Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11]1[CH2:13][C:12]1([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:16][C:17]1([CH3:25])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH:18]1[OH:24].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:11][C:12]([CH3:14])([CH3:15])[CH2:13][O:24][CH:18]1[C:19]([CH3:23])([CH3:22])[CH2:20][CH2:21][C:17]1([CH3:25])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC1(C)CCC(C)(C)C1O
Reactant: CC1(C)CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(COC1C(C)(C)CCC1(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-Cbz-2,2-dimethyl aziridine and 2,2,5,5-tetramethyl-1-cyclopentanol are dissolved in CH2Cl2 at 0° C. under argon. Boron trifluoride etherate is added and the flask is stirred overnight. The contents are poured into saturated NaHCO3 and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Cbz-1-(2-amino-2-methylpropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: C([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[C:14]2[C:17]([N:22]([CH3:24])[CH3:23])=[CH:18][C:19]([CH3:21])=[N:20][C:13]=2[N:12]([CH3:25])[C:11]1=[O:26])(=O)C.[OH-].[K+]>O.CO>[CH3:25][N:12]1[C:13]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([N:22]([CH3:24])[CH3:23])[C:14]=2[C:15](=[O:16])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:27])[C:11]1=[O:26]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(N(C)C)cc(C)nc2n(C)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(N(C)C)c2c(=O)n(CCCC[C@@H](C)O)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To crude (R)-3-(5-acetoxyhexyl)-1,7-dimethyl-5-(N,N-dimethylamino)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was added a solution of potassium hydroxide (100 mg) in 10% water-methanol (2.2 ml). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was treated with saturated aqueous sodium chloride solution (10 ml) and ethyl acetate (10 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford (R)-1,7-dimethyl-5-(N,N-dimethylamino)-3-(5-hydroxyhexyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (55 mg, 79% yield for 2 steps) as an oil. 1H NMR (300 MHz, benzene d6) δ 1.13 (d, 3H), 1.20-1.50 (m, 4H), 1.56-1.72 (m, 2H), 2.11 (s, 3H), 3.40 (s, 3H), 3.55 (m, 1H), 3.90 (t, 2H), 6.21 (s, 1H), 7.15 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:2].[CH2:14]([C:16](=[CH2:20])[C:17](O)=[O:18])[CH3:15]>>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17](=[O:18])[C:16]([CH2:14][CH3:15])=[CH2:20])=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13])#[N:2]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: C=C(CC)C(=O)O
Product: C=C(CC)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Following the procedure described in Example 1, starting from 4-cyano-3-trifluoromethyl-aniline and 2-ethyl-acrylic acid, the title compound was prepared as a yellow solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](N)[CH:18]=1)[CH3:3].N([O-])=O.[Na+].[I:29]I>CCOCC.C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([I:29])[CH:18]=1)[CH3:3]
Reactant: II
Reactant: CCOC(=O)CCCCCCCCCCCc1cccc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)CCCCCCCCCCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.8 %

Procedure:
Glacial acetic acid (4 ml) and concentrated HCl (2.5 ml) were added to a 50 ml Erlenmeyer flask containing ethyl-12-(m-aminophenyl)-dodecanoate (3.92 g, 12.28 mmol). The mixture was cooled in a NaCl/ice bath. A cold aqueous solution of NaNO2 (4 ml, 3.1M) was added to the mixture. The reaction was stirred for 40 minutes before a cold aqueous solution of KI/I2 (2.31 g/1.78 g, 7 ml H2O) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Ether was added to the reaction mixture. The ether layer was separated and extracted with H2O, 10% Na2S2O3, H2O, sat. NaHCO3, and brine. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a reddish oil. The crude product was purified by column chromatography (120 g silica gel, hexanes:-ethyl acetate 20:1) to yield a clear oil, compound 6, ethyl-12-(m-iodophenyl)-dodecanoate (5.28 g, 56.8% yield).
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH2:10]([OH:15])[CH2:11][CH:12]([CH3:14])[CH3:13]>>[CH3:13][CH:12]([CH3:14])[CH2:11][CH2:10][O:15][C:5]1[N:4]=[C:3]([O:15][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:2]=[C:7]([O:15][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[N:6]=1
Reactant: CC(C)CCO
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: CC(C)CCOc1cc(OCCC(C)C)nc(OCCC(C)C)n1
Temperature: 50 °C
Yield: 98.7 %

Procedure:
49.5 g (0.45 mol) of sodium t-amylate are dissolved in 200 ml of isopentanol at 50° C., and 13 ml (0.11 mol) of trichloropyrimidine in 50 ml of isopentanol are added dropwise to this solution over the course of 30 minutes. After the mixture has been warmed at 50° C. for one hour, thin-layer chromatography shows that the mixture no longer contains any starting material. The solvent is removed on a rotary evaporator, and the residue is poured into 200 ml of water. The mixture is extracted three times with 150 ml of toluene in each case, and the organic phases are dried using MgSO4 and filtered. Removal of the solvent gives 37.5 g (98.7% of theory) of 2,4,6-tris(3-methylbut-1-oxy)pyrimidine.
Reaction SMILES: [CH3:1][C:2]([NH:15]C(OCC1C=CC=CC=1)=O)([CH3:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[OH-].[Na+]>CO.O.[OH-].[OH-].[Pd+2]>[CH3:14][C:2]([NH2:15])([CH3:1])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: CC(C)(Cc1ccc2ccccc2c1)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(N)Cc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Palladium hydroxide on carbon (19.7 g) was suspended in methanol (500 ml), to the suspension was added a solution of N-[2-methyl-1-(naphthalen-2-yl)propan-2-yl]-benzyloxycarboxamide (237.6 g) obtained in Step 11 in methanol (2 L), and a hydrogenation reaction was performed at room temperature overnight. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and to the solution was added conc. hydrochloric acid (70 ml) to give crystals. The obtained crystals were suspended in water, and after an addition of 4N aqueous sodium hydroxide solution (350 ml), the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crystals of the title compound (138 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39](=[O:42])(=[O:41])[NH2:40])=[CH:29][C:28]=2[F:43])[C:7](=[O:25])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:21]([F:24])([F:23])[F:22])[N:9]=1)[CH2:2][CH2:3][CH3:4].[F:44][C:45]1[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=1[C:47](O)=[O:48].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>CN(C1C=CN=CC=1)C>[CH2:1]([C:5]1[N:6]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[S:39](=[O:41])(=[O:42])[NH:40][C:47](=[O:48])[C:46]3[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=3[F:44])=[CH:29][C:28]=2[F:43])[C:7](=[O:25])[N:8]([C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:13]=[CH:12][C:11]=2[C:21]([F:24])([F:22])[F:23])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Reactant: O=C(O)c1ccccc1F
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2F)cc1F
Yield: 93 %

Procedure:
Reaction of 5-n-butyl-2,4-dihydro-4-[(3-fluoro-2'-sulfamoyl-biphenyl-4-yl)methyl]-2-[5-(propionylamino)-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step C) with 2-fluorobenzoic acid (3 equivalents), CDI (3 equiv), DBU (3 equiv), and DMAP (3 equiv) according to the method of Example 51 (as modified in Example 81) gave a a 93% yield of the title compound as a white, stiff foam, mp 119°-122° C.; homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 742 (M+1)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH2:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>C(Cl)(Cl)(Cl)Cl>[CH2:10]([C:22]1[CH:23]=[CH:24][C:25]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:26][CH:27]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCC(=O)Cl
Reactant: CCCCCCCCCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(C(=O)CC)cc1

Procedure:
96.0 g (0.72 moles) of anhydrous aluminum chloride was added to a 1 L flask equipped with a stirrer, thermometer, and an addition funnel. 250 mL of carbon tetrachloride was added followed by 68.4 g (0.74 moles) of propionyl chloride from a pipette. This reaction mixture was cooled to 5°±3° C. and 153.9 g (0.625 mole) of "soft" dodecylbenzene (Dodane S, produced by Monsanto Chemical Co.) was then added over a 3 hour period while the temperature was maintained at 5°±3° C. The reaction was held at this temperature for an additional hour at which point approximately 500 mL of 10% HCl was slowly added with the temperature kept below 15° C. The reaction mixture was then washed 3 times with 5% HCL, once with water and the solvent stripped under vacuum. The residue was taken up in toluene and washed twice with 5% NaOH, once with water, once with dil. HCl, once with water and then stripped to give 192.0 g of a light brown, fluid oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)=[O:5])[CH3:2].[CH3:20]I>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[NH:8][C:9](=[O:12])[N:10]([CH3:20])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CNC(=O)NC1c1ccc(F)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CN(C)C(=O)NC1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
4-(4-Fluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (6 g, from Preparation 1), CsCO3 (7.5 g) was added to 50 mL of DMF, followed by CH3I (1.5 mL). The mixture was heated at 60° for 18 hours, then cooled to room temperature and poured into ice water. The resulting precipitate was recovered by filtration and air-dried to give 5.6 g of 4-(4-fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25]O)[CH:23]=2)[CH:18]=[N:17]1>>[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][O:1][C:2]3[N:6]([C:7]4[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=4)[N:5]=[CH:4][CH:3]=3)[CH:23]=2)[CH:18]=[N:17]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cn1ncc2ccc(CO)cc21
Product: Cn1ncc2ccc(COc3ccnn3-c3cc(C#N)ccn3)cc21
Yield: 11 %

Procedure:
The title compound was prepared in 11% yield from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (1-methyl-1H-indazol-6-yl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 4.09 (3H, s), 5.40 (2H, s), 5.78 (1H, d, J=1.6 Hz), 7.19-7.17 (1H, m), 7.40 (1H, dd, J=1.2 Hz, J=5.2 Hz), 7.51 (1H, s), 7.58 (1H, d, J=2.0 Hz), 7.75 (1H, s, J=8.4 Hz), 7.99 (1H, d, J=0.4 Hz), 8.07 (1H, s), 8.71 (1H, d, J=8.4 Hz). [M+H] Calc'd for C18H14N6O, 331; Found, 331.
Reaction SMILES: [ClH:1].[CH3:2][O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[N:13]=[CH:12][N:11]=[C:10]2[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[C:30][Si](C)(C)C)[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(O)C>O1CCCC1>[ClH:1].[C:29]([C:25]1[CH:24]=[C:23]([NH:22][C:10]2[C:9]3[C:14](=[CH:15][C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:7]([O:6][CH2:5][CH2:4][O:3][CH3:2])[CH:8]=3)[N:13]=[CH:12][N:11]=2)[CH:28]=[CH:27][CH:26]=1)#[CH:30]
Reactant: COCCOc1cc2ncnc(Nc3cccc(C#C[Si](C)(C)C)c3)c2cc1OCCOC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A slurry of the silyl compound, 6,7-bis(2-methoxyethoxy)-N-[3-[(trimethylsilyl)ethynyl]phenyl]-4-quinazolinamine monohydrochloride, prepared above (1.22 g, 2.43 mmol) in tetrahydrofuran (6.1 mL) was treated with a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (2.6 mL, 2.55 mmol) and stirred at room temperature for 1 hour. The solution was treated with 2-propanol (12.2 mL) and concentrated by evaporation. The oil in 2-propanol (20 mL) was treated with concentrated hydrochloric acid (0.2 mL) giving a precipitate. The mixture was stirred at room temperature for 1 hour. The solid was collected by filtration, washed with 2-propanol (2 mL) and dried in vacuo to afford the title product (747 mg, 72%) as an off white solid (mp 226-229° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[N:1])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: N#CCCCCCCCCN
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: N#CCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 16.4 %

Procedure:
A solution of 9-aminononanenitrile (2.0 g) in pyridine (60 ml) was treated with 4-chlorobenzenesulphonyl chloride (2.74 g) in portions. The solution was stirred for 18 hours then the solvent was removed in vacuo. The residue was dissolved in dilute hydrochloric acid and extracted with chloroform. The chloroform extract was dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with chloroform to give the title compound (0.7 g) as a low melting solid.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)#[N:2].Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>O.CCO>[OH:14][NH:13][C:1]([C:3]1[C:4]2[CH:5]=[CH:6][NH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)=[NH:2]
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cccc2[nH]ccc12
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
A mixture of 4-cyanoindole (0.64 g; 4.5 mmol), HCl×H2NOH (1.1 g; 15.8 mmol), and Na2CO3 (0.79 g; 7.43 mmol) in H2O (8 ml) and EtOH (2 ml) was gently stirred for 15 min, then refluxed for 6 h under N2. After cooling most of the EtOH was removed under reduced pressure and the product was extracted with EtOAc (3×10 ml). The organic phase was separated, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.74 g; 94%), as a creamy foam. 1H-NMR (DMSO-d6+CDCl3+CD3OD) 7.4-7.3 (m, 1H); 7.2-7.12 (m, 2H); 7.01 (t, 1H, J=7.8 Hz); 6.74 (d, 1H, J=3.1 Hz); 3.68 (HDO); 1.71 (broad s, H2O).
Reaction SMILES: C1C(=O)N(O[C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.[NH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH:21]=1>CN(C)C=O>[O:18]=[C:17]1[CH2:16][CH2:15][C:13](=[O:14])[N:12]1[O:11][C:9]([NH:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[C:22]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH:21]=1)=[O:10]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)ON2C(=O)CCC2=O)ccc1OCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N,N′-Disuccinimidyl carbonate (462 mg, 1.2 eq) was dissolved in 30 mL dimethylformamide and cooled to 0° C. To this was added the tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (500 mg, 1.81 mmol) dissolved in 10 mL dimethylformamide, drop-wise over 30 mins. The solution was removed from the ice bath and stirred at room temperature for 2 hr, then moved to an oil bath and stirred at 65° C. for 30 minutes. It was then removed from heating and allowed to cool to room temperature. It was used in the following step without purification. LCMS m/z (%)=474 (M+H, 100).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([CH2:23][N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:33])[CH2:31][NH2:32])[CH2:25]2)=[CH:21][CH:20]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH:32][CH2:31][C:30]([NH:29][C@H:26]1[CH2:27][CH2:28][N:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:35][CH:34]=2)[CH2:25]1)=[O:33])=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCC(=O)N[C@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N[C@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.060 mmol) in chloroform. (0.4 mL) was added to a solution of (S)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). After the reaction mixture was agitated at room temperature for 2.5 h, (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added and the mixture was agitated at room temperature for 12 h. The reaction mixture was filtered and the resin was washed with dichloromethane (0.5 mL). The filtrate and washing were combined, dichloromethane (4 mL) was added, and the solution was washed with 2 N aqueous NaOH solution (0.5 mL) to give (S)-3-[N-{3,5-bis(trifluoromethyl)benzoyl}glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (compound No. 5) (14.4 mg, 57%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 508.0 (M++H, C22H20ClF6N3O2).
Reaction SMILES: [C:1]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11](SC)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.CCN(C(C)C)C(C)C.[CH3:42][N:43]1[CH2:48][CH2:47][N:46]([C:49]2[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=2)[CH2:45][CH2:44]1>ClCCl>[C:1]([C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[C:11]([NH:53][C:52]2[CH:51]=[CH:50][C:49]([N:46]3[CH2:45][CH2:44][N:43]([CH3:42])[CH2:48][CH2:47]3)=[CH:55][CH:54]=2)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)c1cnc(SC)nc1C(=O)c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1C(=O)c1ccccc1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of Example 3A (200 mg, 0.661 mmol) in dichloromethane (2.2 mL) was added meta-chloroperoxybenzoic acid (179 mg, 0.728 mmol) in a single portion. After 1 hour, the reaction mixture was partitioned between 10% sodium thiosulfate solution and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL). Hunig's base (231 μl, 1.323 mmol) and 4-(4-methylpiperazin-1-yl)aniline (127 mg, 0.661 mmol) were added to the solution, and the reaction was heated to 45° C. for 3 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][C:14]([CH3:17])=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>N1C=CC=CC=1>[CH3:17][C:14]1[S:13][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:16][N:15]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Cc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Compound 105 (250 mg, 0.93 mmol) was suspended in pyridine (0.5 mL). Decanoyl chloride (141 mg, 0.74 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3 N HCl solution (5 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, and filtered. Evaporation of the solvent left a residue which was crystallized from hexanes and ethyl acetate (1:2) to give the product (297 mg, 0.70 mmol, 95%) as a solid, mp 141-142° C.; 1H NMR (500 MHz, DMSO) δ 0.82 (3, t, J=7.0 Hz), 1.10-1.30 (12, m), 1.54-1.63 (2, m), 2.32 (2, t, J=7.0 Hz), 2.45 (3, s), 8.25 (2, d, J=8.0 Hz), 8.28 (2, d, J=8.0 Hz), 10.25 (1, s), 13.87 (1, s); 13C NMR (125 MHz, DMSO) δ 13.9, 16.0, 22.1, 24.9, 28.5, 28.6, 28.8, 28.9, 31.2, 36.4, 118.5, 126.8, 135.5, 142.7, 154.1, 167.6, 171.7; MS (LCQ, ESI+) Calculated for C19H29N4O3S2 425.2, found 425.1 (M+H)+; HRMS (FAB+, m/z) Calculated for C19H29N4O3S2 425.1681, found 425.1678 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([CH3:32])[C:24]=1[S:25]([CH2:28][N+:29]([O-:31])=[O:30])(=[O:27])=[O:26])[NH2:21].O>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:21][C:20]2[CH:19]=[C:18]([CH3:17])[C:24]([S:25]([CH2:28][N+:29]([O-:31])=[O:30])(=[O:27])=[O:26])=[C:23]([CH3:32])[CH:22]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2ccc(Cl)cc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 27 h
Yield: 14.3 %

Procedure:
1.45 g (14.5 mmol) of calcium carbonate and then 2.3 g (10.9 mmol) of 4-chlorobenzenesulphonyl chloride are successively added to a mixture of 1.8 g (7.37 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 45 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 27 h at room temperature and then poured into 200 ml of water. This mixture is extracted 3 times with methylene chloride. The combined organic extracts are washed with water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) and then by recrystallization from chloroform, to give 0.44 g (14%) of 4-chloro-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide.