Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](=[C:3]([C:17]([CH3:19])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-:2].[I-].[Na+].C(N(CC)CC)C.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31]>C(#N)C>[N+:1](=[C:3]([C:17]([O:18][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH2:19])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(O[Si](C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Into 5 ml of dry acetonitrile were suspended 263 mg (1 millimole) of p-nitrobenzyl 2-diazoacetoacetate and 210 mg (1.4 millimoles) of sodium iodide. To the mixture were added 220 μl (1.6 millimoles) of triethylamine and then 190 μl (1.5 millimoles) of trimethylsilyl chloride while agitating in an argon atmosphere at a room temperature. After the resulting orange suspension was agitated at a room temperature for an hour, it was concentrated under a reduced pressure. To the residue was added 20 ml of dry hexane, and the resultant was agitated for 30 min. at a room temperature. Insoluble materials were removed by filtration and the hexane solution was concentrated to dryness under a reduced pressure to give 330 mg (yield 98 %) of the desired compound in a yellow solid. The physical properties of the product were in agreement with those of the product obtained in Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]2[C@H:24]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:25][CH2:26][N:20]2[C:19](=[O:34])[CH2:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[BrH:35]>C(O)(=O)C>[BrH:35].[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]2[C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26][N:20]2[C:19](=[O:34])[CH2:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CCC(=O)N2CC[C@@H](C(=O)OC(C)(C)C)N2C1=O
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CCC(=O)N2CC[C@@H](C(=O)O)N2C1=O
Yield: 65 %

Procedure:
A solution of 0.15 g of tert.butyl 8(S)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylate in 0.3 ml of acetic acid was treated at room temperature for 0.5 hour with 1.3 ml of 45% hydrogen bromide solution in acetic acid. The mixture was then evaporated and the resulting oily solid was triturated with diethyl ether to give 0.11 g (65%) of 8(S)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-2,3,6,7,8,9-hexahydro-5,9-dioxo-1H,5H-pyrazolo[1,2-a][1,2]diazepine-1(S)-carboxylic acid hydrobromide in the form of a light tan coloured solid of melting point 207°-210° C.
Reaction SMILES: O.O[N:3]1[C:7]2C=CC=[CH:11][C:6]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:24]([O:28][C:29]([N:31]1[CH2:38][C@@H:37]([OH:39])[CH2:36][C@H:32]1[C:33]([OH:35])=O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CN(C)C=O>[N:3]1([C:33]([C@@H:32]2[CH2:36][C@H:37]([OH:39])[CH2:38][N:31]2[C:29]([O:28][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:30])=[O:35])[CH2:11][CH2:6][CH2:7]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)N1CCC1
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
2.19 g of 1-hydroxybenzotriazole monohydrate and 2.49 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added under ice cooling to a 25 mL N,N-dimethylformamide solution of 2.50 g of (4S)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline and stirred for 30 minutes. 1.23 g of trimethyleneimine was added dropwise over a period of 1 minute to the reaction mixture, and the reaction mixture was stirred for 16 hours at room temperature. 30 mL of ethyl acetate and 20 mL of a 5% potassium carbonate aqueous solution were added to the reaction solution and stirred for 30 minutes. After liquid separation, the aqueous layer was extracted with ethyl acetate (50 mL×2), and the combined organic layer was washed with water (50 mL×3) and 50 mL of saturated brine, and then dried with anhydrous magnesium sulfate, after which the drying agent was filtered off, and the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate) to obtain 2.81 g of the titled compound (pale yellow solid).
Reaction SMILES: [F:1][C:2]1[C:33]([NH:34][S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])=[CH:32][CH:31]=[C:30]([F:41])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]#[C:17][CH2:18][O:19][CH3:20])=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].CN(C)CC#CC1NC2=NC=C(NC(=O)C3C(F)=CC=C(NS(CCC)(=O)=O)C=3F)C=C2C=1>>[F:1][C:2]1[C:33]([NH:34][S:35]([CH2:38][CH2:39][CH3:40])(=[O:36])=[O:37])=[CH:32][CH:31]=[C:30]([F:41])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(C#CCOC)cn3S(=O)(=O)c2ccccc2)c1F
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C#CCN(C)C)cc3c2)c1F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(CCCOC)c3c2)c1F
Yield: 90 %

Procedure:
2,6-Difluoro-N-(3-(3-methoxypropyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (90%) was prepared according to the general procedure for Example 95 substituting 2,6-difluoro-N-(3-(3-methoxyprop-1-ynyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide for N-(2-(3-(dimethylamino)prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide. 1H NMR (400 MHz, DMSO-d6) δ 11.33 (br s, 1H), 10.83 (s, 1H), 9.79 (br s, 1H), 8.47-8.38 (m, 2H), 7.51-7.57 (m, 1H), 7.24-7.28 (m, 2H), 4.45-4.48 (m, 1H), 3.44-3.49 (m, 2H), 3.11-3.15 (m, 2H), 2.68-2.72 (m, 2H), 1.75-1.81 (m, 4H), 0.98-1.02 (m, 3H); m/z (APCI-pos) M+1=451.2.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)=[N:18][CH2:17][CH2:16]2)[CH3:5])[CH:2]=[CH2:3].[BH4-].[Na+]>C(O)C>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[NH:18][CH2:17][CH2:16]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCCCOc1ccc2c(c1)CCN=C2c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCN(C)CCCCCCOc1ccc2c(c1)CCNC2c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
0.3 g of allyl-[6-[1-(4-bromo-phenyl)-3,4-dihydro-isoquinolin-6-yloxy]-hexyl]-methyl-amine (Ex. 20d) is dissolved in 50 ml of ethanol and cooled to 0° C. using an ice bath. A total of 0.185 g of sodium borohydride is added in three portions within 10 minutes and the mixture is warmed to room temperature and stirred overnight. For the working-up, the reaction mixture is evaporated to a quarter and adjusted to pH~2 with 2M hydrochloric acid solution, again made basic with concentrated ammonia solution and extracted three times with methylene chloride. After evaporation of the organic extracts and chromatography of the residue on silica gel with toluene/acetone/triethylamine (50:49:1) as the eluent there is obtained 0.23 g of (RS)-allyl-[6-[1-(4-bromo-phenyl)-1,2,3,4-tetrahydro-isoquinolin-6-yloxy]-hexyl]-methyl-amine which is converted into the hydrochloride, MS: m/e 457 (M+H+, 1 Br).
Reaction SMILES: [C:1]1([C:7]([CH3:12])([OH:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>CCOCC>[C:1]1([C:7]([CH3:12])([OH:11])[C:8]([O:10][CH2:18][CH3:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC(O)(C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)c1ccccc1

Procedure:
(±)-Phenyllactic acid (4.96 g) and 1/2 ml concentrated sulfuric acid in 150 ml absolute ethanol is refluxed for 18 hours. Solvent is stripped, the residue is dissolved in ether, and extracted with saturated sodium bicarbonate solution. The ether is dried, filtered, and stripped to leave (±)-ethyl phenyllactate. NMR (CDCl3): δ1.3 (t, 3H), 3.0 (d of d, 1H), 3.1 (d of d, 1H), 4.2 (q, 2H), 4.4 (d of d, 1H), 7.3 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](O)=[O:25])=[O:17].Cl.C(N=C=NCCCN(C)C)C.O[C:43]1[C:51]2[N:50]=N[NH:48][C:47]=2[CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([NH:48][C:47]1[CH:46]=[CH:45][CH:44]=[CH:43][C:51]=1[NH2:50])=[O:25])=[O:17]
Reactant: O=C(O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 77.9 %

Procedure:
6-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid (396 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (379 mg, 78% yield) as a brown solid. 1H NMR (DMSO-d6)δ1.36 (m, 2H, CH2), 1.59 (m, 4H, CH2), 2.30 (t, J=8.0 Hz, 2H, CH2CO), 3.29 (t, J=8.0 Hz, 2H, NCH2), 4.80 (s, 2H, benzene-NH2), 6.50 (t, J=8.0 Hz, 1H, Ar—H), 6.69 (d, J=8.0 Hz, 1H, Ar—H), 6.87 (m, 2H, Ar—H), 7.12 (m, 2H, Ar—H), 7.54 (d, J=8.0 Hz, 1H, Ar—H), 7.64 (m, 1H, Ar—H), 7.73 (s, 0.6 H, vinyl-H), 7.83 (m, 1H, Ar—H), 7.94 (m, 1H, Ar—H), 8.15 (s, 0.4 H, vinyl-H), 8.57 (m, 1H, Ar—H), 9.08 (s,1H, benzene-NH), 10.68 (s, 1H, CONH). LC-MS (m/z) 487 (M+1).
Reaction SMILES: [CH2:1]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]([O:23][CH3:24])=[O:22]>C(COC)OC.N1C=CC=CC=1>[CH2:1]([CH2:8][NH:9][C:10]1[CH:11]=[C:12]([NH:13][C:21](=[O:22])[O:23][CH3:24])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])c(NCCc2ccccc2)c1
Reactant: COC(=O)Cl
Solvent: COCCOC
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc([N+](=O)[O-])c(NCCc2ccccc2)c1
Temperature: 20 °C
Yield: 84 %

Procedure:
A stirred solution of 3-(N-benzylmethylamino)-4-nitroaniline (2.2 g, 8.5 mM) in dry dimethoxyethane (15 ml) and pyridine (4 ml) was treated dropwise with methyl chloroformate (10 mM) at 0° C. The mixture was allowed to warm slowly to 20° C. and after 3 h was quenched with water (5 ml). Volatile solvents were removed under vacuum and the residue was extracted with ethyl acetate. After successive washings with aqueous methanesulfonic acid, water, aqueous KHCO3 and brine the organic layer was dried over Na2SO4. Removal of the solvent and chromatography of the residue on silica gel in ethyl acetate-petroleum ether (3:7) gave the product as a bright red oil (2.25 g, 84% yield).
Reaction SMILES: [OH:1][CH:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=2)=[CH:32][CH:31]=1)[CH2:3][CH:4]=[CH:5][C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.Cl>[C].[Pd]>[OH:1][CH:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=2)=[CH:34][CH:35]=1)[CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1
Reactant: CNC(=O)c1cccc(-c2ccc(C(O)CC=Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c1
Agent: [Pd]
Agent: Cl
Product: CNC(=O)c1cccc(-c2ccc(C(O)CCCc3c[nH]cn3)cc2)c1
Yield: 65.8 %

Procedure:
By the reaction in the same manner as in Example 41-(ii) using [4′-[1-hydroxy-(1-trityl-1H-imidazol-4-yl)-3-butenyl]-N-methyl[1,1′-biphenyl]-3-carboxamide (690 mg), 10% palladium carbon (690 mg) and 1N hydrochloric acid (1.17 ml), the colorless amorphous title compound (269 mg) was obtained. The colorless amorphous title compound (420 mg) was obtained.
Reaction SMILES: [Cl-].[NH4+].O.[CH2:4]([O:9][C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:11]=1[C:12]#[N:13])[C:5]([CH3:8])([CH3:7])[CH3:6]>[Fe].C(O)C>[NH2:18][C:15]1[CH:16]=[CH:17][C:10]([O:9][CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: CC(C)(C)COc1ccc([N+](=O)[O-])cc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)COc1ccc(N)cc1C#N
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a dimethylformamide solution (364 ml) containing 2-chloro-5-nitrobenzonitrile (91 g) and neopentyl alcohol (52 g) was added sodium hydride (60% contained, 27.8 g) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give 2-neopentyloxy-5-nitrobenzonitrile (105 g). Subsequently, ammonium chloride (10 g) and iron powder (75 g) were added to a mixed solvent of water (286 ml) and ethanol (753 ml) and the mixture was heated to 65° C. 2-Neopentyloxy-5-nitrobenzonitrile (80.5 g) was added by portions over 20 min and the mixture was stirred at the refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. An aqueous sodium hydroxide solution was added and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (70 g). melting point: 55-56° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:4]>C(#N)C>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][S:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(CSCCNC(=O)CCl)cc1
Solvent: CC#N
Product: COc1ccc(CSCCNCC(=O)NCCSCc2ccc(OC)cc2)cc1

Procedure:
4-Methoxybenzyl chloride (15.6 g) was reacted with 2-aminoethanethiol (7.7 g) in methanol and sodium methoxide, to afford of 2-(4-methoxybezyl-sulfanyl)-ethylamine (1) (18.8 g). One half of this material was taken in dichloromethane (cooling bath 0° C.). Chloroacetyl chloride in the same solvent, was added slowly with stirring, followed by an equivalent of triethyl amine to produce 2-chloro N-[2-(4-methoxybenzyl-sulfanyl)-ethyl]acetamide (2) in a 94% yield. Compound 2 was reacted with an equivalent amount of 1 in refluxing acetonitrile for 6 hrs to provide N-[-2-(4-methoxy-benzylsulfanyl)-ethyl]-2-[2-(4-methoxy-benzylsulfanyl)-ethylamino]-acetamide (3) (40.4 g). Compound 3 was reduced with lithium aluminium hydride (LAH) to yield 4 in 85%.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:10]([Mg]Br)[CH2:11][CH3:12]>O1CCCC1>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:8])[CH2:10][CH2:11][CH3:12])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
To a flame-dried flask under an argon atmosphere is added 0.59 mL of commercially available p-tolualdehyde and charged with 15 mL of tetrahydrofuran. The solution is cooled to 0° C. and is treated with 3.0 mL (2.0M in diethyl ether) of propylmagnesium bromide. The reaction mixture is left to warm to room temperature overnight and then quenched by the addition of aqueous ammonium chloride. After dilution with diethyl ether the phases are separated; the organic layer is washed with saturated ammonium chloride, brine, dried (magnesium sulfate) and finally concentrated under reduced pressure. The residue is flash column chromatographed using 20% to 30% diethyl ether in hexane to yield 980 mg of the title product as a clear, colorless oil.
Reaction SMILES: Br[CH2:2][C:3](=[O:27])[C@:4]1([OH:26])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][C@@H:5]1[CH3:25].[C:28]([O-:31])(=[O:30])[CH3:29].[K+]>>[C:28]([O:31][CH2:2][C:3](=[O:27])[C@:4]1([OH:26])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][C@@H:5]1[CH3:25])(=[O:30])[CH3:29]
Reactant: CC(=O)[O-]
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@]2(C)[C@@]1(O)C(=O)CBr
Agent: [K+]
Product: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Temperature: 25 °C
Yield: 92 %

Procedure:
The suspension of 21-bromo-17α-hydroxy-16β-methyl-4-pregnene-3,11,20-trione is heated under agitation with 61.74 g of potassium acetate and for 90 minutes to 50° C. Then the methanol is extensively removed by distillation, the reaction mixture is allowed to cool down to room temperature, the reaction product is suctioned off, washed with water, and dried under vacuum at 50° C., thus obtaining 42.9 g of 21-acetoxy-17α-hydroxy-16β-methyl-4-pregnene-3,11,20-trione, mp 214°-219° C. Yield=92% of theory. Product purity 93.8%.
Reaction SMILES: [O:1]1CCC[CH2:2]1.[CH2:6]([N:10]1[C:18]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][C:16]2[C:11]1=[N:12][C:13]([C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1)=[N:14][C:15]=2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]1[CH3:31])[CH:7]([CH3:9])[CH3:8].N1(C=O)C2C=CC=CC=2N=N1.[OH-].[Na+]>CCOCC.C(Cl)(Cl)Cl>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[C:18]([N:19]4[CH2:24][CH2:23][N:22]([CH:2]=[O:1])[CH2:21][CH2:20]4)[N:10]3[CH2:6][CH:7]([CH3:9])[CH3:8])=[C:15]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[CH3:31])[N:14]=2)=[CH:33][N:34]=1
Reactant: C1CCOC1
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Agent: O=Cn1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)Cn1c(N2CCN(C=O)CC2)nc2c(N3CCOC[C@@H]3C)nc(-c3cnc(N)nc3)nc21
Yield: 79 %

Procedure:
A tetrahydrofuran (3 ml) solution of 5-{9-isobutyl-6-[(3S)-3-methylmorpholin-4-yl]-8-piperazin-1-yl-9H-purin-2-yl}pyrimidin-2-amine (103 mg, 0.23 mmol) and 1H-benzotriazole-1-carboaldehyde (37 mg, 0.25 mmol) was stirred at room temperature for 16 hours. Chloroform and 2 N aqueous sodium hydroxide solution were added to the reaction mixture and the resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=95:5) to give a solid. Ether was added to the resulting solid and the solid was collected by filtration and dried to give the title compound (86 mg, 79%) as a powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CCC(O)CC2)cc1
Temperature: 95 °C

Procedure:
A 2 liter three necked flask fitted with a mechanical stirrer, theromometer and condenser is charged with 180 g of 4-hydroxypiperidine, 74.4 g of 4-fluorobenzaldehyde, 1 ml of Aliquot 336, 750 ml of dimethylsulfoxide and 82.8 g of anhydrous potassium carbonate. The mixture is heated at 95° C. for three days, then the product mixture is cooled and poured into 3 liters of ice water. The resultant solid precipitate is filtered, washed with water, and vacuum dried. The crude product is recrystallized from toluene, m.p. 115°-118° C.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[N+:8]([C:11]1[CH:16]=CC(O)=[CH:13][CH:12]=1)([O-:10])=[O:9].O>N1C=CC=CC=1>[N+:8]([C:11]1[CH:16]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Acetic anhydride (50 ml) is added to a solution of 4-nitrophenol (5.56 g, 40 mmol) in dry pyridine (50 ml). The solution is stirred at ambient temperature for 2 hr and then at 70° C. overnight with a reflux condenser under Ar. The mixture is poured onto ice, and a white precipitate is formed after standing for several hours. Water (400 ml) is added, and the white solid is collected by vacuum filtration and dried in vacuo to yield a white solid (5.1 g, 70%). ESI-MS (M+H)+: 182.2. 1H-NMR (CDCl3) δ 8.30 (2H, d, J=9.0 Hz, NO2CCH), 7.31 (2H, d, J=9.0 Hz, OCCH), 2.25 (3H, s, CH3).
Reaction SMILES: C([O:3][C:4](=[O:36])[C@@H:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].C(OCC)(=O)C.CCCCCCC>O1CCCC1.O.ClCCl.CO>[CH2:26]([S:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:33][CH2:34][CH3:35])[C:4]([OH:36])=[O:3])=[CH:12][CH:11]=2)=[CH:17][CH:18]=1)(=[O:24])=[O:25])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NS(=O)(=O)Cc3ccccc3)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NS(=O)(=O)Cc3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.1 %

Procedure:
3-[4-{2-(4-Benzylsulfonylaminophenyl)ethoxy}phenyl]-2-(S)-ethoxypropanoic acid ethyl ester (described in Example 66) (0.15 g; 0.29 mmole) was dissolved in tetrahydrofuran(2 ml). Lithium hydroxide (0.0084 g; 0.35 mmole) in water (2 ml) was added. The reaction mixture was stirred at room temperature. After 6 hours, the reaction was checked by TLC (silica gel, ethyl acetate:heptane=50:50) and it was not complete. More. lithium hydroxide (approx. 0.01 g), was added the reaction mixture was stirred overnight and tetrahydrofuran was evaporated. The remaining solution was extracted with diethyl ether. The water phase was acidified with hydorchloric acid (1%) to pH˜2 and extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane and then dichloromethane:methanol (98:2) as eluant gave 0.125 g (88% yield) of 3-[4-{2-(4-benzylsulfonylaminophenyl)ethoxy}phenyl]-2-(S)-ethoxypropanoic acid.