Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@H:6]1[C@@H:11]2[C@@H:9]([C@H:10]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@:8]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:7]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1.C(N(CC)CC)C>ClCCl.O>[C:1]([NH:5][C@H:6]1[C@@H:11]2[C@@H:9]([C@H:10]2[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C@:8]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[C@@H:7]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](N)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]1OCc1ccc(Cl)c(Cl)c1
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
Acetyl chloride (334.31 μL, 368.75 mg, 4.70 mmol) in dichloromethane (5 mL) is added to a stirring, cooled solution of di-tert-butyl (1S,2R,3R,4S,5R,6S)-4-amino-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.30 g, 3.91 mmol) and triethylamine (709.32 μL, 514.97 mg, 5.09 mmol) in dichloromethane (19.57 mL) at 0° C. then stirred. After 90 minutes, dilute with water and extract with dichloromethane (3×25 mL). The combined organic extracts are dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving the title compound (2.40 g, 3.81 mmol, 97%): MS (m/z): 653 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: O[C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5].[H-].[Na+].C(OC(=O)CCCCBr)C.O>CN(C)C=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[C:15]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])[CH:16]=[CH:17][CH:2]=1
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1O
Agent: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccn1)c1cccc(OCC(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 3.5 g of 60% sodium hydride in mineral oil is washed twice with hexane and then suspended in 80 ml of dry dimethylformamide. A solution of 22.5 g (0.069 mole) of 2-hydroxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide in 100 ml of dimethylformamide is added dropwise to the sodium hydride suspension to give a thick foam. After the addition is complete the reaction mixture is stirred for 30 minutes at about 25° C. and for another 30 minutes at about 60° C. A solution of 20.2 g (0.097 mole) of 5-bromovaleric acid ethyl ester in 40 ml of dimethylformamide is added dropwise with stirring to the reaction mixture. The resulting pale brown solution is allowed to stir at about 60° C. for about 16 hours. The solution is poured into about 1 liter of cold water and then chilled. The resulting precipitate is collected, rinsed with cold water and then dissolved in chloroform. The chloroform solution is washed through a short Florisil® column and the eluent is evaporated to give 28.3 g of an ivory, waxy solid. This material is recrystallized from about 280 ml of 2:1 ethanol:water to give 23.1 g of ivory crystalline 2-(4-ethoxycarbonyl-butoxy(-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide, m.p. 88°-90° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[CH3:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>>[C:7]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:3](=[O:4])[CH2:2][NH:1][C:34]([NH:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH3:26])[CH:28]=1)=[O:35]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1-c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2-c2ccccc2)c1
Yield: 45.9 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(2-biphenylyl)acetamido]acetate (5.8 g) and 3-methylphenyl isocyanate (2.3 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-(2-biphenylyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (3.7 g), m.p. 177° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C@H:10]([C:12]([O:14][CH3:15])=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[I-].C([NH3+])(C)(C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.[H-].[Na+]>C([O-])(O)=O.[Na+].CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)[C@H:10]([C:12]([O:14][CH3:15])=[O:13])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(Cl)c1
Agent: CC(C)(C)[NH3+]
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)N(Cc1cccc(OC)c1)c1ccc(F)c(Cl)c1
Temperature: 60 °C

Procedure:
To a flask containing anhydrous DMF (150 mL) was added 1-3 (2.00 g, 8.633 mmol), tertbutylammonium iodide (0.319 g. 0.863 mmol) and 3-methoxy-benzyl bromide (4.340 g, 21.583 mmol) followed by NaH (0.269 g, 11.223 mmol). The resulting solution was heated at 60° C. for 4 days. Upon completion, the reaction mixture was diluted with NaHCO3 (sat. aq), and extracted with ethyl acetate (3×75 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography (SiO2 0-40% ethyl acetate/hexanes gradient) to yield methyl N-(3-chloro-4-fluorophenyl)-N-(3-methoxybenzyl)alaninate (6-1). 1H NMR (300 MHz, CDCl3) δ 7.26 (m, 2H), 6.85 (m, 4H), 6.58 (m, 1H), 4.51 (m, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 1.47 (d, J=7.3 Hz, 3H). MS 352.3 found 352.8 (M+H+) required.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O:17][C:18]1[CH:27]=[C:26]([CH2:28]Br)[C:25]([Br:30])=[CH:24][C:19]=1[C:20]([O:22]C)=[O:21])(=O)C>CC(C)=O>[Br:30][C:25]1[C:26]([CH2:28][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:27][C:18]([OH:17])=[C:19]([CH:24]=1)[C:20]([OH:22])=[O:21]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Br)c(CBr)cc1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1O
Reaction time: 0.5 h

Procedure:
Triethylamine (0.37 ml, 2.63 mmol) and morpholine (0.15 ml, 1.71 mmol) were added to a solution of methyl 2-(acetyloxy)-5-bromo-4-(bromomethyl)benzoate (may be prepared as described in Description 4; 481 mg, 1.31 mmol) in acetone (10 ml). The mixture was stirred for 30 minutes then the solvent was removed in vacuo. The residue was redissolved in dichloromethane (10 ml), washed with water (10 ml), dried (MgSO4) and the solvent removed in vacuo to give the morpholine intermediate.
Reaction SMILES: [O:1]1[C:5]([C@H:6]2[CH2:11][CH2:10][C@H:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]4[N:37]=[CH:38][N:39]=[C:13]34)[CH2:8][CH2:7]2)=[CH:4][N:3]=[CH:2]1.C([Sn](=O)CCCC)CCC.[N:50]([Si](C)(C)C)=[N+:51]=[N-:52].C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:1]1[C:5]([C@H:6]2[CH2:11][CH2:10][C@H:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:52][N:51]=[N:50][N:33]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]4[N:37]=[CH:38][N:39]=[C:13]34)[CH2:8][CH2:7]2)=[CH:4][N:3]=[CH:2]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3cnco3)CC2)c2ncnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](c3cnco3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-({4-[trans-4-(1,3-oxazol-5-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.35 g), dibutyltin oxide (0.051 g), azidotrimethylsilane (2.3 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.18 g, 46%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(O[C:29](OCC)(OCC)[CH2:30][CH2:31][CH2:32][CH3:33])C.Cl.[NH+]1C=CC=CC=1.C>C1(C)C=CC=CC=1.CO>[CH2:30]([C:29]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Reactant: CCCCC(OCC)(OCC)OCC
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (3.46 g, 10.0 mmol) in 50 mL of toluene was treated with triethylorthovalerate (2.5 mL, 14.5 mmol) and the reaction mixture was heated to reflux. A 25 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 4 h. The reaction was then concentrated to dryness under reduced pressure. The residue was dissolved in 50 mL of CH2Cl2 and washed with saturated NaHCO3, H2O and brine. The organic portion was dried over Na2SO4 and concetrated to give a green oil. The green oil was dissolved in 50 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 4.12 g of tert-butyl 2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:31]=[CH:32][CH:33]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][S:35]([NH:34][C:30]1[CH:31]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)[CH:33]=[CH:28][CH:29]=1)(=[O:37])=[O:36]
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Solvent: O
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(-c2cccc(NS(C)(=O)=O)c2)cc1
Temperature: 90 °C
Yield: 65.8 %

Procedure:
(+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (185 mg, 0.47 mmol, prepared in example 17) and N-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide (168 mg, 0.56 mmol) were dissolved in 25 mL of n-propanol and 78 mg (0.56 mmol)of potassium carbonate in 5 mL of water added. A catalytic amount of palladium acetate is added (5 mg) and the mixture refluxed at 90° C. for 4 hours. The reaction is worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with 99:1 methylene chloride:methanol to afford 135 mg (66%) of the title compound as a white solid. The NMR was consistent with the assigned structure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:40]1[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][O:34][CH3:33])[CH2:38][CH2:39]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(C(=O)[C@@H]2C[C@H](NCc3ccc(F)cc3F)CN2Cc2ccccc2)CC1
Yield: 8.9 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(2-methyoxy-ethyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (5.7 mg, 8.9%) as light yellow oil. MS m/e=473.4 [M+H]+.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:7][CH2:8][C:9]([CH2:11]Cl)=O.C(=O)(O)[O-].[Na+]>O>[Cl:7][CH2:8][C:9]1[N:6]=[C:1]([CH2:2][CH2:3][CH3:4])[O:5][CH:11]=1
Reactant: O=C(CCl)CCl
Reactant: CCCC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1nc(CCl)co1
Temperature: 130 °C

Procedure:
A mixture of butyramide (19.88 g) and 1.3-dichloroacetone (24.14 g) was heated at 130° C. for 1.5 hours. After cooling, the mixture was diluted with water, neutralized with aqueous sodium bicarbonate solution and extracted with ethyl ether. The extract was washed with water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel with acetone-hexane (1:9) to yield 4-chloromethyl-2-propyloxazole as an oil (10.70 g 35.3%). NMR (CDCl3)δ: 0.97 (3H, t, J=7.5 Hz), 1.79 (2H, sext, J=7.5 Hz), 2.72 (2H, t, J=7.5 Hz), 4.47 (2H, s), 7.53 (1H, s).
Reaction SMILES: [C@H:1]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>CN(C=O)C>[C:36]([NH:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C@H:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][O:2]3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1)(=[O:27])=[O:26])(=[O:38])[CH3:37]
Reactant: NS(=O)(=O)c1ccc(N2CCN(CC[C@@H]3OCCc4ccccc43)CC2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NS(=O)(=O)c1ccc(N2CCN(CC[C@@H]3OCCc4ccccc43)CC2)cc1
Reaction time: 1 h

Procedure:
(S)-(-)-4-[4-[2-(Isochroman-1-yl)ethyl]piperazin-1-yl]benzenesulfonamide (EXAMPLE 49, 0.203 g) is stirred in DMF (2 ml) and triethylamine (0.211 ml) and acetyl chloride (0.108 ml) is added. The mixture is stirred at 20-25° for one hr and then at 50° for 4 days. After cooling, the mixture is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phases are dried over sodium sulfate, concentrated, and the residue is chromatographed (silica gel; ethyl acetate/dichloromethane (20/80)) to give the title compound after crystallization from methanol/dichloromethane/hexane, mp 160-161°; MS (m/z) 443; IR (mineral oil) 1593, 1157, 1094, 1136 and 1109 cm-1.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[C:9]([N+]([O-])=O)[CH:8]=[C:7]([CH3:14])[N+:6]=1[O-:15]>CO>[Br:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[CH:8]=[C:7]([CH3:14])[N+:6]=1[O-:15]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)[n+]1[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)[n+]([O-])c(Br)c1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Sodium methoxide (94 mg, 1.74 mmol) was added to a solution of 2-bromo-6-methyl-4-nitro-pyridine 1-oxide (408 mg, 1.74 mmol) in dry methanol (20 mL) at 0° C., then warmed to ambient temperature and maintained overnight. The volatiles were evaporated in vacuo and the residue extracted with chloroform (5×40 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate and concentrated to afford a residue which was purified by column chromatography over silica gel (60-120 mesh) using 3% methanol in chloroform as eluent to afford 2-bromo-4-methoxy-6-methyl-pyridine 1-oxide (0.32 g, 84%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C@@:5]([OH:18])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7].[OH-].[Li+]>CO.O>[OH:18][C@:5]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([CH:6]([CH3:7])[CH3:8])[CH2:4][C:3]([OH:19])=[O:2]
Reactant: COC(=O)C[C@@](O)(CCc1ccc(O)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)[C@](O)(CCc1ccc(O)cc1)CC(=O)O

Procedure:
The title compound was prepared by dissolving (S)-3-hydroxy-3-[2-(4-hydroxy-phenyl)-ethyl]-4-methyl-pentanoic acid methyl ester (0.57 g, 2.15 mmol) from Example TTTT in MeOH (30 mL). Lithium hydroxide (0.18 g, 4.29 mmol) in water (10 mL) was added and the reaction heated to reflux for 1 hour, cooled and pumped to dryness under vacuum. The product was partitioned between water and Et2O. The aqueous layer was decanted, acidified with 1N HCl and extracted with Et2O. The solution was dried (MgSO4) and concentrated to give the title compound (m.p. 137°-140° C.).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH2:9][CH2:10][CH2:11]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH2:9][CH2:10][CH2:11][N:29]2[CH2:30][CH2:31][CH:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:28]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cccc(C2CCNC2)c1
Reactant: BrCCCOC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C2CCN(CCCOC(c3ccccc3)c3ccccc3)C2)c1
Temperature: 80 °C
Yield: 51.3 %

Procedure:
A solution of 5.3 g (50 mmole) of 1-(diphenylmethoxy)-3-bromopropane in 50 cm3 of dimethylformamide was added to a mixture of 8.8 g (50 mmole) of 3-(3-methoxyphenyl)pyrrolidine, 13.8 g (100 mmole) of potassium carbonate, a few potassium iodide crystals and 250 cm3 of dimethylformamide. The reactive medium was heated to 80° C. for 12 hours and then filtered after it returned to room temperature. The filtrate was concentrated to dryness under reduced pressure. The residue was taken up with ether and extracted with 500 cm3 of N hydrochloric acid. The aqueous phase was separated, basified with 10N sodium hydroxide solution and extracted with methylene chloride. The organic solution was dried on sodium sulfate. Evaporation of the solvent yielded an oily residue, which was purified by silica gel column filtration (eluent, hexane-ethyl acetate, 1/1). There was obtained 10.3 g (yield: 51.3%) of 1-[3-(diphenylmethoxy)propyl] 3-(3-methoxyphenyl)pyrrolidine.
Reaction SMILES: [CH2:1]([CH:3]1[C:7](C(OCC)=O)([C:8]([O:10]CC)=[O:9])[NH:6][CH:5]=[CH:4]1)[CH3:2].[OH-].[Na+].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([C@@H:3]1[CH2:4][CH2:5][NH:6][C@H:7]1[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)NC=CC1CC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC[C@@H]1CCN[C@H]1C(=O)O
Reaction time: 4 h
Yield: 75.6 %

Procedure:
The pyrroline (4.68 g, 19.5 mM) was added to a mixture of 1M NaOH (80 ml) and ethanol (80 ml) and the solution stirred at 50° for 4 hrs. The solution was then cooled, sodium borohydride (1.0 g) added, and stirred at 25° for a further 10 hours. The solution was then carefully acidified with dilute HCl to pH 4, concentrated and applied to a column of Dowex 50WX8 resin (H+ form, 100 ml) Elution with aqueous ammonia (2 M) yielded a solution which on evaporation gave trans-3-ethyl-dl-proline (2.1 g) m.p. 208≈-209°; RF 3B 0.43. Analysis on a Jeol 6AH amino acid analyser (50 cm column, sodium citrate buffer 0.2 N, pH 3.25 temperature 57°) showed a single peak (elution time 117 mins).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[F:10][C:11]([F:19])([F:18])[C:12](=[O:17])[CH2:13][C:14](=O)[CH3:15]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[N:5]=[C:14]([CH3:15])[CH2:13][C:12](=[O:17])[C:11]([F:19])([F:18])[F:10]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccccc1N
Solvent: CCOCC
Product: COc1ccccc1N=C(C)CC(=O)C(F)(F)F
Temperature: 102.5 °C
Yield: 99.1 %

Procedure:
A mixture of 28.4 g (0.23 mol) of 2-methoxyaniline and 43.2 g (0.28 mol) of 1,1,1-trifluoro-2,4-pentanedione is prepared and heated at 100-105° C. for 1 h, with stirring. After cooling, the reaction mixture is redissolved in ethyl ether and the solution obtained is dried over sodium sulfate and then concentrated under reduced pressure to give 59.1 g of the expected product in the form of a beige solid (yield=99%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3(O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:24])[O:4][N:3]=1.[N:25]1C=CC=CC=1.O=S(Cl)Cl>C1COCC1.N.CO.CC(=O)OCC>[NH2:25][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:24])[CH:8]=2)[NH:12][C:11]1=[O:16]
Reactant: c1ccncc1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccccc1)C(=O)N2
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2c(c1)C(N)(c1ccccc1)C(=O)N2
Reaction time: 0.33 h
Yield: 40 %

Procedure:
Under N2, to a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-hydroxy-3-phenylindolin-2-one (21 g, 65.6 mmol, 1.0 eq) in THF (300 mL) was added dropwise pyridine (30 mL) and SOCl2 (15 mL) at −15° C.˜−20° C., the mixture was stirred for 20 min at −15° C.˜−20° C., quenched with brine (50 mL), washed with brine (300 mL×2), the organic phase was concentrated to give 17.5 g crude product. The crude product was dissolved in NH3/MeOH (7M, 200 mL), and stirred for 2 hours at room temperature. Then the solvent was removed in vacuo to give crude product, which was dissolved in EA (200 mL), washed with water (100 mL), then brine (100 mL), dried over Na2SO4, concentrated to give 15 g crude product, which was purified by sili-gel to give 8.5 g (yield 40%) product as white solid. 1H NMR (DMSO-d6) δH 10.53 (s, 1H), 7.39-7.41 (d, 2H, J=8.0 Hz), 7.29-7.33 (t, 2H, J=8.0 Hz), 7.21-7.26 (m, 2H), 7.14 (s, 1H), 6.98-7.00 (d, 1H, J=8.0 Hz), 2.75 (s, 2H), 2.33 (s, 3H), 2.16 (s, 3H)
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[CH2:6]([S:8]([OH:11])(=[O:10])=[O:9])[CH3:7]>O>[CH2:6]([S:8]([O-:11])(=[O:10])=[O:9])[CH3:7].[CH2:6]([S:8]([O-:11])(=[O:10])=[O:9])[CH3:7].[Ca+2:5]
Reactant: CCS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CCS(=O)(=O)[O-]

Procedure:
Calcium carbonate (1.38 g, 15 mmole) is dissolved by adding a 1.0 mole/l ethanesulfonic acid solution until a stable pH=5.3 is obtained. The solution is diluted with water to 50 ml.