Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O)[S:4]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)(=[O:6])=[O:5])[CH3:2].[CH2:30]([NH2:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>ClCCl>[CH2:1]([N:3]([CH2:17][CH2:18][NH:36][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[S:4]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH:14]=[CH:15][CH:16]=1)(=[O:5])=[O:6])[CH3:2]
Reactant: CCN(CCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1cccc2cnccc12
Reactant: CCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCCCNCCN(CC)S(=O)(=O)c1cccc2cnccc12
Temperature: 110 °C

Procedure:
To 3.96 g of the thus obtained N-ethyl-N-(2-p-toluenesulfonyloxyethyl)-5-isoquinolinesulfonamide were added 1.25 g of hexylamine, 1.14 g of potassium carbonate and 20 ml of dioxane. The mixture thus obtained was heated in a pressure vessel at 110° C. for 72 hours, and then the dioxane was removed under reduced pressure to obtain a crude product. Then, 60 ml of dichloromethane was added to the crude product, and the mixture thus obtained was washed with 30 ml of water and dried with anhydrous magnesium sulfate. The dichloromethane was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, solvent: a 5% methanol solution in chloroform) to obtain 2.50 g of N-ethyl-N-(2-hexylaminoethyl)-5-isoquinolinesulfonamide [Compound (28)]. Compound (28) was analyzed to give the following data.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[N+:14]([O-])([OH:16])=[O:15].N([O-])=O.[Na+]>>[OH:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1O)CCC2=O
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cc2c(c([N+](=O)[O-])c1O)CCC2=O

Procedure:
1,4-Dihydroindeno[1,2-c]pyrazoles of general formula (13), wherein X3, R4, R5, and R6 are as defined in formula (I), can be prepared as described in Scheme 3. 5,6-Dimethoxy-1-indanone, purchased from Aldrich Chemical Co., can be treated with sodium cyanide to provide 5-hydroxy-6-methoxy-1-indanone. 5-Hydroxy-6-methoxy-1-indanone can be treated with nitric acid and sodium nitrite to provide 5-hydroxy-6-methoxy-4-nitro-1-indanone. 5-Hydroxy-6-methoxy-4-nitro-1-indanone can be treated with iodomethane and then methodology described in Scheme 2 to provide compounds of general formula (12). Compounds of general formula (12) can be treated with a reducing agent, including iron metal in the presence of acetic acid, to provide amines of general formula (13).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]1[CH2:24][N:25]1[CH2:29][CH2:28][C@H:27]([NH:30][S:31]([C:34]2[S:38][C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[C:26]1=[O:45])=O)(C)(C)C>>[O:45]=[C:26]1[C@@H:27]([NH:30][S:31]([C:34]2[S:38][C:37]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:28][CH2:29][N:25]1[CH2:24][C:16]1[NH:15][C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccc(Cl)s4)s3)C2=O)cc2cnccc21
Solvent: O=C(O)C(F)(F)F
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3ccc(Cl)s3)s2)CCN1Cc1cc2cnccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (1.0 mL, 13.0 mmol) is added dropwise to a slurry of 2-[3-(S)-(5′-chloro-[2.2′]bithiophenyl-5-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.13 g, 0.22 mmol) in CH2C2 (2 mL) at 0° C. After 30 min the ice bath is removed and the solution is stirred at room temperature for 4 h. The reaction mixture is concentrated to dryness and the crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:30]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)=[O:30])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)Nc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamido-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:36]([O:38][C:39](=[O:50])[CH2:40][C:41]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)=O)[CH3:37].C(N(CC)CC)C>ClCCCl>[CH2:36]([O:38][C:39](=[O:50])[C:40]#[C:41][C:43]1[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=1)[CH3:37]
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOC(=O)C#Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
Prepared in analogy to Synthesis Communications (1989) 3:217-218. To a solution of triphenylphosphine oxide (3.77 g, 14 mmol) in 1,2-dichloroethane (42 mL) was added trifluoromethanesulfonic anhydride (2.25 mL, 14 mmol) dropwise at 0° C. and the grey suspension was stirred at 0° C. for 15 min. Then a solution of 3-(4-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (2.85 g, 14 mmol) in 1,2-dichloroethane (14 mL) was added followed by a dropwise addition of triethylamine (3.78 mL, 28 mmol) at 0° C. The brown solution was refluxed for 2.5 h. After cooling the mixture was poured onto ice-water and the organic layer separated and washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 20% ethyl acetate in heptane) afforded the title compound (1.53 g, 59%) as a yellow solid. MS: m/e=193.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=1>>[N:14]1[CH:13]=[CH:12][CH:11]=[N:16][CH:15]=1.[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Clc1cc(Cl)ncn1
Agent: c1ccc2[nH]ccc2c1
Product: c1cncnc1

Procedure:
In step 2, indole c is reacted with dichloropyrimidine d to yield indole pyrimidine compound e. The reaction of step 2 may be effected in the presence of HOBt and potassium carbonate under polar solvent conditions.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Br:12]Br.Br>[Fe]>[Br:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: BrBr
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [Fe]
Agent: Br
Product: Nc1ccc(C(F)(F)F)cc1Br
Reaction time: 2 h

Procedure:
To 161.0 g of p-aminobenzotrifluoride and 10.0 g of iron filings is added, dropwise, with agitation at 35°-40°, 160.0 g of bromine, using a slow stream of nitrogen to sweep out the evolved hydrogen bromide. Subsequently, the mixture is agitated for an additional two hours and then distilled in vacuo to give 3-bromo-4-aminobenzotrifluoride.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:27])([F:26])[S:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH2:14][CH:13]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH2:12]2)(=[O:7])=[O:6].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCCC.CN(C=O)C>[F:27][C:4]([F:26])([F:3])[S:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:14][CH:13]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH2:12]2)(=[O:6])=[O:7]
Reactant: CCCN(CCC)C1Cc2cc(O)c(OS(=O)(=O)C(F)(F)F)cc2C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)C1Cc2cc(OCc3ccccc3)c(OS(=O)(=O)C(F)(F)F)cc2C1
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.96 g, 24 mmol) was washed with hexane under nitrogen and suspended in DMF (10 mL). 2-(Dipropylamino)-2,3-dihydro-6-hydroxy-1H-inden-5-yl trifluoromethanesulfonate (69, 7.6 g, 20 mmol) in DMF (30 mL) was added dropwise at 0-5° C. over 30 min and the mixture stirred 30 min. Benzyl bromide (5.13 g, 30 mmol) in DMF (5 mL) was added and the resulting mixture was stirred 1 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with water, brine, dried (MgSO4), filtered and concentrated to give the crude product. Chromatographic purification yielded pure product 70 as an oil that was converted into the HCl salt and crystallized from EtOAc/MeOH/hexane to give a white solid (mp 162-163° C.).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][CH2:19][C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[OH-].[Na+]>>[CH3:35][C:21]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=2)[S:24][C:20]=1[CH2:19][CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:36])=[O:5]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1cccc2c1ccn2CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1cccc2c1ccn2CC(=O)O

Procedure:
In analogy to the procedure described in example 2 c], (4-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with NaOH to obtain (4-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid as white solid.
Reaction SMILES: [C:1]([CH:4]([CH2:27][S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:5][N:6]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:7](=[O:21])[NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([NH:12][CH3:13])=[O:11])([OH:3])=O.[OH:35][N:36]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.[Cl-].O[NH3+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.CN(C)C=O>[OH:35][NH:36][C:1]([CH:4]([CH2:27][S:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]([CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C:7](=[O:21])[NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:10]([NH:12][CH3:13])=[O:11])=[O:3]
Reactant: On1nnc2ccccc21
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)N(CCC(C)C)CC(CSc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)N(CCC(C)C)CC(CSc1ccccc1)C(=O)NO
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
In anhydrous methylene chloride (4 ml) are dissolved (2S)-2-[3-[(2RS)-2-carboxy-3-(phenylthio)propyl]-3-isoamylureido]-N-methyl-3-phenylpropionamide (Compound No. 36-2, 100 mg), 1-hydroxybenzotriazole (68 mg) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (96 mg) under a nitrogen atmosphere. Then, N-methylmorpholine (0.05 ml) is added to the solution under ice cooling, and the mixture is stirred for 30 minutes. Next, to the mixture is added a solution containing hydroxylammonium chloride (52 mg) and N-methylmorpholine (0.08 ml) in dimethylformamide (1 ml), and the mixture is stirred under ice cooling for 10 minutes and then at room temperature overnight. A 5% aqueous citric acid solution is added to the reaction mixture, and the whole is extracted with ethyl acetate. The organic layer is washed with a 5% aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 57 mg (54%) of the titled compound (Compound No. 40-1) as noncrystalline powder.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(C1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:24][C:25](=[O:27])[CH3:26])=[CH:18][CH:19]=3)[CH2:14][C:13]=2C=1)(=O)C.S(=O)(=O)(O)O.OO.C(=O)([O-])O.[Na+]>O.ClCCl.C(O)=O>[C:5]([O:4][C:1]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([O:24][C:25](=[O:27])[CH3:26])=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O=CO
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)Cc1cc(OC(C)=O)ccc1-2
Temperature: 25 °C
Yield: 47.2 %

Procedure:
Acetic anhydride (26.2 g) and 88% formic acid (68 g) were added in order to a mixture of 2-acetyl-7-acetoxyfluorene (45 g) and dichloromethane (450 mL). 36M-sulfuric acid (9 mL) was slowly added thereto at 9° C., and then a 34% hydrogen peroxide aqueous solution (25.9 g) was added to obtain a ocherous reaction mixture. This reaction mixture was refluxed for 9 hours by heating, and then it was cooled down to a room temperature and poured into water. The mixture was neutralized with saturated sodium hydrogencarbonate, and then the organic layer was sufficiently washed with 10% sodium hydrogensulfite to remove unreacted peroxide. The separated organic layer was concentrated under reduced pressure, and the resulting residue was purified by means of column chromatography (silica gel, eluting solvent: ethyl acetate) to obtain 2,7-diacetyloxyfluorene (22.5 g) of colorless crystal. Melting point: 167.6-168.3° C.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([Br:28])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[CH3:29][O:30][C:31]([NH:33][CH:34]([CH:38]([CH3:40])[CH3:39])C(O)=O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:29][O:30][C:31](=[O:32])[NH:33][CH:34]([C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([Br:28])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:5])[CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 142.2 %

Procedure:
2-[5-(4-Bromonaphthalen-1-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (3.80 g), 2-methoxycarbonylamino-3-methyl-butyric acid (2.57 g), and HATU (5.88 g) were dissolved in anhydrous DMF (85 mL), and N-methylmorpholine (2.86 mL) was added. The reaction mixture was stirred at ambient temperature for 22 hours and evaporated under vacuum. The oil was dissolved in dichloromethane, purified by chromatography (0-50% ethyl acetate:hexanes), and evaporated under vacuum, giving (1-{2-[5-(4-bromonaphthalen-1-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (6.10 g, crude) as a tan solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:3]1.Br[CH2:28][C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+]>O1CCCC1>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][C@H:7]1[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:3][C:2]1=[O:1])#[N:36]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CC(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2C#N)C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
To a stirred solution of 9.68 g (27.4 mmol) of t-butyl (2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholine carboxylate (Aldrich Chemical Company) and 5.91 g (30.1 mmol, 1.1 eq) of α-bromo-o-tolunitrile in 140 mL of tetrahydrofuran at -78° C. was added dropwise 28.8 mL of a 1.0M THF solution of sodium hexamethyldisilazide (28.8 mmol) over 15 min. The mixture was stirred at -78° C. for 3 h, then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (5×150 mL) and the combined organic extracts washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. Chromatography on silica gel (elution with 20% ethyl acetate-hexanes) gave the product as a white solid (8.01 g, 63%). 1H NMR indicates this compound exists as an approximately 5:1 mixture of rotamers. 1H NMR (400 MHz, CDCl3): major rotamer--δ0.92 (s, 9H), 3.52 (dd; 10, 14 Hz; 1H), 3.62 (dd; 5, 14 Hz; 1H), 5.08 (d, 3 Hz, 1H), 5.40 (dd; 5, 10 Hz; 1H); 5.79 (d, 3 Hz, 1H), 6.52 (d, 8 Hz, 2H), 6.92 (d, 8 Hz, 2H), 7.00-7.70 (m, 1 OH). FAB-MS: calculated for C29H28N2O4 468; found 469 (M+H,30%), 369 (M-BOC, 100%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-phenylpiperazine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=448.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:23][O:24][CH2:25][CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl.O>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH2:26][CH2:25][O:24][CH3:23])=[CH:3][CH:4]=2)[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: COCC=O
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: COCCNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-[(4-aminophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D2) (0.30 g, 1 mmol), (methyloxy)acetaldehyde (D89), sodium tri(acetoxy)borohydride (0.417 g, 2 mmol) and triethylamine (0.165 mL, 1.2 mmol) in 1,2-DCE (15 mL) was stirred under Ar at room temperature for 19 hours. Saturated NaHCO3 (20 mL) was added and reaction mixture stirred for a further 1 hour. The reaction mixture was further diluted with DCM (25 mL) and water (10 mL). The aqueous layer was then extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude material was purified by column chromatography on silica eluting with 0-50% EtOAc/petroleum ether to give the title compound (0.310 g). δH (CDCl3, 400 MHz) 7.12 (2H, d), 6.59 (2H, d), 4.15 (1H, m), 3.99 (1H, br.s), 3.78 (1H, d), 3.61 (2H, t), 3.40 (3H, s), 3.28 (3H, m), 3.08 (1H, td), 2.74 (1H, d), 2.58 (1H, d), 2.06 (1H, m), 1.94 (1H, m), 1.45 (9H, s), 1.21 (3H, d). MS (ES+): 264.2, no molecular ion (MH+) observed.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17](C)=O)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[SH:17][C:13]1[CH:12]=[C:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C1(c2cccc(S(C)=O)c2)CCOCC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)C1(c2cccc(S)c2)CCOCC1

Procedure:
Methyl4-(3-methylsulfinylphenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (12.2 g, 43 mmol) was dissolved in trifluoroacetic anhydride (50 ml) and heated at reflux for 30 min. Volatiles were removed by evaporation and the residue was dissolved into methyl alcohol (100 ml). Triethylamine (100 ml) was added over 5 min and the mixture concentrated to dryness. The residue was dissolved in ethyl acetate (500 ml), washed with saturated aqueous ammonium chloride (200 ml) and brine (200 ml), dried (magnesium sulfate) and concentrated to dryness to provide crude titled compound as a pale black liquid which was used as such without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(Nc2ccccc2N)cc1
Yield: 90 %

Procedure:
The reduction of the nitro function of N-(4-methylphenyl)-2-nitroaniline (Synthesis (1990) 430) is carried out in the presence of Pd/C in ethanol, under the conditions described previously for intermediate 2.2. A violet product is obtained in a semi-oil semi-crystal form with a yield of 90%.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH:14][C:15]([C:17]1[S:18][CH:19]=[C:20]([CH:22]([CH3:24])[CH3:23])[N:21]=1)=O)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:22]([C:20]1[N:21]=[C:17]([C:15]2[CH:2]=[C:1]([OH:3])[C:4]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][C:9]=3[O:10][CH3:11])[N:14]=2)[S:18][CH:19]=1)([CH3:24])[CH3:23]
Reactant: COc1cc(NC(=O)c2nc(C(C)C)cs2)c(C(C)=O)c(OC)c1
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1cc(OC)c2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Yield: 60 %

Procedure:
Compound 43e was synthesized from compound 42e as a yellow solid in 60% yield, according to the procedures as described for compound 43a.
Reaction SMILES: [K].[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[NH:8][C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3].[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:2]([C:4]1([CH3:20])[NH:15][C:14]([CH2:17][CH3:18])([CH3:16])[CH2:13][C:6]2([NH:10][C:9](=[O:11])[N:8]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]2=[O:12])[CH:5]1[CH3:19])[CH3:3]
Reactant: CCCCCCCCBr
Reactant: CCC1(C)CC2(NC(=O)NC2=O)C(C)C(C)(CC)N1
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCCCCCN1C(=O)NC2(CC(C)(CC)NC(C)(CC)C2C)C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To 70 ml of dimethylformamide were added 8 g of the potassium salt of 7,9-diethyl-6,7,9-trimethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 1) and 5.2 g of octyl bromide; the mixture was heated, with stirring, at 60° C for 2 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and benzene was added to the residue. The resulting benzene solution was washed with water and then dried over magnesium sulphate. After removing the benzene, the resulting oily product was first purified by column chromatography on silica gel (eluent: benzene containing 5% of triethylamine) and then by recrystallization from hexane, giving 3.0 g of Compound 5, mp 65° - 67° C.