture of 8-chloro-10H-dibenzo[b,f][1,4]thiazepin-11-one (189JO13) (38 mg, 0.15 mmol) and N,N-dimethylaniline (46 μL, 0.36 mmol) in toluene was added POCl3 (27 μL, 0.29 mmol) and the resulting mixture was stirred for 2 h at 100° C., and then concentrated. Toluene (2 mL) and piperazine (62 mg, 0.73 mmol) were added, and the resulting mixture was stirred at 100° C. for 3 h, and then allowed to obtain room temperature. To the mixture was added aqueous HCl (1 mL, 2 M) and then the aqueous phase was extracted with EtOAc (2×2 mL). To the aqueous phase was added aqueous NaOH (3 mL, 2 M) and the resulting mixture was extracted with EtOAc (3×3 mL). The combined organic phases were concentrated and purified by HPLC to give 6.6 mg of the title compound (189JO16). MS (ESI) 330 (MH+). Purity for MH+ (UV/MS) 99/98.