Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]([CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:6]([OH:8])=[O:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[OH:4][C@@H:5]([CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)O[C@@H](CC1CCCC1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H](O)CC1CCCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 92.1 %

Procedure:
A solution of 395 mg (1.97 mmol) of 2-(S)-acetoxy-3-(cyclopentyl)propanoic acid (from Step E) in 10 mL MeOH and 1 mL of H2O was treated with 1.29 g (9.33 mmol) of K2CO3 and stirred at rt for 30 h. The volatiles were removed under reduced pressure. The crude product was partitioned between 100 mL of ether and 100 mL of H2O and the layers were separated. The aqueous layer was acidified to pH 1-2 using 2.0 N HCl and extracted with 3×150 mL of EtOAc. The combined organic layers were dried over Na2So4 and concentrated to give 287 mg (92%) of the title compound: 1H NMR (300 MHz) δ1.11-2.15 (m, 11H), 4.27 (dd, J=8.1, 4.7, 1H), 6.5 (br, 1H).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34]/[C:35](/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:36]\[CH:37]=O>>[CH3:34]/[C:35](/[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:36]\[CH:37]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)=CCC/C(C)=C/C=O
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)=CCC/C(C)=C/C=CCc1ccccc1
Yield: 28.9 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.48 g, 7.78 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.9 mL, 7.78 mmol, 1.0 equiv.) and (E)-3,7-dimethylocta-2,6-dienal (1.78 g, 11.7 mmol, 1.5 equiv.), 0.54 g (29%) of the title compound as a light yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.CCN(CC)CC.[C]=O.CO.C[CH2:44][O:45][C:46](C)=[O:47]>[Pd](Cl)Cl>[CH3:44][O:45][C:46]([C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:4][C:5]([CH3:21])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[N:7]=1)=[O:47]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1nc(C(=O)N2CCC(N3CCCC3)CC2)c(C)cc1-c1cccc(C(F)(F)F)c1
Yield: 63 %

Procedure:
To a degassed solution of 7.00 g (15.5 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) in 180 ml of MeOH/EtOAc 1:1 were added 0.70 g (0.86 mmol) of (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and 5.4 ml=3.92 g (38.7 mmol) of Et3N. This reaction mixture was stirred in an autoclave and in a carbon monoxide atmosphere at 130° C./70 bar for 30 hours. Then, it was evaporated, the residue dissolved in H2O/EtOAc and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 4.61 g (63%) of the title compound as light brown foam. MS: 476.2 (MH+).
Reaction SMILES: F.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[N:16]1[CH2:21][CH2:20][C@@H:19]([CH:22]([CH3:31])[CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[C@H:18]([O:32][Si](C(C)(C)C)(C)C)[CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][N:8]=[C:7]2[N:16]1[CH2:21][CH2:20][C@@H:19]([CH:22]([CH3:31])[CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:29])=[O:30])[C@H:18]([OH:32])[CH2:17]1
Reactant: COc1cc2ncnc(N3CC[C@@H](C(C)CN4CCCS4(=O)=O)[C@H](O[Si](C)(C)C(C)(C)C)C3)c2cc1OC
Agent: F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2ncnc(N3CC[C@@H](C(C)CN4CCCS4(=O)=O)[C@H](O)C3)c2cc1OC

Procedure:
40% Aqueous hydrofluoric acid (0.5 cm3) was added at room temperature to a stirred solution of trans-2-{2-[1-(6,7-dimethoxyquinazolin-4-yl)-3-t-butyldimethylsilyloxypiperid-4-yl]prop-1-yl}isothiazolidine-1,1-dioxide (diastereomer A; 0.64 g) in acetonitrile (7.0 cm3). After stirring for 16 hours aqueous saturated sodium carbonate solution (5 cm3) was added and the residue was partitioned between water (10 cm3) and chloroform (60 cm3). The dried (MgSO4) organic layer was evaporated and the residue was chromatographed on silica ("Merck" 60.9385) eluting with chloroform to afford a foam which crystallised from ethyl acetate to give trans-2-{2-(1-[6,7-dimethoxy quinazolin-4-yl]-3-hydroxypiperid-4-yl)prop-1-yl}isothiazolidine-1,1-dioxide as microcrystals (diastereomer A) m.p. 173°-174° (0.394 g).
Reaction SMILES: [C:1](=[S:4])([NH2:3])[CH3:2].Br.Br.Br[CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1>CO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:9]3[N:3]=[C:1]([CH3:2])[S:4][CH:8]=3)[CH2:17][CH2:16]2)=[CH:26][CH:27]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Solvent: CO
Product: Cc1nc(CCN2CCC(Cc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 0.75 parts of ethanethioamide, 7 parts of 1-bromo-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]-2-butanone dihydrobromide and 80 parts of methanol was stirred overnight at room temperature. The reaction mixture was evaporated. Water was added. The whole was treated with sodium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography (HPLC) over silica gel using a mixture of hexane, trichloromethane and methanol (45:45:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in ethanol and 2-propanone. The salt was filtered off and dried, yielding 2 parts (33%) of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(2-methyl-4-thiazolyl)ethyl]-4-piperidinyl]methyl]-1H-benzimidazole ethanediote(2:5); mp. 124.1° C. (459).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[OH-].[Na+]>O1CCCC1.O>[CH2:1]([N:7]1[CH2:12][CH2:11][C:10]([CH3:21])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH2:20])[CH:14]=2)[CH:9]([CH3:22])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CCC(C)(c2cccc(C#N)c2)C(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCN1CCC(C)(c2cccc(CN)c2)C(C)C1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred solution of 1-hexyl-3,4-dimethyl-4-(3-cyanophenyl)piperidine (Example 1, 800 mg, 2.68 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. under nitrogen was added lithium aluminium hydride (1.0 M in tetrahydrofuran, 4.0 mL, 4.0 mmol). The reaction mixture was allowed to warm to room temperature, before being heated to 37° C. for 30 minutes. Subsequently, diethyl ether (50 mL), then aqueous sodium hydroxide (0.3 mL, 15% w/v solution) and finally water (0.45 mL) were added. The white solid formed was filtered off. The filtrate was washed with saturated aqueous sodium hydrogencarbonate solution (2×50 mL). The aqueous phases were back-extracted with diethyl ether (50 mL). The combined organics were dried (MgSO4) and concentrated in vacuo to give the title compound as an oil (770 mg).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:2][CH2:3][C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[CH:30]1([CH2:33][NH2:34])[CH2:32][CH2:31]1.C(N(CC)CC)C.Cl>ClCCl.CN(C)C=O>[CH:30]1([CH2:33][NH:34][C:4](=[O:5])[CH2:3][CH2:2][NH2:1])[CH2:32][CH2:31]1
Reactant: NCC1CC1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NCCC(=O)NCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To solution of Fmoc-β-Ala-OH (1.0 g, 3.212 mmol) and oxalyl chloride (0.428 g, 0.29 mL, 3.373 mmol) in dichloromethane (20.0 mL) was added a few drops of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 1 hr followed by addition of cyclopropylmethylamine (0.229 g, 0.28 mL, 3.212 mmol) and triethylamine (0.65 g, 0.90 mL, 6.424 mmol). After 10 min, the mixture was treated with 1 M hydrochloride (10.0 mL) and the aqueous mixture was extracted with dichloromethane (3×30.0 mL). The organic solution was concentrated in vacuo to dryness. The residue was treated with a solution of 20% piperidine in N,N-dimethylforamide (20.0 mL) for 0.5 hr. After removal of the solvent in vacuo, the residue was treated with 1 M hydrochloride (20.0 mL) and ethyl acetate (20.0 mL). The mixture was separated and the aqueous layer was basified with solid sodium hydroxide to pH=8. The precipitate was removed by filtration and the aqueous solution was subjected to ion exchange column eluted with 20% pyridine to give 0.262 g (57%) of N-cyclopropylmethyl β-alanine amide. 1H NMR (200 MHz, CD3OD) δ—0.22 (m, 2H), 0.49 (m, 2H), 0.96 (m, 2H), 2.40 (t, 2H), 2.92 (t, 2H), 3.05 (d, 2H); MS (ES): 143.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:19][N:18]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[O:16])[CH2:11][CH2:10]1.[I-].[Na+].[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([CH:17]2[CH2:19][N:18]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:39](=[O:40])[N:38]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)N2CC2C(=O)N2CCN(c3cc(C)ccc3C)CC2)cc1
Reactant: O=C=Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4cc(C)ccc4C)CC3)N(c3ccccc3)C2=O)cc1

Procedure:
In analogy to example 2, [4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-[1-(toluene-4-sulfonyl)-aziridin-2-yl]-methanone was reacted with sodium iodide and phenylisocyanate to give the title compound as a colorless solid. MS: 532.8 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].[F:15][C:16]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:19]2=[N:20][O:21][N:22]=[C:18]2[CH:17]=1.[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C.O>[NH2:1][C:2]1[N:7]=[C:6]([C:24]2[C:16]([F:15])=[CH:17][C:18]3=[N:22][O:21][N:20]=[C:19]3[CH:23]=2)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: CC1(C)OB(c2cc3nonc3cc2F)OC1(C)C
Reactant: COC(=O)c1nc(Cl)nc(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2cc3nonc3cc2F)nc(N)c1OC
Temperature: 115 °C
Yield: 40.9 %

Procedure:
Methyl 6-amino-2-chloro-5-methoxypyrimidine-4-carboxylate (400 mg, 1.838 mmol), 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (789 mg, 2.390 mmol), bis(triphenylphosphine)palladium(II) chloride (129 mg, 0.184 mmol), and cesium fluoride (558 mg, 3.68 mmol) were combined in 4 mL 1:1 ACN-water and heated at 115° C. for 30 min in a microwave reactor. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaCl, dried, and evaporated. The product was purified by flash chromatography (SiO2, eluting with 5-30% ethyl acetate in dichloromethane) to provide the title compound (240 mg, 39%).
Reaction SMILES: [OH:1][CH:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][C:4]#[N:5].C(OC=C)(=O)C>C(OC(C)C)(C)C>[OH:1][C@H:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][C:4]#[N:5]
Reactant: N#CCC(O)c1cccs1
Solvent: CC(C)OC(C)C
Solvent: C=COC(C)=O
Product: N#CC[C@H](O)c1cccs1
Yield: 42 %

Procedure:
Enzymatic Transesterification of 3-hydroxy-3-(2-thienyl) propanenitrile (1): To a solution of 3-hydroxy-3-(2-thienyl) propanenitrile (1) (5 mmol) dissolved in diisopropyl ether (100 mL), Pseudomonas cepacia lipase immobilized on diatomite (PS-D) (500 mg) and vinyl acetate (25 mmol) were added successively and incubated at 25° C. in an orbital shaker. After 50% completion of the reaction (14 h) as indicated by HPLC, the reaction mixture was filtered and solvent was evaporated under reduced pressure. The residue was subjected to column chromatography to separate the acetate formed and the unreacted alcohol. The optical purity of these compounds were determined by HPLC. (S)-3-hydroxy-3-(2-thienyl) propanenitrile (S-1) 42% yield, ee>99%; [α]30D=−33.5 (c 1, CHCl3); IR (Neat) 3475, 3075, 2878, 2251, 1105, 698 cm−1; 1H NMR (200 MHz, CDCl3) δ 2.82 (dd, 2H, J=3.0 Hz, J=6.6 Hz), 3.0 (s, 1H) 5.25 (t, 1H, J=5.5 Hz), 6.98 (t, 1H, J=4.9 Hz), 7.05 (d, 1H, J=3.7 Hz), 7.28 (d, 1H, J=4.9 Hz); 13C NMR (75 MHz) δ 28.1, 66.0, 117.0, 124.6, 125.6, 127.0, 144.4; Mass (EI) 153 127, 113, 85.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13].C(N(CC)CC)C>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cc1cnc(N)c(N)c1
Reactant: CC(=O)C(C)Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N)c2nc(C)c(C)n2c1
Yield: 37.5 %

Procedure:
To a solution of 2,3-diamino-5-methylpyridine (2.0 g, 16 mmol) in ethanol (100 ml) was added 3-bromo-2-butanon (2.4 g, 16 mmol). The reaction mixture was refluxed for 16 h. An additional amount of 3-bromo-2-butanon (1.0 g 6.7 mmol) and triethylamine (1.0 g, 9.9 mmol) were added and the mixture was refluxed for 2 h. The ethanol was evaporated under reduced pressure and the residue was treated with methylene chloride and a solution of bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The oily residue was purified by column chromatography on silica gel, using methanol:methylene chloride (1:20) as eluent to give the desired product (1.05 g, 37%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[N:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[Cl:36])[CH2:25][CH2:24]3)=[CH:14][CH:15]=2)[N:10]=1)C1C=CC=CC=1>CO.[Pd]>[Cl:36][C:30]1[C:31]([Cl:35])=[CH:32][CH:33]=[CH:34][C:29]=1[N:26]1[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][O:19][C:13]2[N:12]=[C:11]3[C:16]([CH:17]=[CH:18][C:9](=[O:8])[NH:10]3)=[CH:15][CH:14]=2)[CH2:28][CH2:27]1
Reactant: Clc1cccc(N2CCN(CCCOc3ccc4ccc(OCc5ccccc5)nc4n3)CC2)c1Cl
Agent: [Pd]
Solvent: CO
Product: O=c1ccc2ccc(OCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2[nH]1
Yield: 59.6 %

Procedure:
2-Benzyloxy-7-{3-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-propoxy}-[1,8]naphthyridine (367 mg, 0.701 mmol) was hydrogenated using 5% Pd/C (0.1 g) in MeOH (50 mL) for 1 h. The reaction was filtered and concentrated. Purification by liquid chromatography (4–5% MeOH/CH2Cl2) gave the title compound as a white foam (181 mg, 0.418 mmol, 60%). MS: APCI: M+1: 433.1 (Exact Mass: 432.11).
Reaction SMILES: FC(F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=O.CS(C)=O.[CH2:18]([O:25][N:26]1[CH2:30][CH:29]([CH2:31][CH3:32])[CH:28](O)[C:27]1=[O:34])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CO>ClCCl.O>[CH2:18]([O:25][N:26]1[CH2:30][C:29]([CH2:31][CH3:32])=[C:28]([NH:26][CH2:30][C:29]2[CH:31]=[CH:7][C:6]([O:5][CH3:3])=[CH:27][CH:28]=2)[C:27]1=[O:34])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC1CN(OCc2ccccc2)C(=O)C1O
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: CCC1=C(NCc2ccc(OC)cc2)C(=O)N(OCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 105 %

Procedure:
Trifluoroacetic anhydride (1.8 ml, 2.6 g, 12.7 mmol) was added dropwise to a solution of dimethylsulphoxide (1 ml, 1.1 g, 16.2 mmol) in dichloromethane (40 ml) at -78° C. After 10 min 1-Benzyloxy-4-ethyl-3-hydroxypyrrolidin-2-one (0.94 g, 4 mmol) in dichloromethane (8 ml) was added, the mixture stirred for 30 min, then ethyldiiscpropylamine (4.5 ml, 3.4 g, 26.3 mmol) added. After 45 min methanol (1 ml) was added and the solution brought to room temperature. Water was added and the mixture extracted with ether (3×75 ml). The combined organic layers were washed with brine, dried (MgSO4), evaporated in vacuo, and the residue dissolved in methanol (10 ml). 4-Methoxybenzylamine (1.1 ml) was added and the solution kept at room temperature overnight. The solvent was then removed in vacuo, and the product purified by flash chromatography, eluting with light petroleum:ethyl acetate (5:2 v/v) to give 1-benzyloxy-4-ethyl-3-(4-methoxybenzylamino)-2-oxo-2,5-dihydropyrrole as an oil (0.74 g, 55%). 1H NMR (250 MHz, CDCl3) δ7.4-7.5 (5 H, m, ph), 7.22 (2 H, d, J=9 Hz, MeOCCH), 6.85 (2 H, d, J=9 Hz, MeCCHCH), 5.02 (2 H, s, OCH2), 4.32 (2 H, s, CH2NH), 3.78 (3 H, s, OMe), 3.60 (2 H, s, CH2NO), 2.22 (2 H, q, J= 7 Hz, CH2CH3), 0.93 (3 H, t, J=7 Hz, CH3), m/z 353 (M+ +H).
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:18][CH2:19][CH3:20].[Na+].C(Cl)(=O)C.Cl>O1CCCC1>[C:19]([C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:18])[CH3:20]
Reactant: CC[O-]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CCOC(=O)C(C(C)=O)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 2-phenylmalonate (100 mmol) in anhydrous tetrahydrofuran (300 mL) is added sodium ethoxide (110 mmol). The mixture is stirred at room temperature for 30 min, followed by the addition of a solution of acetyl chloride (110 mmol) in tetrahydrofuran (50 mL). After the addition is complete, the mixture is heated to reflux for 3 hours, cooled to room temperature, neutralized with 2 N HCl, then concentrated in vacuo. The residue is partitioned between H20 and CHCl3, the organic extracts washed with sodium bicarbonate, water, and brine, dried (MgS04), filtered and concentrated.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:19][C@H:18]1[CH2:30][OH:31])=[O:16])[CH:12]=[CH2:13].C(N(CC)CC)C>ClCCl>[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([O:22][Si:23]([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:24])[CH3:25])[CH2:19][C@H:18]1[CH:30]=[O:31])=[O:16])[CH:12]=[CH2:13]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O

Procedure:
To a solution of oxalyl chloride (2.53 ml) and dichloromethane (90 ml) was dropwise added dimethyl sulfoxide (4.31 ml) at -40° C.~-50° C. with stirring and the mixture was stirred at the same temperature for 5 minutes. To the solution was added dropwise a solution of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsiloxy-2-(hydroxymethyl)pyrrolidine (8.70 g) in dichloromethane (45 ml) at -40° C.~-50° C. After 10 minutes with stirring, triethylamine (19.2 ml) was dropwise added to the solution and the mixture was stirred at 0°~10° C. for 30 minutes. The insoluble material was filtered off and the filtrate was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsiloxy-2-formylpyrrolidine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[CH:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:33][CH:26]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: NC1CCCCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCCCC3)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and cycloheptanamine as a brown solid (43%). MS 456 (MH+).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.I[CH3:16].O>CN(C=O)C>[CH3:16][S:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CI
Reactant: N#Cc1ccc2nc(S)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccc(C#N)cc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Sodium hydride (60% in mineral oil, 1.92 g, 48 mmol) was suspended in DMF (60 mL) at 0° C. and 2-mercaptobenzo[d]thiazole-6-carbonitrile (5.76 g, 30 mmol) from Step 2 of this Example was added slowly. After gas evolution ceased, iodomethane (8.4 mL, 135 mmol) was added and the reaction mixture was stirred at rt overnight. To the reaction mixture was added 300 mL of water and the precipitate was collected by filtration to give 2-(methylthio)benzo[d]thiazole-6-carbonitrile as a light yellow solid (5.47 g, 89%). 1H NMR (300 MHz, CDCl3) δ 8.08 (d, J=1.1 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.67 (dd, J=1.5, 8.5 Hz, 1H), 2.83 (s, 3H).
Reaction SMILES: C([N:4]=[C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH:8]=[C:7]([CH3:21])[S:6]1)(=O)C.[ClH:22]>C(O)C.O>[ClH:22].[F:19][C:17]([F:18])([F:20])[C:12]1[CH:11]=[C:10]([N:9]2[CH:8]=[C:7]([CH3:21])[S:6][C:5]2=[NH:4])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: CC(=O)N=c1sc(C)cn1-c1ccc(F)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cn(-c2ccc(F)c(C(F)(F)F)c2)c(=N)s1

Procedure:
A mixture of 2-acetylimino-3-(3-trifluoromethyl-4-fluorophenyl)-5-methylthiazoline (3.5 g) and hydrochloric acid (36%, 3.5 ml) in ethanol-water (35 ml) was refluxed for 3 hours. After cooling, the solvent was removed under reduced pressure, and the residue was isolated and washed with a little amount of iso-propanol and hexane to give 2.8 g of 3-(3-trifluoromethyl-4-fluorophenyl)-5-methyl-2-iminothiazoline hydrochloride (compound (i)).