Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:27].[CH3:28]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:28])[CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[CH3:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C)c3)cc2)nc1=O
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(OCCc2ccc(Oc3ccc(Cl)c(C)c3)cc2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.7 %

Procedure:
A mixture solution of 2-[(2-{4-[(4-chloro-3-methylphenyl)oxy]phenyl}ethyl)oxy]-5-ethyl-4(1H)-pyrimidinone (30 mg, 0.078 mmol) and DIPEA (0.027 mL, 0.156 mmol) in DCM (2 mL) was added MeI (9.75 μL, 0.156 mmol). The mixture was stirred at room temperature for 3 h, and quenched with water. The aqueous layer was extracted with DCM. The combined organic layers was dried with anhydrous Na2SO4, filtered, concentrated, and purified via MDAP to afford the title compound (8 mg, 25.7% yield) as oil. LCMS: rt=3.56 min, [M+H+]=399
Reaction SMILES: C(OC(=O)C)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:19]1[CH2:23][CH2:22][O:21][CH2:20]1.C([N:27](C(=O)C)[C:28]1[NH:29][C:30](=[O:37])[C:31]2[NH:32][CH:33]=[N:34][C:35]=2[N:36]=1)(=O)C>C1(C)C=CC=CC=1>[OH:19][CH2:23][CH2:22][O:21][CH2:20][N:34]1[CH:33]=[N:32][C:31]2[C:30](=[O:37])[NH:29][C:28]([NH2:27])=[N:36][C:35]1=2
Reactant: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Reactant: C1COCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To a mixture of acetic anhydride (1.2 ml) and p-toluenesulfonic acid (0.09 g) was added with stirring dioxolane (1.02 g)--caution, exothermic. The solution was allowed to cool for several minutes. Diacetylguanine (1.45 g) and dry toluene (9 ml) were added and the reaction mixture was stirred at reflux for 18 hr. and then allowed to cool to room temperature. The toluene was decanted off and the residue triturated several times with benzene. Methanol (10 ml) was added to the residue and evaporated under reduced pressure. To the residue was added 40% aqueous methylamine (10 ml) and the mixture heated on a steam bath for 20 min. The water and methylamine were removed under reduced pressure, ethanol (10 ml) was added and evaporated. The residue was thoroughly extracted with boiling methanol (700 ml total) and the combined extracts evaporated. The resulting solid was triturated with cold ethanol and then recrystallized from methanol to give 9-(2-hydroxyethoxymethyl)guanine (0.3 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:13])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CSc1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of 50.0 g (325 mMol) of 4-(methylthio)benzyl alcohol in 350 ml of toluene stirring at room temperature under nitrogen, was added 5 drops of pyridine, and then 28.4 ml (46.4 g, 390 mMol, 1.2 eqs) of thionyl chloride was added dropwise. After 3 hours, ice water was added and the mixture was stirred for 20 minutes. The mixture was transferred to a separatory funnel and shaken thoroughly. The organic layer separated and was dried over sodium sulfate, filtered, and evaporated. Distillation of the residue under reduced pressure gave (4-methylthiophenyl)chloromethane (50.54 g) as a colorless liquid: b.p. 89°-95° C. (1 mm).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.NC1CCN(CCN2CCOCC2)CC1>C(N(CC)CC)C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][CH:2]=[N:3][CH:4]=3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: NC1CCN(CCN2CCOCC2)CC1
Solvent: CCN(CC)CC
Product: c1ncc2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[4-(1-2-(4-morpholinyl)ethyl))piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(2-(4-morpholinyl)ethyl)piperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:32][O:33][C:34](=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=O.Cl.[NH2:46][CH2:47][C:48]([C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[O:57][CH:58]([CH3:60])[CH3:59])=[O:49]>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](=[O:43])[NH:46][CH2:47][C:48]([C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[O:57][CH:58]([CH3:60])[CH3:59])=[O:49]
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: CC(C)Oc1ccc(Cl)cc1C(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCCCCCC(=O)NCC(=O)c1cc(Cl)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 4224.7 %

Procedure:
Add diisopropylethylamine (99 ml, 568 mmol) dropwise to a solution of EDC HCl (38.01 g, 198 mmol), HOBt (19.19 g, 142 mmol) and octanedioic acid monomethyl ester (53.44 g, 1.42 mmol) in methylene chloride (800 mL) at 0° C. under nitrogen. Warm the mixture to room temperature and stir for 1 hour. Add 2-amino-1-(5-chloro-2-isopropoxyphenyl)ethanone hydrochloride (53.44 g, 142 mmol) to the mixture and stir for 18 hours. Remove the solvent under reduced pressure, dilute the residue in ethyl acetate (300 mL), wash with water (100 mL) and brine (100 mL), and dry over magnesium sulfate. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (4:6 to 0:10), to afford 7-[2-(5-chloro-2-isopropoxyphenyl)-2-oxoethylcarbamoyl]-heptanoic acid methyl ester (23.87 g, 23% over three steps).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:25]4[O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[OH-].[K+].Cl>C1COCC1.CO.C(OCC)(=O)C>[CH:23]1[C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][C:25]=2[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][S:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)CCSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
A solution of 3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-propanoic acid methyl ester (210 mg, 0.46 mmol) in THF (2 mL) and methanol (2 mL) was cooled to 0° C. and treated with 2 N KOH (1.0 mL). After stirring at room temperature for 1 h the solution was acidified with 10% HCl to pH 2 and diluted with ethyl acetate (25 mL). After being seperated, the aqueous layer was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried over MgSO4 and concentrated. Purification by flash column chromatography (2-5% methanol in dichloromethane) provided 3-(4′-dibenzofuran-4-yl-biphen-4-ylmethylsulfanyl)-propanoic acid (180 mg, 90%) as white solid. 1H NMR (CDCl3), 8.01 (d, J=8 Hz, 2H), 7.94 (d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 5H), 3.82 (s, 2H), 3.82 (s, 2H), 2.76 (m, 2H), 2.56 (t, J=6 Hz, 2H). LCMS 462 (M++23).
Reaction SMILES: [C:1](=[O:4])(O)[O-:2].[Na+].[CH3:6][O:7][C:8]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=2)[CH2:13][NH:12][CH2:11]1)=[O:9]>C(Cl)Cl>[CH3:6][O:7][C:8]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=2)[CH2:13][N:12]([C:1]([O:2][C:10]([CH3:14])([CH3:11])[CH3:8])=[O:4])[CH2:11]1)=[O:9]
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1cccc(Br)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Add a saturated aqueous solution of sodium bicarbonate (350 mL) to a solution of trans-4-(3-bromo-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (11 g, 38 mmol) in methylene chloride (350 mL). Cool the mixture to 0° C. and add BOC-anhydride (8.9 g, 41 mmol) dropwise. Slowly warm the mixture to room temperature and stir for 12 h. Extract the reaction mixture with methylene chloride, dry the combined organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. Purify the residue by silica gel chromatography to provide 13 g of trans-4-(3-bromo-phenyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[N+:13]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].[CH3:23][O:24][CH2:25][C@@H:26](O)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:23][O:24][CH2:25][C@H:26]([O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)[CH3:27]
Reactant: COC[C@H](C)O
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC[C@@H](C)Oc1cccc([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 65.8 %

Procedure:
DEAD (1.97 mL, 10.8 mmol) was added dropwise to a stirred mixture of 3-nitrophenol (2.50 g, 18 mmol), (2S)-1-methoxypropan-2-ol (648 mg, 7.2 mmol) and triphenylphosphine (2.84 g, 10.8 mmol) in DCM (10 ml). The reaction mixture was stirred for 16 h then treated with saturated aqueous sodium hydrogen carbonate solution. The resultant mixture was partitioned and the organics were washed with 1M NaOH, dried and concentrated by evaporation. The residue was triturated with 1:1 EtOAC/hexanes. and filtered. The filtrate was concentrated by evaporation and the residue was purified by chromatography eluting with 25% EtOAc/hexane to give the title compound (1 g) as an oil; 1H NMR (400 MHz, DMSO) δ1.24 (d, 3H), 3.24 (s, 3H), 3.44-3.60 (m, 2H), 4.71-4.89 (m, 1H), 7.38-7.48 (m, 1H), 7.57 (t, 1H), 7.70-7.76 (m, 1H), 7.76-7.86 (m, 1H).
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)(=O)=O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2ccccc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCCCc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Yield: 100.4 %

Procedure:
Sodium iodide (29.25 g) was dissolved in acetone (195 ml); 4-[4-(benzyloxy)phenyl]butyl methanesulfonate (13 g) was added, followed by refluxing at 80° C. for 1.5 hours. After cooling, the solvent was distilled off; to the residue, ethyl acetate (750 ml) was added; the mixture was washed sequentially with water, an aqueous solution of sodium thiosulfate, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure to yield the titled compound (14.29 g) as an oily substance. This product was used for the next process without purification.
Reaction SMILES: [CH:1]1([O:11][C:4]2([CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[O:3]1)[CH3:2].[CH:12]([C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:20])=[C:17](O)[CH:16]=1)([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOCC.CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:24](=[O:25])[C:23]2[CH:34]=[CH:35][CH:36]=[CH:37][C:22]=2[NH:21][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:39][C:38]=2[O:10][CH:7]2[CH2:8][CH2:9][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:5][CH2:6]2)=[N:28][CH:29]=1
Reactant: CC1OC2(CCC(O)CC2)O1
Reactant: CC(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCC3(CC2)OCCO3)c1
Reaction time: 1 h

Procedure:
4-Hydroxycyclohexanone-1,1-ethylene ketal (0.63 g, 4 mmol), 2-[4-isopropyl-2-hydroxybenzoylamino]-N-(5-chloropyridin-2-yl)benzamide (1.64 g, 4 mmol), triphenyl-phosphine (1.05 g, 4 mmol), and dry DMF (2 mL) were sonicated for 5 min at room temperature. DIAD (0.8 mL, 4 mmol) was added and sonication was continued for 1 h. Ether (40 mL) was added and the solution was chilled overnight in the freezer to crystallize triphenylphosphine oxide. The crystals were filtered, washed with a little ether, and the combined filtrates were evaporated to dryness to give a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH:13]=[O:14])[C:4](=[O:15])[N:3]1[CH3:16].CC(=CC)C.Cl([O-])=[O:23].[Na+].P([O-])([O-])[O-].[K+].[K+].[K+]>C(O)(C)(C)C.O>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]([OH:23])=[O:14])[C:4](=[O:15])[N:3]1[CH3:16]
Reactant: [O-][Cl+][O-]
Reactant: Cn1c(-c2ccccc2)c(C=O)c(=O)n1C
Agent: CC=C(C)C
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cn1c(-c2ccccc2)c(C(=O)O)c(=O)n1C
Temperature: 25 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
1,2-Dimethyl-3-oxo-5-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde was dissolved in t-butyl alcohol (23.5 mL) and 2-methyl-2-butene (8.3 mL, 78.5 mmol) was added at 0° C. After adding an aqueous solution of sodium chlorite (80% tech, 0.95 g, 8.7 mmol) in water (10 mL) and a suspension of potassium phosphite monobasic (3.44 g, 25.3 mmol) in water (23.5 mL) to the resulting reaction mixture, the mixture was stirred at room temperature for 10 hours. After adding water to the stirred reaction mixture, the aqueous layer was extracted with ethyl acetate, dichloromethane and 10:1 dichloromethane/methanol. The organic layer was collected, dried with sodium sulfate, and then filtered. The filtrate was concentrated. The resulting residue was washed with a small volume of ethyl acetate to give the target compound as a white solid (350 mg, 1.5 mmol, 35% yield).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:48])[CH2:14][N:15]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:16]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:27]([O:29]C(C)(C)C)=[O:28])=[O:21])=[O:17])=[O:7])(C)(C)C>Cl.O1CCOCC1>[CH2:41]([N:15]([CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:48])[C:16]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:19][C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[C:27]([OH:29])=[O:28])=[O:21])=[O:17])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CN(Cc1ccccc1)C(=O)N(CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CCCN1C(=O)CN(Cc1ccccc1)C(=O)N(CC(=O)N1CCC[C@@H]1C(=O)O)Cc1ccccc1
Yield: 40.7 %

Procedure:
A solution of 220 mg (0.33 mmol) (R)-1-[[1,3-Dibenzyl-3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-ureido]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml 4 N hydrochloric acid solution in dioxane was stirred for 5 h at room temperature. The product was extracted with 1 N sodium hydroxide solution, the basic extract was acidified with 1 N hydrochloric acid solution to pH 4 and the product extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and evaporated to give 74 mg (41 %) of the title compound as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:15]([O:14][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C

Procedure:
A solution of 4-nitrobenzenesulfonyl chloride (4.44 g) in methylene chloride (50 ml) was added to a stirred solution of tert-butyl 3-(R)-hydroxypyrrolidine-1-carboxylate (3.75 g) and pyridine (2.5 ml) in methylene chloride (30 ml) at 10° C. and the mixture allowed to warm to ambient temperature with stirring. The reaction mixture was poured into saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and dried over sodium sulfate. The solution was evaporated under vacuum to give tert-butyl3-(R)-[(4-nitrophenyl)sulfonyloxy]pyrrolidine-1-carboxylate as a yellow crystalline solid. (4.37 g, 59%); 1H NMR Spectrum: (CDCl3) 1.43 (s, 9H), 1.80-2.40 (m, 2H), 3.30-3.65 (m, 4H), 5.20 (hs, 1H), 8.10 (d, 2H), 8.42 (d, 2H).
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH3:29])[C:6]([C:8]1[CH:21]=[N:20][C:19]2[C:10](=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]([C:22]([O:24]CC)=[O:23])[C:14]3=[O:27])[CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]>Cl>[CH2:1]([N:5]([CH2:28][CH3:29])[C:6]([C:8]1[CH:21]=[N:20][C:19]2[C:10](=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]([C:22]([OH:24])=[O:23])[C:14]3=[O:27])[CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC)C(=O)c1cnc2c3c(ccc2c1)C(=O)C(C(=O)OCC)C=N3
Agent: Cl
Product: CCCCN(CC)C(=O)c1cnc2c3c(ccc2c1)C(=O)C(C(=O)O)C=N3
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 8-(N-butyl-N-ethylcarbamoyl)-3-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline (12 g) and 2M hydrochloric acid (300 ml) was stirred at reflux for 2 hours. The mixture was cooled to ambient temperature, filtered and the solid washed with water. The solid so obtained was recrystallised from acetonitrile to give 8-(N-butyl-N-ethylcarbamoyl)-3-carboxy-4-oxo-3,4-dihydro-1,10-phenanthroline in 76% yield, mp 236-237° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][N:15]1[CH2:27][C:26]2[C:17](=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]([CH3:28])[NH:21][CH2:20][CH2:19]3)[C:16]1=[O:29]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[C:26]5[CH2:27][N:15]([CH3:14])[C:16](=[O:29])[C:17]5=4)[CH:22]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1ccc1c2C(=O)N(C)C1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc3c(c2CCN1C(=O)c1cc2ncc(Br)cn2n1)C(=O)N(C)C3

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-2,3,6,7,8,9-hexahydro-pyrrolo[3,4-f]isoquinolin-1-one to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([CH:8]1[CH2:13][C:12]2([CH2:16][NH2:17])[CH2:14][CH2:15][C:9]1([C:18]([OH:20])=O)[CH2:10][CH2:11]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)([N:23]1C=CN=C1)=O.[NH4+].[OH-].O>CN(C=O)C>[C:1]([CH:8]1[CH2:13][C:12]2([CH2:16][NH2:17])[CH2:11][CH2:10][C:9]1([C:18]([NH2:23])=[O:20])[CH2:15][CH2:14]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)C1CC2(CN)CCC1(C(=O)O)CC2
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CC2(CN)CCC1(C(N)=O)CC2

Procedure:
A stirred solution under N2 of 12.0 g (42.5 mmol) of the product from step B in 100 ml of DMF was treated with 8.0 g (49.3 mmol) of carbonyldiimidazole. After 30 min the DMF was evaporated in vacuo to afford 50-60 ml of a light brown paste, which was stirred and treated with 70 ml of conc. NH4OH rapidly added. The initial solution turned to a white paste within 30 min, after which H2O was added up to a total volume of 400 ml to complete precipitation of product, which was triturated and isolated by filtration and washing with H2O, and dried in vacuo to yield the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:49]=1[NH2:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:50][C:49]4[CH:51]=[C:52]([CH3:55])[CH:53]=[CH:54][C:48]=4[F:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(F)c(N)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cc(C)ccc2F)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2-fluoro-5-methylaniline (Aldrich) to give the title product. LC-MS (ES+) 772 [(M+H)+].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH3:16])[C:5]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6]>O>[F:1][C:2]([F:17])([F:18])[CH2:3][C@@H:4]([CH3:16])[C:5]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6]
Reactant: CC(CC(F)(F)F)C(=O)N[C@@H](C)c1ccccc1
Solvent: O
Product: C[C@H](CC(F)(F)F)C(=O)N[C@@H](C)c1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
Impure 4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide (94(R):6(S)) (5.0 g), prepared by a method similar to that described in step a) above, was dissolved in industrial methylated spirits (18.75 ml) by heating under reflux with stirring. Water (18.75 ml) was then added slowly, while continuing to heat the solution under reflux. The mixture was then heated under reflux for a further 45 minutes, and was then allowed to cool to room temperature, with continued stirring, overnight. The mixture was then filtered, and the crystalline product was washed with water (10 ml) and dried at 65° C. to give the title compound 4.45 g (89%). The product contained only 0.3% of the unwanted (S)-diastereomer.