Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[C:26]([F:34])[CH:27]=[CH:28][C:29]=2[NH2:33])[N:24]=1>>[NH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[C:26]([F:34])[CH:27]=[CH:28][C:29]=2[NH:33][CH:11]2[C:5]3[C:4](=[C:3]([O:20][CH3:21])[C:2]([Cl:1])=[CH:7][CH:6]=3)[C:8]([CH3:18])([CH3:19])[CH2:9][C:10]2([OH:17])[C:13]([F:14])([F:16])[F:15])[N:24]=1
Reactant: Nc1ccc2c(N)ccc(F)c2n1
Reactant: COc1c(Cl)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Product: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2nc(N)ccc12

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 250 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 137 mg of 2,5-diamino-8-fluoroquinoline. The title compound is obtained analogously to Example 3 by reaction of the imine that is formed with 1.0 ml of titanium tetrachloride solution (1 M in dichloromethane).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH:5]=[O:6].C[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH:9]1[SH:19]>C1(C)C=CC=CC=1>[CH2:3]([O:4][C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH:9]1[SH:19])=[O:6])[CH3:2]
Reactant: O=COCCCl
Reactant: CCOC(=O)C1CCN(C)C(S)C1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(C(=O)OCC)C(S)C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
106.3 g (0.88 mol) of chloroethylformate are added dropwise with stirring over a period of 30 minutes to a solution of 100 g (0.48 mol) of 1-methyl-4-ethoxycarbonyl-mercapto-piperidine in 80 ml of toluene which has been heated to 90° C. The solution is then heated for two hours to from 100° to 110° C. After repeated addition of 40 g of chloroethylformate the solution is heated for a further three hours. After leaving it to stand overnight at room temperature it is drawn off by suction using a glass fibre filter. The solution is concentrated on a rotary evaporator and the residue is distilled off. 20 g (94% of the theoretical yield) of 1-ethoxycarbonyl-4-ethoxycarbonyl-mercapto-piperidine are obtained. B.P. 138°-140° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[F:35][C:36]([F:47])([F:46])[O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44]N)=[CH:40][CH:39]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:42]4[C:41](=[CH:40][CH:39]=[C:38]([O:37][C:36]([F:35])([F:46])[F:47])[CH:43]=4)[NH:44][C:22]=3[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=3)[CH2:16][CH2:17]2)[CH:7]=1)=[O:4]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc([N+](=O)[O-])c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc([N+](=O)[O-])c4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(3-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 609.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:11][C:12]1[C:17]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:16][C:15](Br)=[CH:14][N:13]=1>C1C=CC=CC=1>[NH2:11][C:12]1[C:17]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[N:16][C:15]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:14][N:13]=1
Reactant: Nc1ncc(Br)nc1N1CCOCC1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Nc1ncc(OCc2ccccc2)nc1N1CCOCC1

Procedure:
Sodium hydride (0.1 mole) is added to benzyl alcohol (0.1 mole) in 100 ml. dry benzene and the mixture is refluxed one to two hours. The cooled solution is treated with 0.1 mole of 2-amino-3-morpholino-5-bromopyrazine in 100 ml. of benzene and the resulting mixture refluxed for 20-60 hours whereupon it is cooled, washed with water, dried and evaporated to give 2-amino-3-morpholino-5-benzyloxypyrazine.
Reaction SMILES: [C-:1]#[N:2].[K+].[I:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl>[I:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[CH:10]=[CH:11][CH:12]=1
Reactant: BrCc1cccc(I)c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: N#CCc1cccc(I)c1
Yield: 90.8 %

Procedure:
A mixture of potassium cyanide (4 g) and tetra-n-butylammonium bromide (0.32 g) in water (20 ml) was added to a solution of 3-iodobenzyl bromide (5.92 g) in methylene chloride (20 ml) and the mixture was heated to reflux for 2 hours. The organic phase was separated, washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using methylene chloride as eluent to give 3-iodophenylacetonitrile (4.4 g).
Reaction SMILES: [ClH:1].[CH3:2][O:3][N:4]=[C:5]1[CH2:10][NH:9][CH:8]=[N:7][CH2:6]1.Cl.CO.[BH4-].CN(C)C>CO>[ClH:1].[ClH:1].[CH3:2][O:3][NH:4][CH:5]1[CH2:10][NH:9][CH:8]=[N:7][CH2:6]1
Reactant: CON=C1CN=CNC1
Agent: CN(C)C
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: CONC1CN=CNC1
Yield: 38 %

Procedure:
A solution of 1,6-dihydro-5-(4H)-pyrimidinone O-methyloxim monohydrochloride (2.8 g, 17.1 mmol) in dry methanol was added dropwise to a stirred solution of HCl/methanol (49 ml of a 3N solution) and trimethylamine borohydride (1.36 g, 18.7 mmol) at room temperature under a nitrogen atmosphere. After 1 hour the reaction product crystallised spontaneously. Recrystallization from methanol/ethyl acetate gave a light-brown material in 38% yield (1.30 g). Mp. 214.0° C.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[C:3]1(/[CH:2]=[CH:1]/[C:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17]3[NH:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C(=Cc1ccncc1)c1ccccc1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C1=C(/C=C/c2ccccc2)CCN(Cc2nc3ccccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-styrylpyridine (4.0 g, 22.1 mmol) and 2-chloromethylbenzimidazole (3.7 g, 22.1 mmol) in dimethylformamide (20 ml) was heated at 110°-120° C. under a nitrogen atmosphere for 1.5 hours. The mixture was cooled to room temperature, diluted with ethanol (380 ml) and carefully treated with sodium borohydride (880 mg, 23.2 mmol). The mixture was stirred at room temperature for 2 hours, then heated at reflux for 1 hour before stirring at room temperature overnight. The ethanol was evaporated in vacuo and the residue partitioned between ethyl acetate (100 ml) and sodium carbonate (half saturated, 100 ml). The phases were separated and the aqueous was extracted with ethyl acetate (2×100 ml). The combined organics were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated in vacuo to give a reddish gummy residue which was purified by flash chromatography (eluting with 5% methanol in dichloromethane) to give a yellow gummy solid. The gum was triturated with ethyl acetate and recrystallised from ethyl acetate to give the title compound as a mustard solid (912 mg, 13%). M.p. 225°-227° C. (EtOAc); (Found: C, 79.74; H, 6.89; N, 13.47. C21H21N3 requires C, 79.97; H, 6.71; N, 13.32%); δH (DMSO-d6) 2.37 (2H, br s, tetrahydropyridinyl CH2), 2.69 (2H, t, J 5.6 Hz, tetrahydropyridinyl CH2), 3.17 (2H, br s, tetrahydropyridinyl CH2), 3.83 (2H, s, NCH2Ar), 5.91 (1H, s, CH=CR), 6.48 (1H, d, J 16.2 Hz, CHCHPh), 6.91 (1H, d, J-16.2 Hz, CHPh), 7.13-7.22 (3H, m, ArH), 7.29-7.33 (2H, m, ArH), 7.42-7.47 (3H, m, ArH), 7.54 (1H, m, ArH), and 12.31 (1H, br s, NH); m/z (CI+, NHs) 316 (M+1)+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[NH:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)[CH:12]=1.C(C1C=NC=CC=1)(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:57][CH2:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([O:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([C:74]([F:77])([F:76])[F:75])[CH:69]=2)[CH2:63][CH2:62]1)=[O:60]>CN(C=O)C.O>[O:60]=[C:59]([N:61]1[CH2:62][CH2:63][CH:64]([O:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([C:74]([F:77])([F:75])[F:76])[CH:69]=2)[CH2:65][CH2:66]1)[CH2:58][NH:57][C:22]([C:19]1[CH:18]=[C:17]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[NH:21][N:20]=1)=[O:24]
Reactant: O=C(O)c1cc(-c2cccnc2)[nH]n1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CC(=O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2cccnc2)[nH]n1
Reaction time: 8 h
Yield: 66 %

Procedure:
DIPEA (290 mg, 2.26 mmol) was added to a stirred solution of 5-pyridin-3-yl-1H-pyrazole-3-carboxylic acid hydrochloride (prepared by the method used for the synthesis of Intermediate 29, starting from 3-acetylpyridine) (100 mg, 0.44 mmol) in DMF (2 mL) followed by HOBt (63 mg, 0.46 mmol) and EDCI.HCl (90 mg, 0.46 mmol). After 5 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (150 mg, 0.44 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by filtering through 60-120 silica gel column and filtrate collected was concentrated under reduced pressure to afford 138 mg (66% Yield) of 5-pyridin-3-yl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 474, 94.7%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (s, 1H), 9.4 (s, 1H), 8.56 (d, 1H), 8.16 (m, 1H), 7.46 (m, 2H), 7.22 (m, 4H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.44 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([CH3:21])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[N:33][C:32]([CH:35]=[CH2:36])=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([CH3:21])[CH:12]=2)[C:8]([NH:28][C:29]2[CH:34]=[N:33][C:32]([CH:35]=[CH2:36])=[CH:31][N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=Cc1cnc(N)cn1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)O)ccc1S(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(C)c2)cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionic acid (prepared as in Example 57, 465 mg, 1.5 mmol) in methylene chloride (20 mL) was treated with oxalyl chloride (0.3 mL, 3.4 mmol) and N,N-dimethylformamide (1–2 drops). The solution was stirred at 0° C. for 5 min and then at 25° C. for 15 min. The reaction mixture was concentrated in vacuo. The residue was dissolved in methylene chloride (20 mL), cooled to 0° C., and then treated with a solution of 2-amino-5-vinylpyrazine (prepared as in Example 54, 182 mg, 1.5 mmol) and pyridine (0.37 mL, 4.6 mmol) in methylene chloride (5 mL). The mixture was stirred at 0° C. then stirred at 25° C. overnight. The solution was diluted with methylene chloride (25 mL). The organic layer was washed with a 1N aqueous sodium hydroxide solution (25 mL) and a 1N aqueous hydrochloric acid solution (25 mL). Each aqueous phase was back-extracted with a small volume of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/3 to 1/1 ethyl acetate/hexanes) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-N-(5-vinyl-pyrazin-2-yl)-propionamide (385 mg, 63%) as a white foam: (ES)+-HRMS m/e calcd for C22H27N3O3S (M+H)+ 414.1846, found 414.1849.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:8]2[C:9](OC(=O)[NH:13][C:7]2=[CH:6][CH:5]=1)=[O:10])([O-:3])=[O:2].[BH4-].[Na+]>C(O)C.[OH-].[Na+]>[OH:10][CH2:9][C:8]1[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH2:13]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])cc1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
5-Nitroisatoic anhydride (4.0 g, 19.22 mmol) is suspended in ethanol (32 mL) and cooled to 0° C. using an ice bath under a nitrogen atmosphere. A solution of 2.18 g (57.66 mmol) of sodium borohydride in 16 mL of 0.1 M NaOH is added dropwise over 25 minutes while keeping the temperature at 0-18° C. using an ice bath. The reaction mixture is stirred at room temperature for 3 hours, cooled in an ice bath, and carefully quenched by the addition of 6N sulfuric acid (6.5 mL) over a period of 20 minutes (0-37° C.), followed by stirring for an additional 20 minutes at 0° C. After neutralization with 6N NaOH (10 mL), the reaction mixture is poured onto 30 mL of ice water and 10 mL of 0.1 M NaOH. The orange-yellow solid is isolated by vacuum filtration and washed with water (70 mL). The resulting solid is stirred in 0.1 N NaOH (30 mL) for 95 minutes, isolated by vacuum filtration, and washed with water (3×25 mL). The yellow solid is dried under vacuum at 60° C. to constant weight, affording 2.75 g (80%) of product; 1H-NMR (300 MHz, DMSO-d6); δ 8.05 (s, 1H), 7.90 (d, J=8.6 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 6.45 (s, 2H), 5.32 (br s, 1H), 4.39 (d, J=4.65 Hz, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)CCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(N2CCCC2=O)cc1
Temperature: 50 °C
Yield: 87.8 %

Procedure:
To a stirred solution of ethyl 4-(4-bromobutyramido)cinnamate (420 mg) in N,N-dimethylformamide (5 ml) was added potassium carbonate (552 mg) at ambient temperature and the resulting mixture was warmed at 50° C. for three hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with chloroform to afford ethyl 4-(2-oxo-1-pyrrolidinyl)cinnamate (281 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[NH:30][CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)N1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Product: CCOC(=O)N1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Yield: 35.4 %

Procedure:
The title compound was made by a procedure identical to that of Example 60 using 1.0 g of 4-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperazine-1-carboxylic acid ethyl ester and 0.44 g of benzaldehyde (4.16 mmol, 2 equiv.) to give 0.42 g of the title compound as a light pink solid. 1H NMR (300 MHz, d6-DMSO): □ 1.00-1.01 (d, J=5.5 Hz, 6H); 1.14-1.19 (t, 3H), 1.56-2.00 (m, 2H); 2.48 (s, 4H); 2.56-2.65 (m, 4H); 3.39-3.51 (m, 5H); 3.72-3.76 (dd, 1H); 4.00-4.07 (q, 2H); 4.96 (s, 1H); 6.62-6.70 (m, 3H); 7.09-7.63 (m, 10H); 9.37 (s, 1H). Calculated for C34H42N4O4.0.44 CH2Cl2: C, 68.02; H, 7.11; N, 9.21. Found: C, 68.00; H, 7.20; N, 9.12.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]([OH:12])[C:7](=[CH:10][CH:11]=1)[CH:8]=[O:9])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C(#N)C.C(OCC)(=O)C>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:5]=1)[CH3:14]
Reactant: ClCCN1CCCCC1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)c1ccc(C=O)c(OCCN2CCCCC2)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In 90 mL of acetonitrile was dissolved 2.8 g (14.6 mmol) of 4-diethylaminosalicylaldehyde. To this solution were added 14.3 g (43.8 mmol) of cesium carbonate and 2.8 g (15.3 mmol) of 1-(2-chloroethyl)piperidine hydrochloride at room temperature and the mixture was stirred at 80° C. for 4 hours. Water (150 mL) was added to the resulting reaction mixture and extraction with ethyl acetate (100 mL×3) was performed. The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to quantitatively give 4.5 g of the title compound.
Reaction SMILES: [CH2:1]1[CH2:6][C@@H:5]([C:7]([OH:9])=[O:8])[NH:4]C[CH2:2]1.[CH2:10](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C1C[C@@H](C(O)=O)NCC1.C(=O)([O-])[O-].[Na+].[Na+].BrCC(C1C=CC=CC=1)=O>CO>[NH2:4][C@H:5]([C:7]([OH:9])=[O:8])[C@H:6]([CH2:1][CH3:2])[CH3:10]
Reactant: O=C(O)[C@@H]1CCCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 152.5 %

Procedure:
Using the procedure described in example 5, 55 mg (0.17 mmol) of L-homoproline-L-isoleucine benzylamide (prepared from L-homoproline (Bachem Bioscience, Philadelphia, Pa.) using the procedure described in examples 3, and 4), was treated with sodium carbonate (39 mg, 0.37 mmol), and 2-bromoacetophenone (59 mg, 0.29 mmol, 1.7 eq) in methanol (5 mL). A sample of the crude mixture was purified by preparative TLC to provide 34 mg (45%) of L-isoleucine, N-[1-(2-phenyl-2-oxoethyl)-L-homoproline] benzylamide.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@H:13]([C@H:15]2[O:24][C@@H:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C@@H:17]3[CH2:16]2)[OH:14])(=O)=O)=CC=1.[C:25]([O-])([O-])=O.[K+].[K+]>CO>[CH3:22][C:20]1([CH3:23])[O:19][C@H:18]2[O:24][C@H:15]([C@@H:13]([OH:14])[CH2:12][O:11][CH3:25])[CH2:16][C@H:17]2[O:21]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@@H]2C[C@H]3OC(C)(C)O[C@H]3O2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC[C@H](O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a stirred solution of [(2S)-2-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-hydroxy-ethyl] 4-methylbenzenesulfonate (compound 6a, 3.2 g, 8.9 mmol) in methanol (50 mL) was added K2CO3 (5.4 g, 40 mmol). After being stirred at room temperature for 2 hours, the resulting solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:10 EtOAc in petroleum ether) to afford 1.62 g of (1S)-1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-methoxy-ethanol (compound 21b) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH2:7][CH:8]2[CH2:16][N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:10]3[CH2:9]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@@H:8]2[CH2:16][N:11]3[CH2:12][CH2:13][N:14]([C:22]4[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[N:21]=4)[CH2:15][C@@H:10]3[CH2:9]2)=[CH:17][CH:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Fc1ccc(OCC2CC3CNCCN3C2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: Fc1ccc(OC[C@H]2C[C@H]3CN(c4cncc(Cl)n4)CCN3C2)cc1
Temperature: 25 °C
Yield: 67.7 %

Procedure:
A mixture of 0.500 g (2.00 mmol) of (7SR,8aSR)-7-(4-fluorophenoxy)methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 3), 1.49 g (10.0 mmol) of 2,6-dichloropyrazine, and 0.508 g (4.79 mmol) of sodium carbonate in 50 mL of isoamyl alcohol was heated to reflux for 16 hours. The reaction was cooled to ambient temperature, the solvent removed in vacuo, the residue taken up in ethyl acetate and water, the pH was adjusted to 11 with sodium carbonate and the layers were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 90:10 ethyl acetate:hexane gave 0.491 g (68%) of the title compound. Mp (.HCl) 209-212° C. HRMS calc'd for C18H21ClFN4O (MH+): 363.1388, found: 363.1384.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=1.[Br:11]N1C(=O)CCC1=O>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]=1[Br:11]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: O=C1CCC(=O)N1Br
Product: CC(C)(C)c1noc(N)c1Br
Yield: 64 %

Procedure:
5-Amino-4-bromo-3-tert-butylisoxazole was prepared from 5-amino-3-tert-butylisoxazole and N-bromosuccinimide in 64% yield as described in Example 25a.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:9]2([OH:17])[O:14][CH2:13][C@@H:12]([CH3:15])[NH:11][C@H:10]2[CH3:16])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[NH2:25][S:26]([C:29]1[C:30]([Cl:47])=[CH:31][C:32]([NH:40][CH2:41][C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[C:33]([CH:39]=1)[C:34]([O:36][CH2:37]Cl)=[O:35])(=[O:28])=[O:27]>C(#N)C>[NH2:25][S:26]([C:29]1[C:30]([Cl:47])=[CH:31][C:32]([NH:40][CH2:41][C:42]2[O:43][CH:44]=[CH:45][CH:46]=2)=[C:33]([CH:39]=1)[C:34]([O:36][CH2:37][N:11]1[C@H:12]([CH3:15])[CH2:13][O:14][C@:9]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)([OH:17])[C@@H:10]1[CH3:16])=[O:35])(=[O:27])=[O:28]
Reactant: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1
Reactant: NS(=O)(=O)c1cc(C(=O)OCCl)c(NCc2ccco2)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H]1CO[C@@](O)(c2cc(F)cc(F)c2)[C@H](C)N1COC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
A solution of free base of (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (20a) (0.023 mole) (U.S. Pat. No. 5,104,870), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate (15) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (2S,3S,5R)-4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (520). See eg., U.S. Pat. No. 5,104,870) and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).