Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:6][C:7](=[O:10])[O:8][CH3:9].C[O-].[Na+].[CH3:20][C:21](=[CH:23][CH2:24][CH2:25]/[C:26](=[CH:28]/CO)/[CH3:27])[CH3:22].CO>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:5]([CH2:4][C:3]([O:2][CH2:1]/[CH:28]=[C:26](/[CH2:25][CH2:24][CH:23]=[C:21]([CH3:20])[CH3:22])\[CH3:27])=[O:16])[CH2:6][C:7](=[O:10])[O:8][CH2:9]/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])\[CH3:22])/[CH:20]=[C:21](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])\[CH3:22]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: COC(=O)CN(CC(=O)OC)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)=CCC/C(C)=C/COC(=O)CN(CC(=O)OC/C=C(\C)CCC=C(C)C)CC(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 1 h

Procedure:
To a mixture of N,N-bis(2-methoxy-2-oxoethyl)glycine methyl ester (7.0 g, 30 mmol, 1 eq) in toluene (80 ml) under argon was slowly added some sodium methoxide (0.49 g, 0.009 mol, 3*0.10 eq) and geraniol (14.57 g, 95 mmol, 3*1.05 eq). The mixture was heated under vacuum (10 mm Hg) and the methanol produced by the transesterification reaction is distilled with toluene over two hours after which the reaction appeared completed by 1H NMR. Any remaining toluene is evaporated under vacuum. Diethyl ether was added (200 ml) and the mixture stored at 4° C. for one hour prior to filtration. The filtrate was then concentrated under vacuum yielding to the expected N,N-bis(2-geranyloxy-2-oxoethyl)glycine geranyl ester as a yellow oil (quantitative yield).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26](O)(=[O:30])[CH2:27][CH2:28][CH3:29]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: CCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (12.9 mg, 46%), MS (ISP) m/z=401.4[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and butyric acid
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]1=[O:17].[CH3:18][OH:19]>>[CH3:18][O:19][C:6]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][CH2:2][CH2:3][CH2:4]1)=[O:17]
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Reactant: CO
Product: COC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21

Procedure:
3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid methyl ester was prepared from 3-(3-chloro-propyl)-6-nitro-3H-benzoxazol-2-one and methanol in an analogous manner to Example 1426a. Product isolated as a yellow oil (388 mg, 66%). LCMS (m/e) 253 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.91-7.81 (m, 2H), 7.56-7.37 (m, 1H), 4.32-4.18 (m, 2H), 3.95-3.80 (m, 2H), 3.79 (s, 3H), 2.22-2.12 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH2:5][OH:6])[CH2:3][OH:4].[CH2:23](C(CC)(CC)C([O-])([O-])[O-])[CH3:24].C(O)(=O)C>C(#N)C>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:2]2([CH2:5][OH:6])[CH2:3][O:4][C:23]([CH3:24])=[N:1]2)=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(CO)(CO)CCc1ccc(OCc2ccccc2)cc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC1=NC(CO)(CCc2ccc(OCc3ccccc3)cc2)CO1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 2-amino-2-[2-(4-benzyloxy-phenyl)-ethyl]-propane-1,3-diol (31.1 g, 0.10 mol) in acetonitrile (2.38 l) is added triethylortho acetate (17.1 ml, 0.12 mol, 1.2 eq) and acetic acid (5.48 ml, 0.11 mol, 1.1 eq), the reaction mixture is then stirred at 80° C. for 5 hours. The reaction mixture is then concentrated under vacuum, {4-[2-(4-benzyloxy-phenyl)-ethyl]-2-methyl-4,5-dihydro-oxazol-4-yl}-methanol is isolated after crystallization with ethyl acetate.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[N+:17]([C:20]1[CH:21]=[C:22]([NH2:30])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)([O-:19])=[O:18].Cl>O.O1CCOCC1>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:30][C:22]3[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc([N+](=O)[O-])cc(C(F)(F)F)c3)nc21
Temperature: 25 °C
Yield: 49 %

Procedure:
2-Chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one of (2 g; 8.30 mmol) and 3-nitro-5-trifluoromethyl-phenylamine (1.71 g; 8.30 mmol) were diluted in 10 ml of water and 10 ml of 1,4-dioxane. 2 ml of HCl 37% were added. The reaction mixture was refluxed 48 h, then cooled to room temperature. The desired product precipitated from the reaction mixture, so, it was filtered, washed with water and dried in vacuo. Recrystallisation with 1,4-dioxane/water 1:1 gave 1.65 g (4.04 mmol; 49% yield) of white-yellow powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5](C)=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O[CH:20](C1OC=CC(=O)C=1O)C.C(Br)C1C=CC=CC=1>>[OH:1][CH:2]([C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:20]
Reactant: CC(O)c1occc(=O)c1O
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Agent: BrCc1ccccc1
Product: CC(O)c1occc(=O)c1OCc1ccccc1

Procedure:
The title compound was prepared by the method outlined for 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one, using 4.68 g (30 mmol, 1 eq.) of 2-(1-hydroxyethyl)-3-hydroxy-pyran-4(1H)-one and 5.64 g benzyl bromide (33 mmol, 1.1 eq.) to yield the pure product 6.1 g (82%) after recrystallisation from CH2Cl2/Pet. ether 40/60, as a white crystalline solid. m.p. 97-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[N+:12]=[N-:13])(=[O:9])=[O:10])=[CH:4][CH:3]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-hydroxybenzenesulfonyl azide synthesized in Synthetic example 2 (1.72 g, 8.63 mmol, and 1.00 Eq) was dissolved in DMF (17 mL), and then sodium hydroxide (354 mg, 8.85 mmol, and 1.03 Eq) and allylbromide (14.0 g, 116 mmol, and 13.4 Eq) were added thereto. The solution was stirred at room temperature for 16 hours and water (50 mL) was added thereto, followed by extraction with diethylether (3×20 mL). The obtained organic layer was dried with sodium sulfate and the organic solvent was removed by the evaporator (30° C.). The product was purified by column chromatography (hexane/ethyl acetate 10:1) to obtain 4-allyloxybenzenesulphonyl azide as pale yellow oil (0.89 g, and 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([N:25]([CH2:36][CH3:37])[CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:24].COCCOCCOC>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:33][C:32]3[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:25]([CH2:36][CH3:37])[CH2:23][CH3:24])=[CH:35][CH:34]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Solvent: COCCOCCOC
Solvent: O
Product: CCN(CC)CCOc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1
Temperature: 150 °C

Procedure:
A mixture of 0.155 g (0.40 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37, 0.167 g (0.80 mmol) of 4-(2-diethylaminoethoxy)aniline and 1 mL of (2-methoxyethyl)ether (bp 162° C.) was heated with stirring in a 150° C. oil bath. All solid gradually dissolved over a period of 10 minutes. The solution was heated another 10 minutes and cooled to 100° C. Water was added dropwise until slight turbidity. The crystals that separated on inducement were filtered, washed with 0.5 mL of ether and 2 mL of water, and dried; wt 0.105 g. Purification was effected by chromatography eluting with chloroform, then ethyl acetate and finally 10% methanol/chloroform to obtain fraction with pure product. The eluent was evaporated to dryness. The remaining amorphous solid was dissolved in 1 mL of warm ethyl acetate. The crystals that separated on inducement were filtered and washed sparingly with ethyl acetate and ether; wt 0.042 g; mp 141°-143° C.
Reaction SMILES: [CH3:1][N:2]([OH:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[O:4].C(=O)([O-])[O-].[K+].[K+].CS(C)=O.Cl[CH:26](Cl)[CH3:27]>O>[CH3:1][N:2]1[C:3](=[O:4])[N:5]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])[CH2:27][CH2:26][O:14]1
Reactant: CN(O)C(=O)Nc1ccc(Cl)cc1Cl
Reactant: CC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1OCCN(c2ccc(Cl)cc2Cl)C1=O
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
A mixture of 11 g of N-methyl-N-hydroxy-N'-(2,4-dichlorophenyl)-urea, 55 g of potassium carbonate and 66 ml of dimethylsulfoxide was stirred for 20 minutes at 20° C and then 11 g of dichloroethane were added. The mixture was stirred for 16 hours at 20°-25° C and was then poured into water. The mixture was vacuum filtered and the recovered precipitate was taken up in ethyl acetate. The solution was dried and evaporated to dryness under reduced pressure. The residue was crystallized from isopropyl ether to obtain 8 g of 2-methyl-4-(2',4'-dichlorophenyl)-3-oxo-5,6-dihydro-1,2,4-oxadiazine melting at 94°-95° C.
Reaction SMILES: CN(C)CCN.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][NH2:16])=[CH:11][CH:10]=1.C(O)(=O)C.[C:21]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO>[Cl:35][C:33]1[CH:32]=[CH:31][C:30]([NH:36][S:37]([C:40]([F:43])([F:41])[F:42])(=[O:39])=[O:38])=[C:29]([C:21](=[N:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:34]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(Cl)cc1
Agent: CN(C)CCN
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=S(=O)(Nc1ccc(Cl)cc1C(=NOc1ccc(Cl)cc1)c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.9 %

Procedure:
N,N-Dimethylethylenediamine (82 μL, 0.75 mmol) was added to a suspension of O-(4-chlorophenyl)hydroxylamine hydrochloride (141 mg, 0.51 mmol) in EtOH (15 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (3 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (170 mg, 0.47 mmol) in EtOH (5 mL), and the reaction stirred for 63 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in CH2Cl2 (50 mL), washed with water (twice), brine, dried over MgSO4 and the solvent evaporated under reduced pressure. The residue was filtered through a pad of silica (eluting with CH2Cl2/PE, 3:7) and purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 119 to 1:4) to afford N-{4-chloro-2-[(4-chlorophenoxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 164 (140 mg, 61%), as a orange-brown solid. M.p. 86-87° C. 1H n.m.r. (200 MHz, CDCl3) δ 10.99, br s, 1H; 7.73, d, J=8.8 Hz, 1H; 7.54, m, 3H, 7.43-7.27, m, 5H, 7.07, m, 1H, 7.01, m, 2H. O-(4-Chlorophenyl)hydroxylamine hydrochloride was prepared by the procedure described in Example 2C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(Oc3cccc(F)c3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
144 (440 mg, 1.47 mmol) is dissolved in 10 ml of methanol and treated with a solution of LiOH (70 mg, 1.47 mmol) in 5 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[O:28][C@@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:7]1[O:8]C(=O)C1C=CC=CC=1)(=[O:4])C.[C:39](Cl)(=O)[CH3:40]>ClCCl.C(OCC)(=O)C>[C:2]([O:5][C@@H:6]1[O:28][C@@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:7]1[OH:8])(=[O:4])[C:40]1[CH:39]=[CH:27][CH:17]=[CH:7][CH:6]=1
Reactant: CC(=O)Cl
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 63.7 %

Procedure:
HCl (gas) was bubbled for 1.5 hours into a solution of 50 g (99.16 mole) of the compound (12) dissolved in 460 ml of anhydrous dichloromethane and 7.5 ml of acetyl chloride at 0° C. The resulting solution was kept in a refrigerator for 12 hours and then evaporated in vacuo. The residue was coevaporated with toluene (3×150 ml) at 45° C. and redissolved in 105 ml of acetonitrile. To this solution, 13 ml of water was added dropwise at 0° C. A white solid began to precipitate from the mixture after 30 minutes, after which the mixture was kept in a refrigerator for 2 hours to induce additional precipitation. After filtration of the resulting solid, the filter cake was carefully washed with cold diethylether to remove the reaction by-product 1-hydroxy-isomer, which is indistinguishable by TLC from the compound (13). The white solid thereby obtained was dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate to remove the remaining HCl, dried over MgSO4 and filtered. The solvent was removed from the filtrate to obtain 29.2 g (Yield: 63.7%) of the compound (13) in the form of a white solid. m.p.: 137-139° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH:6]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH2:5]1)(=[O:3])[CH3:2].[Cl-:21].[Na+]>C(#N)C.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([Cl:21])[CH:11]=2)[CH:6]([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: [Cl-]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CN2C(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)N(C(C)=O)CC2CCNC(C)=O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
To a solution of N-[2-(1-acetyl-5-methoxyindolin-3-yl)ethyl]acetamide (0.29 mmol) in acetonitrile (1.5 ml) is added bis(trifluoroacetoxyiodobenzene) (PIFA 1.2 eq) and the medium is left stirring for 1 min at room temperature. Saturated sodium chloride solution (0.5 ml) is next added and, after 15 min, the mixture is diluted with dichloromethane (10 ml) and dried over magnesium sulphate. The crude product obtained after evaporation is chromatographed on a column of flash silica (5/95 methanol/dichloromethane) and N-[2-(1-acetyl-6-chloro-5-methoxyindolin-3-yl)ethyl]acetamide (70 mg) is thus obtained.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[CH:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([O:15][CH:16]2[O:21][CH:20]([CH2:22][OH:23])[CH:19]([OH:24])[CH:18]([OH:25])[CH:17]2[OH:26])[CH:7]=1.NCC(O)=O.[OH-].[Na+]>>[CH:10]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:6][CH:7]=[C:8]([O:15][C@@H:16]2[O:21][C@H:20]([C:22]([OH:3])=[O:23])[C@@H:19]([OH:24])[C@H:18]([OH:25])[C@H:17]2[OH:26])[CH:9]=1
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(OC2OC(CO)C(O)C(O)C2O)cc1
Agent: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 0.5 h

Procedure:
The reagent solutions were: NaAc buffer: 200 mM sodium acetate buffer pH 4.5; Substrate: 50 mM p-nitrophenyl-α-D-glucopyranoside (Sigma N-1377) in NaAc buffer (0.3 g/20 ml) and stop solution: 800 mM glycine-NaOH buffer pH 10. 30 μl filtered supernatant was placed in a fresh 96-well flat bottom micro titer plate (MTP). To each well 50 μl NaAc buffer and 120 μl substrate was added and incubated for 30 minutes at 50° C. (Thermolab systems iEMS Incubator/shaker HT). The reaction was terminated by adding 100 μl stop solution. The absorbance was measured at 405 nm in a MTP-reader (Molecular Devices Spectramax 384 plus) and the activity was calculated using a molar extinction coefficient of 0.011 μM/cm.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([SH:25])[S:24][C:20]=2[CH:19]=1)[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[CH2:15]([O:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([S:25][CH:2]3[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]3)[S:24][C:20]=2[CH:19]=1)[CH3:16]
Reactant: CCOc1ccc2nc(S)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOc1ccc2nc(SC3CCN(C(=O)OC(C)(C)C)CC3)sc2c1
Reaction time: 20 h
Yield: 65 %

Procedure:
To the mixture of tert-butyl 4-hydroxy-1-piperidinecarboxylate (2 g, 10 mmol), 6-ethoxy-1,3-benzothiazol-2-thiol (2.54 g, 12 mmol), triphenylphosphine (3.9 g, 15 mmol) and THF (60 ml) was dropwise added a solution of 40% diethyl azodicarboxylate in toluene (5.23 g, 15 mmol) under ice cooling over a period of 10minutes. The mixture was stirred at room tmperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate (50 ml). The organic layer was washed with aqueous solution of 0.5N-sodium hydroxide (30 ml),and saturated aqueous solution of sodium chloride (30 ml), successively, dried-over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 50 g, ethyl acetate/hexane=1/20 to 1/5), and the desired fraction was concentrated under reduced pressure. To the concentrate was added hexane (10 ml) and the precipitates were collected by filtration to give the titled compound (2.6 g, 6.5 mmol) as white powdery crystals.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][S:12][C:11]3[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:10]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][S:12][C:11]3[CH:15]=[C:16]([NH:19][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])[CH:17]=[CH:18][C:10]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)SCCN2CCN1CCCCC1
Agent: I
Product: N=C(Nc1ccc2c(c1)SCCN2CCN1CCCCC1)c1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23 %

Procedure:
A suspension of 4-(2-(piperidin-1-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.90 g, 3.24 mmol) and methyl thiophene-2-carbimidothioate hydroiodide (1.85 g, 6.49 mmol) was stirred at room temperature overnight (16 hours) under an argon atmosphere. The reaction was concentrated, and the residue was partitioned between saturated sodium bicarbonate solution (50 mL) and dichloromethane (25 mL). After stirring for an hour, the mixture was poured into a separatory funnel. The organic layer was removed, and the aqueous layer was extracted into dichloromethane (2×20 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was subjected to column chromatography on silica gel (2:98 to 5:95 MeOH:CH2Cl2 followed by 5:95 (2M NH3 in MeOH):CH2Cl2) to give compound 14 as yellow solid (0.288 g, 23%). 1H-NMR (DMSO-d6) δ 7.69 (d, J=3.3 Hz, 1H), 7.57 (d, J=4.5 Hz, 1H), 7.09-7.06 (m, 1H), 6.67 (d, J=8.7 Hz, 1H), 6.52-6.47 (m, 2H), 6.39 (brs, 2H), 3.56-3.53 (m, 2H), 3.39-3.33 (m, 2H), 3.03-3.01 (m, 2H), 2.45-2.39 (m, 6H), 1.49-1.48 (m, 4H), 1.39-1.38 (m, 2H); ESI-MS (m/z, %): 387 (MH+, 77), 276 (46), 194 (100).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:49])[C@@H:14]([NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:42])=[O:41])[CH2:15][NH:16][C:17]1[C:18]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)[C:19]=2[N:20]=[C:21]([CH3:23])[N:22]=1)(C)(C)C>C(Cl)Cl>[CH3:23][C:21]1[N:22]=[C:17]([NH:16][CH2:15][C@H:14]([NH:39][S:40]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)(=[O:41])=[O:42])[C:13]([OH:49])=[O:12])[C:18]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]3[NH:33][CH2:34][CH2:35][CH2:36][N:37]=3)[C:19]=2[N:20]=1
Reactant: Cc1nc(NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)O)c2ccn(CCCC(=O)NC3=NCCCN3)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 ml of TFA were added to a solution of 70 mg of (2S)-3-(2-methyl-7-[3-(1,4,5,6-tetrahydro-pyrimidin-2-ylcarbamoyl)-propyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(benzenesulfonylamino)-propionic acid tert-butyl ester (example 4b) in 5 ml DCM and stirred for 2 h at room temperature. Solvent and TFA were removed in vacuo, the residue was lyophilized from AcOH/H2O (1:1). Yield: 71 mg.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].[N:23]([O-])=[O:24].[Na+].CO.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Yield: 27.3 %

Procedure:
5.4 g of 1-(2-chloroethyl)-3-n-butyl-3-D-mannopyranosylurea are dissolved in 20 ml of formic acid, and 3.5 g of sodium nitrite are added gradually thereto for 2 hours under ice-cooling and stirring. 40 ml of methanol and 30 g of potassium carbonate anhydrate are added to said mixture. Then, said mixture is further stirred for 10 minutes under ice-cooling. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.6 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-mannopyranosylurea are thereby obtained as yellow caramel.