Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=[O:7])[O:4][C:3]1=[O:8].[CH2:10]([OH:12])[CH3:11]>>[CH2:10]([O:12][C:5](=[O:7])[CH2:6][C:2]([CH3:9])([CH3:1])[C:3]([OH:8])=[O:4])[CH3:11]
Reactant: CCO
Reactant: CC1(C)CC(=O)OC1=O
Product: CCOC(=O)CC(C)(C)C(=O)O

Procedure:
3,3-Dimethyl-dihydro-furan-2,5-dione (6.4 g) was heated at 50° C. in ethanol (150 mL) overnight. The solvent was removed in vacuo and the residue triturated with hexane to yield 2,2-Dimethyl-succinic acid 4-ethyl ester (4.66 g) which was used without further purification. t-Butanol (7.5 mL) was added to a mixture of 2,2-Dimethyl-succinic acid 4-ethyl ester (2.74 g, 15.7 mmol) in dichloromethane (62 mL) containing magnesium sulfate (7.5 g) and conc. sulfuric acid (0.85 mL) and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added and the product was extracted into dichloromethane, washed with brine solution, dried and concentrated to yield the diested as a colorloess oil (1.89 g). The ethyl ester was hydrolyzed by trating the crude sample with potassium hydroxide (2.75 g) in a mixture of ethanol (50 mL) and water (25 mL) at room temperatire for 2 h. The reaction was acidified using 1N HCl (aq) and extracted into ether, dried and concentrated to yield 2,2-Dimethyl-succinic acid 1-tert-butyl ester (1.4 g). This acid was treated under the conditions of Example 320 (step 1) to yield 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid tert-butyl ester (1.9 g). This t-Bu ester was deprotected using formic acid (19 mL) at 50° C. for 20 min. The crude product was concentrated and triturated with a mixture of ether and hexane to yield 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid (1.12 g). To a solution of 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid (561 mg, 2 mmol) and triethylamine (1.1 mL, 8 mmol) in THF (9 ml), isobutyl chloroformate (0.31 mL, 2.4 mmol) was added dropwise at −78 ° C. After being stirred for 1 h, hydrazine hydrate (1 mL, 11 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and concentrated. A small amount of ice was added to quence any excess reagent and precipitate the product, which was collected by filtration to give 482 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[N+:11]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(O)(=O)C1C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:18]([C:17]3[CH:20]=[CH:21][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=3)[O:8][CH2:7][C:6]=2[CH:9]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: OCc1cc(Br)ccc1O
Agent: O=C(O)c1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C2OCc3cc(Br)ccc3O2)cc1
Temperature: 5 °C
Yield: 69.8 %

Procedure:
An intimately ground mixture of 5-bromo-2-hydroxybenzyl alcohol (4.06 g), 4-nitrobenzaldehyde (3.93 g) and benzoic acid (0.2 g) was stirred and heated to 85° C. (±5° C.) under nitrogen for 88 hours. The clear melt which formed initially gradually solidified throughout the reaction period. The resulting solidified mass was cooled and dissolved in ethyl acetate (250 ml). The solution was then washed with 20% aqueous sodium carbonate, 20% aqueous sodium bisulphite and finally with brine. After drying over sodium sulphate, the organic phase was evaporated to yield a solid residue which was purified by briefly suspending in hot ethanol (approx. 75 ml) and cooling to 0°-5° C. The pure product was obtained as pale buff-coloured crystals (4.69 g, 70%), mp 163°-164° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1>>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][N:4]3[C:8](=[O:9])[C:7]4=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]4[C:5]3=[O:14])[CH2:30][CH2:29]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1
Reactant: c1ccc(C(c2cccnc2)N2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(C(c2ccccc2)c2cccnc2)CC1
Yield: 53 %

Procedure:
The title compound was prepared in a yield of 53% in a similar manner to that described in Preparation 1' by reacting N-(2-bromoethyl)phthalimide and 4-[α-(3-pyridyl)benzyl]piperazine.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([CH:10]=[CH:11][C:12]([CH3:16])([OH:15])[CH:13]=[CH2:14])=[C:3]1[CH3:17].C(N(CC)CC)C.[CH3:25][Si:26]([CH3:29])([CH3:28])Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH3:8])([CH3:9])[C:4]([CH:10]=[CH:11][C:12]([CH3:16])([O:15][Si:26]([CH3:29])([CH3:28])[CH3:25])[CH:13]=[CH2:14])=[C:3]1[CH3:17]
Reactant: C[Si](C)(C)Cl
Reactant: C=CC(C)(O)C=CC1=C(C)C(=O)CCC1(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(C)(C=CC1=C(C)C(=O)CCC1(C)C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-(3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-1,4-pentadiene-3-ol (2.34 g, 10 mmoles)(prepared as described in J. Org. Chem. 47, 2130-2134 (1982)) in methylenechloride is added triethylamine (2.08 ml, 15 mmoles), trimethylchlorosilane (1.9 ml, 15 mmoles), and N,N-dimethyl-4-aminopyridine (5 mg, catalytic amount). The mixture is stirred at room temperature for four hours, followed by concentration in vacuo and trituration with dry diethylether. The suspension is filtered and the filtrate is concentrated in vacuo yielding the title compound as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21]CC)=[O:20])[O:16]2)=[CH:11][CH:10]=1.I[CH3:33]>>[Cl:1][C:2]1[CH:27]=[C:26]([C:28]([CH3:31])([CH3:29])[CH3:30])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH3:33])([C:19]([OH:21])=[O:20])[O:16]2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(C(C)(C)C)cc3Cl)cc2O1
Reactant: CI
Product: CC1(C(=O)O)CCc2ccc(OCCCOc3ccc(C(C)(C)C)cc3Cl)cc2O1

Procedure:
The title compound was prepared from ethyl 7-(3-(2-chloro-4-tert-butylphenoxy)propoxy)-chromane-2-carboxylate following the procedures described in Example 1, Step C employing iodomethane instead of iodoethane, followed by hydrolysis as described in Example 1, Step G.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH:34]1([N:37]([CH3:44])[CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][NH:40]2)[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:34]1([N:37]([CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH3:44])[CH2:35][CH2:36]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: CN(C[C@@H]1CCCN1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (165 mg, 0.33 mmol), cyclopropyl-methyl-(S)-1-pyrrolidin-2-ylmethyl-amine (65 mg, 0.46 mmol), HOBt (687 mg, 0.5 mmol), EDAC (101 mg, 0.53 mmol) and TEA (0.1 mL) in DMF (4 mL) was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate, extracted with DCM. The combined DCM was dried, concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][O:33][CH3:34])[CH:26]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:34][O:33][CH2:32][O:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]2)[CH:30]=[CH:29][CH:28]=1
Reactant: COCOc1cccc(CCc2ccccc2OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCOc1cccc(CCc2ccccc2OCCC2CCN(C)CC2)c1
Yield: 62.1 %

Procedure:
Following a procedure similar to that described in Example 38, 1.40 g of 1-t-butoxycarbonyl-4-(2-{2-[2-(3-methoxymethoxyphenyl) ethyl]phenoxy }ethyl) piperidine [prepared as described in Example 55 (a) ] were reacted with 240 mg of lithium aluminum hydride dispersed in 30 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38, and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 710 mg of the title compound as a colorless oil.
Reaction SMILES: C1C2N(C(=O)CC2)C(=O)C1.O[N:12]=[C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:14][CH2:15][C:16](O)=[O:17].[H][H]>[Rh]>[O:17]=[C:16]1[NH:12][CH:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:14][CH2:15]1
Reactant: [H][H]
Reactant: O=C(O)CCC(CCC(=O)O)=NO
Agent: [Rh]
Agent: O=C1CCC2CCC(=O)N12
Product: O=C(O)CCC1CCC(=O)N1

Procedure:
In a process for preparing dihydro-1H-pyrrolizine-3,5(2H, 6H)-dione comprising the steps of catalytically hydrogenating an ester of 4-(hydroxyimino)heptanedioic acid and subsequently cyclizing the resulting product to dihydro-1H-pyrrolizine-3,5(2H,6H)-dione, the improvement comprises reacting an alcoholic solution of a mono(lower alkyl) ester of 4-(hydroxyimino)heptanedioic acid, wherein lower alkyl comprises from one to three carbon atoms, with hydrogen gas at a temperature of about 60° C. in the presence of rhodium/alumina catalyst and a tertiary lower alkyl amine, wherein said lower alkyl amine comprises from three to nine carbon atoms, to produce 5-oxo-2-pyrrolidinepropanoic acid; and thereafter heating said 5-oxo-2-pyrrolidinepropanoic acid in the presence of a cyclizing agent selected from acetic anhydride, 2,2,6-trimethyl-1,3-dioxen-4-one, and diketene at a temperature of about 90° C. to produce dihydro-1H-pyrrolizine-3,5(2H,6H)-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(=[CH:41][C:42]([O:44][CH3:45])=[O:43])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:17]([C:16]1[CH:15]=[C:14]([C:12]([CH:11]=[CH:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:41][C:42]([O:44][CH3:45])=[O:43])[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: N#Cc1cccc(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=C(C=Cc1ccc([N+](=O)[O-])cc1)c1cccc(C#N)c1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
Part B. 3-[3-(4-nitrophenyl)-1-oxo-2-propenyl]benzonitrile (0.500 gm, 1.79 mmol) was suspended in toluene and methyl (triphenylphosphoranylidene)acetate (0.600 gm, 1.79 mmol) was added. The suspension was heated to reflux (at which point the solution becomes homogeneous) for 5 hrs. The reaction was cooled to room temperature and the solvent removed under vacuum. The residue was chromatographed on silica gel (20% ethyl acetate/toluene) to afford methyl 3-(3-cyanophenyl)-5-(4-nitrophenyl)-2,4-pentadienoate 0.441 gm (74%) as a mixture of the E/Z isomers. MS: 335(M+H)+ ; 1H NMR (CDCl3): 3.6 (s, 3H), 3.8 (s, 3H), 5.9 (s, 1H), 6.25 (m, 2H), 6.6 (d, 1H), 7.15 (m, 2H), 7.6 (m, 11H), 8.2 (d, 4H), 8.65 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1c(Cl)cccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2,6-dichlorophenyl)-1-propanol (125 mg, 0.61 mmol) and triethylamine (123 mg, 1.22 mmol) in methylene chloride (3 mL), methanesulfonyl chloride (105 mg, 0.915 mmol) was added under ice cooling, followed by stirring at room temperature for 2 hours. Brine was added to the reaction mixture. The organic layer was allowed to separate, was collected, and was then dried over anhydrous sodium sulfate. Subsequent to concentration under reduced pressure, the residue was purified by chromatography on a silica gel column (hexane/ethyl acetate=10/1) to yield the title compound as a pale yellow syrupy substance (yield: quantitative).
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[C:20]([O:22]CC3C=CC=CC=3)[C:19]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:18][C:17]=2[CH2:37][CH3:38])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:39]=[N+:40]=[N-:41].[Na+].Cl.C(N(CC)CC)C.Cl>CN(C)C=O>[C:1]1([CH:7]([C:8]2[NH:9][N:41]=[N:40][N:39]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[C:20]([OH:22])[C:19]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:18][C:17]=2[CH2:37][CH3:38])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCCCC(C#N)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCCCC(c1ccccc1)c1nnn[nH]1
Temperature: 110 °C
Yield: 107 %

Procedure:
2-Phenyl-7-(2-ethyl-4-(4-fluorophenyl)-5-benzyloxyphenoxy)heptanenitrile (700 mg, 1.38 mmol) was dissolved in dimethylformamide (20 mL) and sodium azide (0.6 g) and triethylamine hydrochloride added (1.2 g) and the stirred suspension heated at 110° C. for 3 days. The suspension was then added to 1M hydrochloric acid (100 mL) and the solution extracted 4 times with chloroform. The combined chloroform extracts were washed with water and dried with magnesium sulfate. On evaporation the solution yielded 680 mg (72%) of the title compound as a crude oil which was then directly deprotected.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:14][N:15]1[C:23]2[C:18](=[C:19]([O:24][CH2:25][CH2:26]Br)[CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[C:28]([O:30][CH3:31])=[O:29].[I-].[K+]>C(#N)C>[Cl:10][C:11]1[CH:12]=[C:13]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:14][N:15]1[C:23]2[C:18](=[C:19]([O:24][CH2:25][CH2:26][N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]3)[CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1cc2c(OCCBr)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reactant: OCCN1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc2c(OCCN3CCN(CCO)CC3)cccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
1-(2-Hydroxyethyl)piperazine (175 mg) was added to a stirred solution of methyl N-(3,4-dichlorobenzyl)-4-(bromoethyloxy)indole-2-carboxylate (278 mg) and potassium iodide (10 mg) in acetonitrile (15 ml). The reaction was heated at 80° C. for 16 hours. The reaction was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water, saturated aqueous sodium chloride solution and dried (MgSO4). The solvent was removed in vacuo to give the product as a colourless oil (215 mg, 70%); NMR d (CD3SOCD3) 2.31-2.57 (m, 10H), 2.78 (t, 2H), 3.47 (dd, 2H), 3.80 (s, 3H), 4.20 (t, 2H), 4.30 (t, 1H), 5.79 (s, 2H), 6.61 (d, 1H), 6.88 (dd, 1H), 7.13 (d, 1H), 7.22 (t, 1H), 7.29-7.32 (m, 2H), 7.51 (d, 1H); M/z (+) 506 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:19])[C:11](=[CH2:18])[CH:12]([O:14][C:15](=[O:17])[CH3:16])[CH3:13].CO[CH2:22][N:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:24][Si](C)(C)C>C(Cl)Cl>[CH3:8][O:9][C:10]([C:11]1([CH:12]([O:14][C:15](=[O:17])[CH3:16])[CH3:13])[CH2:18][CH2:22][N:23]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:24]1)=[O:19]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(C(=O)OC)C(C)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(C(C)OC(C)=O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Trifluoroacetic acid (0.5 g, 4.38 mmol) was added to a solution of methyl-3-acetoxy-2-methylenebutyrate (5 g, 29.03 mmol) (1) and N-Methoxymethyl-N-trimethylsilylmethylbenzylamine (6.89 g, 29.03 mmol) (2) in MeCl2 (100 ml) at 0° C., then stirred overnight at room temperature. The solvent was evaporated, and residue extracted with EtOAc (200 ml), NaHCO3 (30 ml and H2O (100 ml). The organic layer was separated, dried (MgSO4), filtered and solvent evaporated yielding an oil which chromatographed on silica gel eluting with 30% v/v (EtOAc/hexanes) yielding product (3) as colorless oil (7.53 g, 85% yield). ESMS MH, 306 (C17H23NO4)
Reaction SMILES: [CH3:1][C:2]([NH:6][CH3:7])([CH3:5])[CH2:3][OH:4].[CH2:8]1[O:18][C:17]2[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][C:10]=2[O:9]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]([N:6]([CH2:13][C:12]1[CH:15]=[CH:16][C:17]2[O:18][CH2:8][O:9][C:10]=2[CH:11]=1)[CH3:7])([CH3:5])[CH2:3][OH:4]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CNC(C)(C)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1ccc2c(c1)OCO2)C(C)(C)CO
Yield: 58 %

Procedure:
A mixture of 2-methyl-2-methylaminopropanol (1.5 g), 3,4-methylenedioxybenzyl chloride (2.5 g) and potassium carbonate (2 g) in acetonitrile (50 ml) was heated under reflux for 4 hours and evaporated. The residue was partitioned between ether and 2M hydrochloric acid and the acidic layer was washed with methylene chloride, basified with 10% aqueous sodium carbonate solution and extracted into methylene chloride. The organic extract was dried over magnesium sulphate and evaporated to give essentially pure 2-methyl-2-[N-(3,4-methylenedioxybenzyl)-N-methylamino]propanol as a yellow oil (2.0 g, 58%) which was used directly in Example 34. A small portion of this product was dissolved in ether and the solution was treated with excess saturated ethereal hydrogen chloride and evaporated. The residue was triturated with acetone/ethyl acetate to give the title compound as a colourless solid, m.p. 157°-159°.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][O:4][CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:6]1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:19]([NH:26][C@H:10]1[CH2:9][CH2:8][N:7]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:6][C@H:5]1[O:4][CH2:3][CH:2]([F:18])[F:1])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCN(C(=O)C(F)(F)F)CC1OCC(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(N1CC[C@H](NCc2ccccc2)[C@H](OCC(F)F)C1)C(F)(F)F
Yield: 79.2 %

Procedure:
The same operation as in Example (90c) was performed using 3-(2,2-difluoroethoxy)-1-(trifluoroacetyl)piperidin-4-one obtained in Example (121c) (1.1 g, 4 mmol), benzylamine (0.54 g, 5 mmol), sodium (triacetoxy)borohydride (0.85 g, 6 mmol) and 1,2-dichloroethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 1.16 g of the title compound as a yellow oily substance (79%).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:18][CH3:19])[CH2:3][CH2:4][C@H:5]([NH:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[C:6]([OH:8])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:35][C:36]1([C:47]#[N:48])[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH2:38][CH2:37]1>ClCCl>[C:47]([C:36]1([NH:35][C:6]([C@@H:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH2:4][CH2:3][C:2]([CH3:1])([CH3:20])[CH2:18][CH3:19])=[O:8])[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][CH3:46])[CH2:38][CH2:37]1)#[N:48]
Reactant: COCCCN1CCC(N)(C#N)CC1
Reactant: CCC(C)(C)CC[C@H](NC(=O)N1CCOCC1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(C)(C)CC[C@H](NC(=O)N1CCOCC1)C(=O)NC1(C#N)CCN(CCCOC)CC1
Yield: 15.5 %

Procedure:
A solution of (S)-5,5-Dimethyl-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (4.70 g, 16.4 mmol) in dichloromethane (75 mL), cooled in an ice water bath, was treated with HOBT (2.45 g, 18.13 mmol), then EDC (3.47 g, 18.1 mmol). The reaction mixture was stirred with cooling for 35 min, then the ice bath was removed and a solution of 4-amino-(3-methoxy-propyl)-piperidine-4-carbonitrile (3.61 g, 18.3 mmol) in dichloromethane (25 mL) was added. The reaction mixture was stirred overnight, then concentrated on a rotary evaporator. The resulting residue was taken up in ethyl acetate (300 mL) and washed with saturated sodium bicarbonate solution (2×300 mL). The organic phase was then dried (magnesium sulfate) and concentrated to provide 8.1 grams of crude material. This material was further purified on a shimadzu reverse phase hplc using a gradient of acetonitrile in water (40 to 65% over 35 min flow rate 45 mL/min) to provide 1.18 g (25.8%) of the desired product as a white crunchy foam; m/z calculated for C24H43N5O4 465.6, found 466.6 (M+H)+
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([OH:44])=[N:12][C:13]([C:20]2([CH3:43])[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:22][N:21]2C(OCC2C=CC=CC=2)=O)=[N:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[C:1]([O:9][C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:14][C:13]([C:20]2([CH3:43])[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:23][CH2:22][NH:21]2)=[N:12][C:11]=1[OH:44])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2(C)CN(C(=O)OC(C)(C)C)CCN2C(=O)OCc2ccccc2)nc(O)c1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C2(C)CN(C(=O)OC(C)(C)C)CCN2)nc(O)c1OC(=O)c1ccccc1

Procedure:
1-benzyl 4-tert-butyl 2-[5-(benzoyloxy)-4-hydroxy-6-(methoxycarbonyl)pyrimidin-2-yl]-2-methylpiperazine-1,4-dicarboxylate (C-43) was dissolved in AcOEt and hydrogenated at 1 atm on 10% (w/w) Pd/C over night. After filtration of the catalyst, solvent was evaporated to give the crude title compound (C-44).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12]C)[CH:3]=1.Br.N>O>[OH:12][C:4]1[CH:3]=[C:2]([Br:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: COc1cc(Br)cc2ncccc12
Agent: Br
Agent: N
Solvent: O
Product: Oc1cc(Br)cc2ncccc12
Temperature: 25 °C

Procedure:
1.5 g (0.0064 mol) of 7-bromo-5-methoxy-quinoline were refluxed with 48% HBr (30 ml) for 20 h. After cooling to room temperature reaction mixture was poured into 100 ml of water and basified with saturated ammonia solution. Product was filtered off, washed with water and dried at 50° C. in vacuo. Yield of 7-bromo-5-hydroxy-quinoline was 600 mg (41%).