Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:11]([CH3:13])([CH3:12])[C:9](=[O:10])[N:8]([CH2:14][CH2:15][CH2:16][NH2:17])[C:6]1=[O:7].C(#N)C=C>>[C:2]([CH2:3][CH2:4][N:5]1[C:11]([CH3:12])([CH3:13])[C:9](=[O:10])[N:8]([CH2:14][CH2:15][C:16]#[N:17])[C:6]1=[O:7])#[N:1]
Reactant: CC1(C)C(=O)N(CCCN)C(=O)N1CCCN
Solvent: C=CC#N
Product: CC1(C)C(=O)N(CCC#N)C(=O)N1CCC#N

Procedure:
A diamine containing the hydantoin ring is 1,3-bis-(3-aminopropyl)-5,5-dimethylhydantoin which may be prepared as described by Sato, Nippon Kaguku Zasshi, 83, 318-23 (1962). 5-5-dimethylhydantoin is reacted with acrylonitrile yielding 1,3-bis (2-cyanoethyl)-5,5-dimethylhydantoin which is further reacted with hydrogen gas in the presence of Raney nickel to yield 1,3-bis-(3-aminopropyl)-5,5-dimethylhydantoin. This compound is available semi-commercially from Glyco, Inc. as Dantomin DAP.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:36])[NH:6][C@H:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15](=[O:29])[NH:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([NH2:28])=[N:23][CH:22]=[CH:21]2)=[O:9])(C)C.COC(N[C@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)=O>>[CH3:1][O:4][C:5](=[O:36])[NH:6][C@H:7]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15](=[O:29])[NH:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([NH2:28])=[N:23][CH:22]=[CH:21]2)=[O:9]
Reactant: CC(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)c1ccccc1
Agent: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)c1ccccc1
Yield: 74 %

Procedure:
Using the procedure described for example 91d 0.36 g of 1-[(R)-methoxycarbonylamino-phenyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid was converted into 040 g (74%) of the title compound. (+)-APCI-MS: 462 (MH+).
Reaction SMILES: N1C=CC=CC=1.F.[Si]([O:25][CH2:26][C@@H:27]([NH:48][C:49]([C:51]1[S:52][C:53]2[CH2:54][N:55]([CH3:60])[CH2:56][CH2:57][C:58]=2[N:59]=1)=[O:50])[C@H:28]([NH:35][C:36]([C:38]1[NH:39][C:40]2[C:45]([CH:46]=1)=[CH:44][C:43]([Cl:47])=[CH:42][CH:41]=2)=[O:37])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1>O1CCCC1>[Cl:47][C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([C:36]([NH:35][C@@H:28]([C@H:27]([NH:48][C:49]([C:51]1[S:52][C:53]3[CH2:54][N:55]([CH3:60])[CH2:56][CH2:57][C:58]=3[N:59]=1)=[O:50])[CH2:26][OH:25])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:37])=[CH:46]2
Reactant: CCOC(=O)C[C@@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1nc2c(s1)CN(C)CC2
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)[C@@H](CO)NC(=O)c1nc2c(s1)CN(C)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
After hydrogen fluoride-pyridine (0.4 ml) was added dropwise to a mixture sulution composed of the compound (0.54 g) obtained in Example 175, pyridine (4.0 ml) and tetrahydrofuran (10 ml) under ice cooling, the reaction mixture was stirred for 18 hours while the temperature thereof was gradually raised to room temperature. The reaction mixture was concentrated, and the resultant residue was purified by column chromatography on silica gel (chloroform:methanol=9:1) to obtain the title compound (0.31 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[N:13]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[C:12]([CH3:27])([CH3:26])[CH2:11][CH2:10]1.[Cl-].[NH4+:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[N:13]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([NH2:29])=[O:25])=[C:16]3[N:15]=2)[C:12]([CH3:27])([CH3:26])[CH2:11][CH2:10]1
Reactant: [NH4+]
Reactant: CC1(C)CC[C@H](c2cc(F)ccc2F)N1c1ccn2ncc(C(=O)O)c2n1
Agent: [Cl-]
Product: CC1(C)CC[C@H](c2cc(F)ccc2F)N1c1ccn2ncc(C(N)=O)c2n1
Yield: 33 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and ammonium chloride. The crude material was purified by reverse phase HPLC (0-70% acetonitrile/water) to provide the title compound (8.5 mg, 33% yield). MS (apci) m/z=372.1 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[N:6][CH:7]=1.[C:12]([C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[CH3:41])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:18])#[CH:13]>>[NH2:11][C:9](=[O:10])[CH2:8][C:5]1[N:6]=[CH:7][C:2]([C:13]#[C:12][C:14]2[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=2[CH3:41])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)=[C:22]([C:34]([F:35])([F:37])[F:36])[CH:21]=2)=[O:18])=[N:3][CH:4]=1
Reactant: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Reactant: NC(=O)Cc1cnc(Br)cn1
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc(CC(N)=O)cn1

Procedure:
The title compound can be prepared as for example 1 using 2-(5-bromopyrazin-2-yl)acetamide and 3-ethynyl-4-methyl-N-{4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl}-benzamide.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C@@H:8]1[CH:13]=[CH:12][CH2:11][C:10]([CH3:15])([CH3:14])[C@H:9]1[C:16](OC)=[O:17].[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1.CCOCC.CC(C)=O>[CH3:7][C@@H:8]1[CH:13]=[CH:12][CH2:11][C:10]([CH3:14])([CH3:15])[C@H:9]1[CH2:16][OH:17]
Reactant: COC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: C[C@@H]1C=CCC(C)(C)[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a stirred suspension of LiAlH4 (1.55 g, 41 mmol) in THF (50 ml) at room temperature was added dropwise a solution of methyl trans-2,6,6-trimethyl-3-cyclohexene-1-carboxylate (10.0 g, purity 98%, 54 mmol) in THF (50 ml). After two hours at room temperature, the mixture was diluted with ether (150 ml), acetone (3 ml) was added dropwise, then 1 N aqueous NaOH (8 ml) was added and the mixture was stirred at room temperature during 30 minutes. Na2SO4 was added, the solids filtered off and the filtrate concentrated. Bulb-to-bulb distillation (oven temperature 160° C./16 mbar) afforded trans-2,6,6-trimethyl-3-cyclohexene-1-methanol as a colourless liquid (8.40 g, purity >99%, yield 99%).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[CH:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.C(I)C.Cl>C1COCC1>[CH2:1]([C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)C1CCC1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of lithium diisopropylamide (800 ml; 2.0 M THF solution) in THF (800 ml) was added dropwise over a period of 50 minutes under cooling with ice, a solution of cyclobutanecarboxylic acid (80 g) in THF (100 ml) and the mixture was stirred at room temperature for two hours. To the mixture ethyl iodide (64.0 ml) was added dropwise and the mixture was stirred at room temperature overnight. To the reaction solution was added 2N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed by water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give 1-ethylcyclobutanecarboxylic acid (142 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[O:16][CH2:17][C:18](=[O:25])[C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:10]([CH3:26])[CH:9]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[C:29]([CH:36]=O)=[CH:28]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:27]1[C:35]2=[N:34][CH:33]=[CH:32][CH:31]=[C:30]2[C:29]([CH:36]=[C:17]2[O:16][C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[CH:9][C:10]=3[CH3:26])=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:25])=[CH:28]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(OCCOCCO)cc2C)OCC1=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCCOCCO)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 12.6 %

Procedure:
To a solution of ethyl 2-({4-[2-(2-hydroxyethoxy)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.15 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 74, First step to Fourth step and 7-azaindole-3-carboxaldehyde (0.070 g, 0.50 mmol) in ethanol (10 mL), L-proline (0.010 g, 0.087 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with diethyl ether then dried to afford the titled compound (0.031 g, y. 15%) as solid.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)=[CH:22][CH:21]=1
Reactant: OCCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccc(F)cc2)cc1
Yield: 76.6 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (249 mg, 0.991 mmol) prepared in Example 1 (1a) and 2-(4-fluorophenyl)ethanol (150 μL, 1.20 mmol) to give 241 mg of the title compound (yield: 91%).
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[NH2:10].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:12]([N:14]1[C:3](=[O:11])[C:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=2[NH:10][C:15]1=[O:16])[CH3:13]
Reactant: COC(=O)c1cccnc1N
Reactant: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCn1c(=O)[nH]c2ncccc2c1=O
Temperature: 25 °C
Yield: 11.9 %

Procedure:
A mixture of 20.00 g (0.132 mol) of 2-aminonicotinic acid methyl ester, 17.67 g (0.248 mol) ethyl isocyanate and 2 g (0.016 mol) 4-dimethylaminopyridine in dry pyridine was refluxed for 23 hours. The pyridine was removed under reduced pressure and the residue was treated with 370 ml methanol. The mixture was refluxed for 10 minutes and allowed to cool down first to room temperature. The mixture is further cooled to 0° C. and the crude 3-ethyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was allowed to crystallize over night. The crude 3-ethyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was further purified by preparative column chromatography on straight phase silica (eluent:chloroform:methanol 9:1). The isolated 3-ethyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was recrystallized from dimethyl formamide, isolated by filtration and washed twice with ethanol and twice with tert butyl methyl ether. The isolated compound was further recrystallized from methanol. A first crop of 2.5 g was isolated. Upon concentration of the filtrate a second crop of 0.5 g was isolated. Both fractions were pooled and finally 3.00 g (12%) of 3-ethyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was isolated (m.p. 240-1° C.)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH:10][C:11]1[CH:27]=[CH:26][C:14]([O:15][CH2:16][CH2:17][NH:18][C:19](=O)OC(C)(C)C)=[CH:13][CH:12]=1)=[O:9].[ClH:28].C([O:32][CH2:33][CH3:34])(=O)C>CO>[ClH:28].[OH:32][C@H:33]([C:34]1[CH:8]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:19][NH:18][CH2:17][CH2:16][O:15][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:27][CH:26]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(NC(=O)Cc2ccccn2)cc1
Agent: Cl
Solvent: CO
Product: O=C(Cc1ccccn1)Nc1ccc(OCCNC[C@H](O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.62 g of tert-butyl N-[2-[4-[[2-(2-pyridyl)acetyl]amino]phenoxy]ethyl]carbamate in 30 ml of methanol was added 50 ml of a 4N hydrochloride-ethyl acetate solution. After the reaction solution was stirred at room temperature for eight hours, the solvent was evaporated in vacuo. To the residue were added an aqueous solution of sodium hydrogen carbonate and potassium carbonate to adjust to pH about 12. The resulting aqueous phase was extracted with a mixed solvent of chloroform and tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate and concentrated, the resulting residue was dissolved in 40 ml of methanol, and 1.02 g of (R)-styrene oxide was added thereto. After the reaction solution was heated to reflux for 26 hours, the solvent was evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1→10/1) and dissolved in methanol, 0.59 ml of a 4N hydrogen chloride-ethyl acetate solution was added, and the solvent was evaporated in vacuo. The resulting crude crystals were recrystallized from methanol-ethanol to give 320 mg of (R)-4′-[2-[(2-hydroxy-2-phenylethyl)-amino]ethoxy]-2-(2-pyridyl)acetanilide hydrochloride
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12][CH2:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[NH2:16])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N1C=CC=CC=1.Cl[C:28]([O:30][CH3:31])=[O:29].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([S:12][CH2:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[NH:16][C:28](=[O:29])[O:30][CH3:31])=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccccc1CSc1ncc(C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Nc1ccccc1CSc1ncc(C(F)(F)F)cc1Cl
Reaction time: 2 h
Yield: 72.1 %

Procedure:
A solution of 2.23 g of 2-(3-chloro-5-trifluoromethyl-2-pyridylthiomethyl)aniline and 0.83 g of pyridine in 10 ml of toluene was drop-wise added to a solution of 1.1 g of methyl chloroformate in 10 ml of toluene under stirring at 10° to 15° C. After completion of the drop-wise addition, the reaction was continued at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into water, subjected to extraction with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was washed with hexane. The precipitated solid was filtered off to obtain 1.9 g of the desired product (Compound No. 1) having a melting point of 111° to 113° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10](OC)=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(O)(=[O:22])C>CN(C)C=O.O>[OH:22][C:8]1[C:9]2[CH:14]=[CH:15][CH:16]=[N:17][C:10]=2[S:11][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: COC(=S)c1cccnc1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1c(-c2ccccc2)sc2ncccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A suspension of 12.9 g (50 mmol) of methyl 2-phenylmethylthionicotinate and 2.6 g (110 mmol) of sodium hydride in 100 mL of dry N,N-dimethylformamide was stirred for 4 hours at room temperature. The solution was diluted with 200 mL water and acidified with glacial acetic acid. The precipitate was collected, washed with water, and dried to afford 10.6 g (93%) of a white crystalline solid to be used in the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCOc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 145 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(2-bromoethoxy)-4-chlorobenzene and conditions outlined in procedure V. LCMS: 456 [M+H]; Rt=1.07 min.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([N:31]([C:33]1([C:38]#[CH:39])[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:32])[CH:29]=[CH2:30]>>[CH2:28]([N:31]([CH3:32])[C:33]1([C:38]#[C:39][C:16]2[CH:15]=[CH:14][C:13]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:8][CH:7]=4)=[N:10][S:11][C:12]=3[CH:17]=2)[CH2:34][CH2:35][CH2:36][CH2:37]1)[CH:29]=[CH2:30]
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CC1(N(C)CC=C)CCCC1
Product: C=CCN(C)C1(C#Cc2ccc3c(-c4ccc(C(F)(F)F)cc4)nsc3c2)CCCC1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and Allyl-(1-ethynyl-cyclopentyl)-methyl-amine were converted to yield Allyl-methyl-{1-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ylethynyl]-cyclopentyl}-amine as light yellow oil, MS: 441 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:25]C3C=CC([N+]([O-])=O)=CC=3)[N:9]=2)=[CH:4][CH:3]=1>O1CCCC1>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[N:9][C:10]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:25])[C:15]=3[C:13]3[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=3)[N:16]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(-c2nc3cccc(Nc4ccc([N+](=O)[O-])cc4)c3nc2-c2ccc(C)cc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3ccc(N)c(-c4ccc(N)cc4)c3nc2-c2ccc(C)cc2)cc1

Procedure:
5.9 g (13.2 mmol) of 2,3-di(4-methylphenyl)-5-(4-nitrophenyl)aminoquinoxaline was dissolved in 70 ml of tetrahydrofuran, and the reaction container was purged with nitrogen. Thereafter, 2.0 g of 5% Pd/C (hydrous) was added to the system, which was satisfactorily purged with nitrogen again. This system was subsequently purged with hydrogen gas and reacted at room temperature for 13 hours. After completion of the reaction, the system was filtered. The resulting filtration residue was washed with tetrahydrofuran and filtered again. The solvent was removed from the resulting filtrate, after which a reaction product was extracted by means of a silica gel column.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:30](=[O:31])[N:7]2[C:8]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:9](CO)[CH2:10][S:11][C@H:6]12)(=[O:3])[CH3:2].C(NC1C(=O)N2[C:39]([C:45]([O:47][CH:48](C3C=CC=CC=3)C3C=CC=CC=3)=[O:46])=[C:40](C=O)CS[C@H]12)(=O)C.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.C1C=CC=CC=1.CC(C)=O>[C:1]([NH:4][CH:5]1[C:30](=[O:31])[N:7]2[C:8]([C:14]([O:16][CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:9]([CH:40]=[CH:39][C:45]([O:47][CH3:48])=[O:46])[CH2:10][S:11][C@H:6]12)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=O)CS[C@H]12
Agent: O=[Cr](=O)=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COC(=O)C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(C)=O)[C@H]2SC1
Reaction time: 0.02 h

Procedure:
To a stirred cooled (0°-5° C.) solution containing 220 mg. of benzhydryl 7-acetamido-3-hydroxymethyl-3-cephem-4-carboxylate dissolved in 10 ml. of dry acetone there was added 15 drops of Jones reagent. The mixture was stirred at 0°-5° C. for 1 minute and then quenched with isopropanol and a small amount of saturated sodium bicarbonate solution. Ethyl acetate was added and the resulting solution was washed with saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution again, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 225 mg. of benzhydryl 7-acetamido-3-formyl-3-cephem-4-carboxylate (one spot on a thin layer chromatogram). This aldehyde material was dissolved in a mixture of 10 ml. of dry benzene and 10 ml. of isopropanol. Then 1 equivalent of (carbmethoxymethylene)-triphenylphosphorane was added as a solid. The mixture was stirred for 1 hour at room temperature, evaporated under reduced pressure to dryness, taken up in ethyl acetate and washed with cold 5 percent v/v hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give 293 mg. of the crude titled product mixed with triphenylphosphine oxide bi-product. When the crude product was applied to two commercially available preparative thin layer chromatography plates (solvent, 1:1 v/v ethyl acetate:benzene), there was obtained 90 mg. of the purified titled product whose NMR, IR and UV spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13](C(OCC)=O)[CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].Br.[OH-].[Na+].Cl>C(O)C.O>[ClH:1].[Cl:9][C:6]1[CH:5]=[C:4]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: CCOC(=O)N1CCN(c2cc(Cl)c(Cl)c(Cl)c2)CC1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1cc(N2CCNCC2)cc(Cl)c1Cl

Procedure:
1-(3,4,5-Trichlorophenyl)-4-ethoxycarbonylpiperazine (12.3g) was refluxed with 48% hydrobromic acid (100 ml) overnight. The reaction was cooled, water added followed by aqueous sodium hydroxide solution (600 ml; 10%). The product was extracted into ether (3 × 100 ml), the ether extracts combined, washed with water (3 × 100 ml) till neutral, dried (anh. Na2SO4) and evaporated giving a brown oil which soon solidified (10.14g). The free base was converted to the hydrochloride (9.42g) by dissolving in dry ethanol and adding ethereal HCl till the hydrochloride precipitated out.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:25]#[N:26])([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:13][CH2:12]1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])([C:25]#[N:26])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(C#N)(c2ccc(Cl)cc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1(c2ccc(Cl)cc2Cl)CCN(CCCN)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To 3-[4-cyano-4-(2,4-dichlorophenyl)-piperidin-1-yl]-propyl-carbamic acid tert-butyl ester (0.589, 1.42 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.423 g (93%) of 1-(3-aminopropyl)-4-(2,4-dichlorophenyl)-piperidine-4-carbonitrile which was used as such for the subsequent step.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][C@H:6]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[CH2:22]([Mg]Br)[CH2:23][CH3:24].C1COCC1>>[OH:11][C@@:10]1([CH2:22][CH2:23][CH3:24])[CH2:9][CH2:8][N:7]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C@H:6]1[CH3:5]
Reactant: C[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Reactant: CCC[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC[C@]1(O)CCN(C(=O)OCc2ccccc2)[C@H]1C

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (12.9 g), 2 mol/L propylmagnesium bromide—THF solution (20 mL) and benzyl (2S)-2-methyl-3-oxopyrrolidine-1-carboxylate (3.5 g), the title compound was obtained as pale-yellow oil (yield: 2.32 g, yield: 56%).