Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[O:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:26])([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CN=N1.[C:32](Cl)(Cl)=[O:33]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[N:1]1([C:32]([O:25][C:19]([CH3:26])([C:16]2[CH:17]=[CH:18][C:13]([O:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:14][CH:15]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:33])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C(C)(O)c1ccc(Oc2ccccc2)cc1
Reactant: c1nc[nH]n1
Agent: c1c[nH]nn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(OC(=O)n1cncn1)c1ccc(Oc2ccccc2)cc1
Temperature: 103 °C
Yield: 102.9 %

Procedure:
A mixture of 6.9 g of 1,2,4-triazole, 100 mL of toluene, 14.3 g of ethyl 2-(4phenoxyphenyl)lactate, and 20 g of triethylamine was heated to 103° C. to dissolve the triazole and then cooled to -60° C. Phosgene (6.4 g) was added at 57°-60° C. over 2.5 h. After holding the reaction mixture at 59°-60° C. for 1.25 h, the reaction mixture was cooled to -5° C. Ice (100 g) was added, and the temperature dropped to -8° C. The aqueous layer was separated and extracted one time with 15 mL of toluene. The organic layers were combined and washed with cold water (2 times with 25 mL), dried (MgSO4), filtered, and evaporated in vacuo to yield 19.6 g of the title compound as a viscous oil. 1H NMR (300 MHz, CDCl3): δ8.85 (s, 1H), 8.08 (s,1H), 7.59-7.00 (m, 11H), 4.25 (m,2H), 2.18 (s,3H), 1.23 (t,3H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]Br>ClCCl>[Br:15][C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9][C:10]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1cc(-c2ccccc2)n[nH]1
Reactant: BrBr
Solvent: ClCCl
Product: CCCc1[nH]nc(-c2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 3-phenyl-5-propyl-1H-pyrazole (3.83 g, 20.56 mmol) in dichloromethane (118.0 mL) was added bromine (1.05 mL, 20.56 mmol) at 25° C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then quenched with 2 M Na2CO3 (aq.) to pH 12 and the organics were separated. The aqueous layer was extracted with DCM (thrice). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a red oil. This oil was purified by silica gel flash chromatography to give the title compound as a yellow oil (3.44 g). LCMS m/z=265.1, 267.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.33 Hz, 3H), 1.63-1.74 (m, 2H), 2.57 (t, J=7.58 Hz, 2H), 7.37-7.48 (m, 3H), 7.77-7.82 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[Cl:18]N1C(=O)CCC1=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:6]([Cl:18])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc2c1c(Cl)cn2C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 ml round bottom flask was added methyl 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylate (1.100 g, 3.71 mmol) as a solution in THF and a magnetic stir bar. To the same was added 1-chloro-2,5-pyrrolidinedione (0.546 g, 4.09 mmol) and the system stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue dissolved in EtOAc (60 ml) and washed with saturated NaHCO3 (20 ml) and brine (8 ml). The organic layer was dried over Na2SO4, filtered and concentrated. Purification of the residue by column chromatography provided methyl 6-bromo-3-chloro-1-isopropyl-1H-indole-4-carboxylate (as a thick gold oil), which was used in the next step. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J=1.52 Hz, 1H), 7.93 (s, 1H), 7.50 (d, J=1.77 Hz, 1H), 4.90 (quin, J=6.63 Hz, 1H), 3.89 (s, 3H), 1.43 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 332.2.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([O:10]C2OC(CO)C(O)C(O)C2O)[CH:2]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH:5]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=[C:3]([OH:10])[CH:4]=1
Reactant: O=[N+]([O-])c1ccc(OC2OC(CO)C(O)C(O)C2O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
A definite amount of a sample, whose β-glycosidase activity is desired to be measured, is sufficiently homogenized at a pH of 6.5 to 7.0 with an appropriate amount of water (which amount is usually 5 to 15 times the weight of the sample in a dry state). The resulting mixture is adjusted to a pH of 5.0, and then centrifuged to obtain a supernatant, which is a crude enzyme solution. To 0.5 ml. of the crude enzyme solution is added 2.0 ml. (0.005 mole) of p-nitrophenyl-βD-glucopyranoside, and the resulting mixture is subjected to incubation at 30° C. for a definite period of time (e.g. 10 to 30 minutes), and then charged with 2.5 ml. (0.5 mole) of Na2CO3 to terminate enzyme reaction. The reaction liquid is measured in absorbance (O.D.) at 420 mμ, and, from this O.D. value is substracted the absorbance (O.D.) of a blank (a liquid prepared by adding 2.5 ml. (0.5 mole) of Na2CO 3 and the same substrate as above to 0.5 ml. of the above-mentioned enzyme solution, and then subjecting the resulting mixture to the same incubation as above) to obtain a ΔO.D. value. From this ΔO.D. value, the amount of p-nitrophenol formed by the enzyme reaction is calculated. In case the said ΔO.D. value is zero or substantially zero, the amount of formed p-nitrophenol is zero, and thus it is understood that β-glycosidase has been inactivated. This activity measurement is carried out according to the modified method of J. E. Citti et al. [Journal of Bacteriology, Vol. 89, page 937(1965)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:7]=1.[C:19]([O-])(=O)[CH3:20].[Na+]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH3:20])=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:8]2=[O:17]
Reactant: CC(=O)[O-]
Reactant: O=C(Cc1ccc(F)cc1)c1cc(Br)ccc1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1oc2ccc(Br)cc2c(=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
Intermediate 6 (6.1 g, 19.73 mmoles) was taken in a RB flask and to this acetic anhydride (40 ml) and sodium acetate (11.3 g, 137.75 mmoles) were added and the mixture was refluxed for 12 h. After cooling to RT, the reaction mixture was quenched by the addition of ice cold water. The solid formed was filtered and washed with water. The product was dried under vacuum to afford the title compound as white solid (4.1 g, 63% yield). 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 8.35(d, J=1.9Hz, 1H), 7.77(dd, J=8.8, 1.9Hz, 1H), 7.37(d, J=8.9Hz, 1H), 7.27(t, J=5.7Hz, 2H), 7.17(t, J=8.6Hz, 2H), 2.33(s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[N:19]=[C:18]([Cl:20])[CH:17]=[C:16](Cl)[N:15]=2)=[CH:9][CH:8]=1)=[O:5].[CH3:26][C:27]1[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=1.[I-].[Na+].C(N(CC)C(C)C)(C)C>O.CN(C)C=O>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([NH:32][C:29]3[NH:30][N:31]=[C:27]([CH3:26])[CH:28]=3)[N:15]=2)=[CH:9][CH:8]=1)=[O:5]
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)c1ccccc1Cl
Reactant: Cc1cc(N)[nH]n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)c4ccccc4Cl)cc3)n2)[nH]n1
Temperature: 90 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
A 250 mL round bottom flask was charged with 2-chloro-N-[4-(4,6-dichloro-pyrimidin-2-ylsulfanyl)-phenyl]-benzamide (12.5 g, 30.4 mmol), 5-methyl-2H-pyrazol-3-ylamine (3.55 g, 36.5 mmol), sodium iodide (4.56 g, 30.4 mmol), N,N-diisopropylethylamine (6.9 mL, 40.0 mmol) and N,N-dimethylformamide (125 mL) under nitrogen. The reaction mixture was stirred at 90° C. for 5 h, then allowed to cool to room temperature. Water (600 mL) was added and the resulting suspension stirred at room temperature for 2 h and the solid collected by filtration and dried. The resulting white solid was triturated with hot ethyl acetate (50 mL), filtered and washed with ethyl acetate (1×20 mL) to give the title compound as a white solid (11.76 g, 82%). 1H NMR (DMSO): 2.16 (3H, s), 5.30 (1H, s), 6.48 (1H, s), 7.49-7.62 (6H, m), 7.89 (2H, m), 10.28 (1H, s), 10.84 (1H, s), 11.93 (1H, s); MS (ES+): 471.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]([CH3:14])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[NH:4]N=1.Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+].[CH3:38]N(C=O)C>>[F:35][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:4]3[C:5]4[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=4[C:2]([CH3:38])=[CH:1]3)[S:21][CH:22]=2)[CH:30]=[CH:29][C:28]=1[C:31]([F:34])([F:33])[F:32]
Reactant: Cc1n[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: CN(C)C=O
Reactant: O=C(CBr)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(CC(=O)Nc2nc(-c3ccc(C(F)(F)F)c(F)c3)cs2)c2c(=O)n(C)c(=O)n(C)c12

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 3 (50 mg, 0.258 mmol) with 2-bromo-N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}acetamide (119 mg, 0.310 mmol) in the presence of NaH (15 mg, 0.375 mmol) in dry DMF (5.0 mL) to give 90 mg of the product as a white solid; 1H-NMR (δ ppm, DMSO-d6, 300 MHz) 2.29 (s, 3H), 3.16 (s, 3H), 3.59 (s, 3H), 5.26 (s, 2H), 7.12 (s, 1H), 7.82-8.00 (m, 4H), 12.71 (br s, 1H, exchangeable with D2O); APCI-MS (m/z) 494.30 (M−H)−.
Reaction SMILES: C([O:8][C:9](=[O:41])[CH2:10][CH:11]([N:24]1[CH:28]=[CH:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CCO>[C:32]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([N:26]2[CH:27]=[CH:28][N:24]([CH:11]([C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:41])=[O:8])[CH2:25]2)=[CH:34][CH:33]=1
Reactant: CNC(=O)[C@@H](NC(=O)C(CC(=O)OCc1ccccc1)N1C=CN(c2ccc(-c3ccccc3)cc2)C1)C(C)(C)C
Solvent: CCO
Product: CNC(=O)[C@@H](NC(=O)C(CC(=O)O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1)C(C)(C)C

Procedure:
According to the procedure described in in Example 1(a), a suspension of 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid benzyl ester in EtOH was hydrogenated to provide 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid as a solid, mp 187.0-8.2° C. FABMS: 463.2 (C26H31N4O4; M+H+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([N:13]2[CH2:17][CH2:16][S:15][CH2:14]2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5].I([O-])(=O)(=O)=[O:19].[Na+]>CO.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([N:13]2[CH2:17][CH2:16][S:15](=[O:19])[CH2:14]2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: N#Cc1c(F)cccc1S(=O)(=O)N1CCSC1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1c(F)cccc1S(=O)(=O)N1CCS(=O)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
54 mg of 2-Fluoro-6-(thiazolidine-3-sulfonyl)-benzonitrile in 10 ml of methanol and 1 ml of water are treated with 45 mg of sodium periodate, and the mixture is stirred for 14 hours at room temperature. The reaction mixture is poured into water, and the aqueous layer is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo. Purification by reverse phase HPLC affords 40 mg of 2-Fluoro-6-(1-oxo-1 lambda*4*-thiazolidine-3-sulfonyl)-benzonitrile.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[CH:8])(C)(=O)=O.[CH2:9]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:5]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:17][CH2:18]1)[CH2:6][C:7]#[CH:8]
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: C#CCCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC(Cc2ccccc2)CC1
Yield: 94.6 %

Procedure:
A mixture of 1-mesylbut-3-yne (3.03 g, 20.0 mmol), 4-benzylpiperidine (4.21 g, 24.0 mmol) and K2CO3 (8.28 g, 60.0 mmol) in 50 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×30 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as pale yellow oil (4.30 g, 95%): 1H NMR (CDCl3) 1.32 (m, 2 H), 1.51 (m, 1 H), 1.65 (m, 2 H), 1.94 (m, 3 H), 2.36 (m, 2 H), 2.54 (m, 4 H), 2.86 (d, J=11.4 Hz, 2 H), 7.12-7.27 (m, 5 H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.Cl.[CH3:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:21]>CN1C(=O)N(C)CC1.CCOC(C)=O.O>[F:8][C:7]1[CH:6]=[N:5][C:4]2[NH:9][CH:10]=[CH:11][C:3]=2[C:2]=1[N:14]([CH3:13])[C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:21]
Reactant: Fc1cnc2[nH]ccc2c1Cl
Reactant: CN[C@H]1CCCC[C@H]1C
Agent: Cl
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CCCC[C@@H]1N(C)c1c(F)cnc2[nH]ccc12
Temperature: 210 °C
Yield: 3.3 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (100 mg) and (1S,2R)—N,2-dimethylcyclohexanamine hydrochloride (288 mg) in DMI (1 mL) was heated in the microwave reactor (210° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and water (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (chloroform:methanol=10:1) gave 5-fluoro-N-methyl-N-[(1S,2R)-2-methylcyclohexyl]-1H-pyrrolo[2,3-b]pyridin-4-amine (5 mg) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.N#N>C(O)(C)C.C1(C)C=CC=CC=1.CCOCC>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(O)c1sccc1Br
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1cccc(-c2ccsc2C(=O)O)c1
Temperature: 80 °C
Yield: 69.2 %

Procedure:
3-Bromothiophene-2-carboxylic acid (600 mg; 2.9 mmol) was dissolved in isopropanol (7 ml)/toluene (7 ml), followed by the addition of K2CO3 solution (aq; 2M; 9 ml) and 3-methoxybenzeneboronic acid (440 mg; 2.9 mmol). The reaction mixture was deoxygenized with N2 (g) for 3 minutes followed by the addition of tetrakis-(triphenylphosine)-palladium and subsequently heated to 80° C. for 14 h. The mixture was cooled to rt, ether was added and the organic layer was extracted with 2M NaOH-solution. The aq. layer was acidified by the addition of 2M HCl. The product precipitated and was filtered off and dried at high vacuum to give 470 mg of 3-(3-methoxy-phenyl)-thiophene-2-carboxylic acid; LC-MS: tR=0.94 min; [M−H]+=235.27.
Reaction SMILES: C([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])C.[CH2:10](N(CC)CC)[CH3:11].[C:17](Cl)(=[O:19])[CH3:18]>>[CH2:10]([CH2:18][C:17]([NH:5][C:4]1[CH:3]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:19])[CH3:11]
Reactant: CCc1ccccc1N
Reactant: CC(=O)Cl
Reactant: CCN(CC)CC
Product: CCCC(=O)Nc1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 104.5 %

Procedure:
2-Ethylaniline (82.6 mmol, 10 gams) was taken in round bottom flask equipped with a liquid addition funnel and a guard tube. Triethylamine (165 mmol, 16.69 grams) was added to it in one lot. The mass, thus obtained, was cooled to 0-5° C. and added acetyl chloride (123 mmol, 9.73 grams) drop wise, while maintaining the mass temperature below 10° C. After addition of acetyl chloride, cooling was removed and reaction was stirred at 25-28° C. for a period of 3 hours. After completion of the reaction, the reaction mixture was poured onto 200 mL of ice water and aqueous layer was extracted with dichloromethane (2×100 mL). The combined dichloromethane extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 14.09 grams of compound.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:12][CH2:11][N:10]2[C:13](=[O:30])[C:14]3[C:19]4[CH2:20][CH2:21][C:22]([CH:28]=[O:29])=[C:23]([S:24][CH2:25][CH2:26][CH3:27])[C:18]=4[S:17][C:15]=3[N:16]=[C:9]2[CH2:8][CH2:7]1)=[O:5])C.O>C1COCC1.O[K].O.CO>[CH:28]([C:22]1[CH2:21][CH2:20][C:19]2[C:14]3[C:13](=[O:30])[N:10]4[CH2:11][CH2:12][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][C:9]4=[N:16][C:15]=3[S:17][C:18]=2[C:23]=1[S:24][CH2:25][CH2:26][CH3:27])=[O:29]
Reactant: CCCSC1=C(C=O)CCc2c1sc1nc3n(c(=O)c21)CCC(C(=O)OCC)CC3
Agent: O[K]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCSC1=C(C=O)CCc2c1sc1nc3n(c(=O)c21)CCC(C(=O)O)CC3

Procedure:
Compound 22 (130 mg) in THF (2 ml) and 0.7 ml 10% KOH H2O/MeOH (2:1) were stirred over night in room temperature. The reaction mixture was poured into water and washed with ether. The water phase was acidified with HCl and extracted with EtOAc. Organic phase was washed with brine and dried with Na2SO4. After filtration the solvent was evaporated and the product recrystallized from ethanol.
Reaction SMILES: [N+:1](=[CH:3][C:4](=[O:7])[CH2:5][CH3:6])=[N-:2].[CH2:8]([O:10][P:11]([C:16]([P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH2:17])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:9]>CCOCC>[CH2:20]([O:19][P:18]([C:16]1([P:11](=[O:15])([O:10][CH2:8][CH3:9])[O:12][CH2:13][CH3:14])[CH2:17][C:3]([C:4](=[O:7])[CH2:5][CH3:6])=[N:1][NH:2]1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCC(=O)C=[N+]=[N-]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)CC(C(=O)CC)=NN1
Reaction time: 8 h

Procedure:
1-Diazo-2-butanone (I, PREPARATION 4, 3.1 g) in ether (50 ml) is treated with ethenylidene bisphosphonic acid tetraethyl ester (II, PREPARATION 1, 9.5 g), stirred at 20°-25° overnight, and concentrated. The concentrate is crystallized twice from methylene chloride/SSB to give the title compound, mp 96°-98°; MS (m/e) 398, 261, 233 and 205; IR (mineral oil mull) 3210, 0664, 1265, 1245, 1046, 1024, 997 and 983 cm-1 ; NMR (CDCl3) 6.92, 4.14-4.33, 3.48, 2.82, 1.30-1.36 and 1.12 δ; CMR (CDCl3) 196, 149, 66, 64, 36, 31, 16 and 8 δ.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH2:3][CH:4]=[C:5]1[CH2:27][CH2:26][C:8]2([S:12][CH2:11][C:10](=[O:13])[N:9]2[CH2:14][CH2:15][C:16]([O:18]CC2C=CC=CC=2)=[O:17])[CH2:7][CH2:6]1.[OH-].[Na+].C(Cl)(Cl)Cl.O>O1CCOCC1>[CH3:1][CH:2]([CH3:28])[CH2:3][CH:4]=[C:5]1[CH2:27][CH2:26][C:8]2([S:12][CH2:11][C:10](=[O:13])[N:9]2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:7][CH2:6]1
Reactant: CC(C)CC=C1CCC2(CC1)SCC(=O)N2CCC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CC=C1CCC2(CC1)SCC(=O)N2CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
In 40 ml of dioxane was dissolved 4.11 g of benzyl 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate. Then, 20.5 ml of 1 mol/L aqueous solution of sodium hydroxide was added at 0-5° C., and the resulting mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into a mixture of chloroform and water, the aqueous layer was separated, ethyl acetate was added to the aqueous layer, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography (eluent: chloroform:ethanol=50:1) gave 2.72 g of 3-[8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid as a light yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Product: CS(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Yield: 28 %

Procedure:
8-(4-Amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione was condensed with methanesulfonyl chloride under the conditions previously described to give the stated sulfonamide as an off-white solid (28%); 1H NMR(DMSO-d6, 300 MHz) δH 13.42 (s, 1H), 9.61 (s, 1H), 7.30–6.90 (m, 8H), 5.04 (s, 2H), 3.94 (s, 2H), 3.77 (d, J=6.6 Hz, 2H), 2.87 (s, 3H), 1.25–1.05 (m, 1H), 0.40–0.25 (m, 4H); EI-HRMS m/e calculated for C24H24FN5O4S (M+) 497.1533, found 497.1528.
Reaction SMILES: [H][H].[C:3]([N:6]1[C:15]2[C:10](=[C:11]([O:29][CH2:30][CH2:31][CH3:32])[C:12]([C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]=3)=[CH:13][CH:14]=2)[CH2:9][CH2:8][C@@H:7]1[CH3:33])(=[O:5])[CH3:4]>CO.[OH-].[OH-].[Pd+2]>[C:3]([N:6]1[C:15]2[C:10](=[C:11]([O:29][CH2:30][CH2:31][CH3:32])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17]3)=[CH:13][CH:14]=2)[CH2:9][CH2:8][C@@H:7]1[CH3:33])(=[O:5])[CH3:4]
Reactant: [H][H]
Reactant: CCCOc1c(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCOc1c(C2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Balloon pressured hydrogen gas was charged into a round bottom flask containing a suspension of (S)-tert-butyl 4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (500 mg, 1.17 mmol) and 20% palladium hydroxide on carbon (30 mg, 0.21 mmol) in methanol (10 mL). The reaction was stirred under balloon pressure for 2 hours. The reaction was vented to nitrogen and filtered through a pad of Celite. The filtered solution was concentrated in vacuo and purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 20-40% ethyl acetate-hexane) to afford tert-butyl (S)-4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate (500 mg, 100%) as a colorless oil. MS (ESI, pos. ion) m/z 432 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:12]([OH:13])=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:12]([O:13][CH2:25][CH2:24][CH2:23][CH2:22][S:21][C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[CH:20][CH:19]=2)=[CH:11][C:5]2[CH2:6][O:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Cl)c(O)cc2CO1
Reactant: Cc1ccc(SCCCCCl)cc1
Product: Cc1ccc(SCCCCOc2cc3c(cc2Cl)NC(=O)OC3)cc1

Procedure:
Prepared analogously to Example 4 from 7-chloro-6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.