Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][CH:5]([CH2:20][CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](O)=[O:17])=[CH:9][CH:8]=1>C(O)C>[NH2:22][CH2:21][CH2:20][CH:5]([CH3:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:17])[NH:2][N:3]=2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)Cc1ccc(C(=O)CCC(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CC(CCN)Cc1ccc(C2=NNC(=O)CC2)cc1
Yield: 82 %

Procedure:
9.61 g of hydrazine monohydrate was added to an ethanol solution (500 ml) containing 15.06 g of 4-(2-methyl-4-phthalimidobutyl)-1-(3-hydroxycarbonylpropionyl)benzene, and the mixture was refluxed under heating for 2.5 hours. After cooling, precipitated crystal was collected by filtration and recrystallized from ethyl acetate to obtain 8.14 g of 6-[4-(4-amino-2-methylbutyl)phenyl]-4,5-dihydropyridazin-3(2H)-one.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([Al](CC)CC)C.[CH:17]12[O:23][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18]2.[OH-].[Na+]>ClCCl.CCCCCC>[CH2:1]([N:5]([C@@H:21]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:22]1[OH:23])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCC2OC2C1
Reactant: CCCCNCCCC
Agent: CC[Al](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCN(CCCC)[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
A! A solution of 43 ml (0.25 mole) of dibutylamine in 770 ml of dichloromethane was added with a 0.91M solution of 280 ml (0.025 mole) of triethyl-aluminium in hexane, at 0° C. under argo, and the resultant reaction mixture was stirred for 30 minutes at room temperature, then dropwise added with 25.8 ml (0.25 mole) of 7-oxabicyclo[4.1.0]heptane, and stirred overnight. A 6M solution of 200 ml (1.2 moles) of sodium hydroxide was added very slowly, and the mixture was stirred for 2 hours at room temperature. The phases were separated, and the organic one was washed with water (2×50 ml), anhydrified over sodium sulfate and evaporated. The resultant crude was distilled under vacuum to provide 43.7 g (yield: 75%) of trans-2-(N,N-dibutylamino)-cyclohexanol (b.p.--105°-107° C./1 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]2=[O:20])=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)cc2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CNCCN1Cc1ccc(Cl)cc1

Procedure:
A cold (0° C.) solution of tert-Butyl 4-(4-chlorobenzyl)-3-oxopiperazine-1-carboxylate (3.2 g, 9.9 mmol) in ethyl acetate (100 mL) was saturated with HCl gas. The resultant mixture was stirred at 0° C. for 1 h. The product mixture was concentrated under vacuum. The residue was treated with dichloromethane saturated with ammonia gas. The resultant chalky mixture was filtered, and the filtrate concentrated under vacuum. The residue was diluted with benzene and concentrated under vacuum to provide 1-(4-chlorobenzyl)-piperazin-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(CC(=O)C)(=O)C.C[N:45](C=O)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:25]1([C:23]([C:10]2[C:11]3[CH2:20][S:19](=[O:22])(=[O:21])[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:12]=3[N:8]([C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[NH2:45])[N:9]=2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(c1nn(-c2cccc(Br)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: CN(C)C=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)CC(C)=O
Product: Nc1cccc(-n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)c1
Temperature: 90 °C

Procedure:
1-(3-Bromophenyl)-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (0.15 g, 0.308 mmol), copper acetate (6 mg, 0.03 mmol), cesium carbonate (200 mg, 0.616 mmol) and acetyl acetone (13 μL, 0.123 mmol) are taken DMF purged with NH3 gas. The reaction mixture is heated to 90° C. for 24 h. After this time, reaction mixture is concentrated under reduced pressure and purified by column chromatography (100% EtOAc) to afford the title compound as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ=7.99-7.97 (m, 1H), 7.62-7.60 (m, 1H), 7.24-7.20 (t, J=7.84 Hz, 1H), 6.98-6.95 (m, 1H), 6.75-6.73 (d, J=9.32 Hz, 1H), 6.58-6.56 (m, 2H), 5.57 (s, 2H), 4.87 (s, 2H), 3.95 (m, 2H), 3.66 (m, 6H), MS (ESI+): 425.0. HPLC (max plot): 94.69%; Rt 2.65 min.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@H:9]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10]([O:12]N1C(=O)CCC1=O)=[O:11]>O1CCOCC1>[CH3:8][C@@H:9]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[C:10]([OH:12])=[O:11]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 8 h

Procedure:
To a mixture of Z--(L)--mesoDAP (2) (1.50 g) and triethylamine (1.0 g) in aqueous dioxane (dioxane 30 ml and water 20 ml) was added Boc--D--Ala--OSu (3) (1.32 g) and the mixture was allowed to stand overnight at room temperature. Dioxane was evaporated, and the resulting aqueous solution was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to give Boc--D--Ala--(D)--Z--(L)--mesoDAP (4) (1.90 g) as a white foam.
Reaction SMILES: [C:1]1([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(OC)(O[CH3:20])(=O)=O.[Cl-].[NH4+]>S(C1C=CC(C)=CC=1)([O-])(=O)=O.C([N+](CC)(CC)CC)C.C(#N)C.[Pt]>[C:1]1([CH:11]([CH3:20])[C:12]([O:14][CH3:15])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)Cc1cccc2ccccc12
Agent: [Pt]
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC#N
Product: COC(=O)C(C)c1cccc2ccccc12
Yield: 92 %

Procedure:
Into the cathode chamber of an electrolytic cell divided with an ion-exchange resin diaphragm was placed a solution of 10 mmols of methyl 1-naphthylacetate, 12 mmols of dimethyl sulfate and 1.0 g of tetraethylammonium tosylate in 30 ml of acetonitrile. The anode chamber was supplied with a solution of 2.0 g of tetraethylammonium tosylate in 10 ml of acetonitrile. Constant current electrolysis was conducted at 0.2 A/cm2 with use of platinum for both the cathode and the anode. After passing 1.5 F of electricity per mol of the methyl 1-naphthylacetate at room temperature, the cathode solution was added to a saturated aqueous solution of ammonium chloride and the mixture was extracted twice with ether. The ether was distilled off and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (10:1), giving methyl 1-naphthyl(α-methyl)acetate in a yield of 92%. The spectral data of the ester were as follows.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][N:31]([C:8](=[O:9])[CH2:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:17][CH2:18]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from benzeneacetyl chloride and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=443.4.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][O:19]C(=O)C)[C:13](=[O:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[C:13](=[O:23])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OCCN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1CCO
Yield: 97.1 %

Procedure:
To 4-(2-acetoxy-ethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (925 mg) in methanol (10 ml) was added potassium carbonate (800 mg) in water (4 mL). After 2 hours at room temperature the mixture was diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(2-hydroxy-ethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (780 mg). This material was dissolved in ethanol and stirred over 10% Pd/C under an atmosphere of hydrogen for 24 hours. The reaction mixture was then filtered through celite and the solvent removed in vacuo to give 1-(2-hydroxy-ethyl)-piperazin-2-one (413 mg), which was used in a standard reductive amination procedure with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde to give 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-(2-hydroxy-ethyl)-piperazin-2-one. This compound (150 mg) was used in a Suzuki coupling with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (96 mg) to give after flash silica purification the title compound (39 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (320 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (275 mg, 1.2 mmol) according to the general procedure M. Obtained as a red viscous oil (196 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:14]2[C:15]3[N:16]([CH:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=3)[C:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CCOC(=O)c1cn2c(-c3cccs3)cnc(N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn2c(-c3cccs3)cnc(N3CCNCC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A 25 mL round bottom flask was charged with ethyl 8-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(thiophen-2-yl)imidazo[1,2-a]pyrazine-2-carboxylate (1.13 g, 2.47 mmol), trifluoroacetic acid (5 mL) and CH2Cl2 (10 mL). The mixture was stirred at 25° C. for 1 h. Reaction progress was monitored by LC-MS. Work-up: the solvent was evaporated. The residue was mixed with saturated aqueous NaHCO3 and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with a 1:20 MeOH/CH2Cl2, to afford 0.75 g (84%) of the product. 1H NMR (300 MHz, CD3OD) δ: 8.40 (s, 1H), 7.69 (dd, J=5.1, 1.2 Hz, 1H), 7.58 (s, 1H), 7.52 (dd, J=3.9, 1.2 Hz, 1H), 7.28 (dd, J=5.1, 3.9 Hz, 1H), 4.54 (t, J=5.1 Hz, 4H), 4.41 (q, J=7.2 Hz, 2H), 3.39 (t, J=5.1 Hz, 4H), 1.38 (t, J=7.2 Hz, 3H). MS m/z: 358 (M+H+).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:9][CH2:8][C@@:7]([NH:18][C:19]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[S:20])([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[C@H:6]([CH2:30]O)[CH2:5]2)[CH2:3][CH2:2]1.C(OC[C@@H]1OC[C@]2(C3C=CC(F)=CC=3F)N=C(NC(=O)C3C=CC=CC=3)SC[C@@H]2C1)C1C=CC=CC=1>>[CH:1]1([C@@H:4]2[O:9][CH2:8][C@:7]3([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=4[F:17])[N:18]=[C:19]([NH:21][C:22](=[O:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[S:20][CH2:30][C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](C2CC2)C[C@H]1CO)c1ccccc1
Agent: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@H]2CS1)c1ccccc1

Procedure:
rel-N-{[(3S,4R,6R)-6-Cyclopropyl-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C21) was converted to the product using the method described for synthesis of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C8) in Preparation P1. The product was obtained as a solid. Yield: 1.42 g, 3.31 mmol, 88%. LCMS m/z 429.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 11.7-12.5 (v br s, 1H), 8.24 (br d, J=7.6 Hz, 2H), 7.48-7.54 (m, 1H), 7.38-7.48 (m, 3H), 6.82-6.97 (m, 2H), 4.08 (br dd, J=12.4, 1.3 Hz, 1H), 3.80 (d, J=12.3 Hz, 1H), 3.05-3.13 (m, 1H), 2.93-3.04 (m, 2H), 2.64 (dd, J=12.8, 2.6 Hz, 1H), 2.05-2.18 (m, 1H), 1.75-1.83 (m, 1H), 0.96-1.06 (m, 1H), 0.50-0.62 (m, 2H), 0.40-0.46 (m, 1H), 0.22-0.29 (m, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]#[N:16])=[C:12]([CH3:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][OH:19]>>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:18][OH:19])[NH2:16])=[C:12]([CH3:17])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C#N
Reactant: NO
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)sc1C(N)=NO

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1d) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-methylthiophene-2-carbonitrile (2.5 g, 9.2 mmol) that was obtained in Example 11 (11c) and a 40% aqueous solution of hydroxylamine (20 mL). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (1.4 g) in a yield of 52% as a white crystalline solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[C@H:35]1[CH2:40][CH2:39][C@H:38]([CH2:41][CH3:42])[CH2:37][CH2:36]1)(=O)=O>C(O)(C)(C)C.CC(=O)CC>[CH2:41]([C@@H:38]1[CH2:39][CH2:40][C@H:35]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:5]3)[CH2:36][CH2:37]1)[CH3:42]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Reactant: CC[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCC(C)=O
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](CC)CC4)ccc3c2)CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 1-((6-hydroxynaphthalen-2-yl)methyl)piperidine-4-carboxylate (2.43 g, 8 mmol, 1.0 eq) in the co-solvent t-butanol/2-butanone (40 mL/20 mL) was added cesium carbonate (5.0 g, 16 mmol, 2.0 eq). The mixture was stirred at 80° C. for 10 min and then trans-4-ethylcyclohexyl methanesulfonate (3.2 g, 16 mmol, 2.0 eq) was introduced. The suspension was stirred at 80° C. under N2 for 15 h. Then the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (EtOAc/PE=1:5) to give ethyl 1-((6-(cis-4-ethylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate as a slight yellow solid (1.6 g, yield: 46%). ESI-MS (M+H)+: 424.3. 1H NMR (400 MHz, CD3OD) δ: 7.63-7.56 (m, 3H), 7.30 (dd, J=8.4, 1.6 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.8, 2.4 Hz, 1H), 4.68-4.66 (m, 1H), 4.01 (q, J=7.2 Hz, 2H), 3.66 (s, 2H), 2.85-2.80 (m, 2H), 2.25-2.22 (m, 1H), 2.11-2.08 (m, 2H), 1.96-1.92 (m, 2H), 1.81-1.77 (m, 2H), 1.65-1.45 (m, 6H), 1.33-1.30 (m, 2H), 1.22-1.12 (m, 3H), 1.13 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH2:26]>N1C=CC=CC=1>[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH:26][C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N[C@@H]3CCCC[C@H]3N)cc21
Yield: 66.3 %

Procedure:
A mixture of 2.53 g of 1-ethyl-6 7-difluoro-1,4- dihydro-4-oxo-3-quinolinecarboxylic acid and 4.6 g of trans-(-)-1,2-diaminocyclohexane in 10 ml of pyridine was reacted as described in Example 1 to give 2.3 g of the desired product, m.p. 230°-231°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:14]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[O:14])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(C(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.1 %

Procedure:
To a mixture of 2-(piperidin-4-yl)-acetic acid ethyl ester (211.4 mg, 1.234 mmol, Oakwood,) in N,N-dimethyl formamide (5.0 mL) was added 1,1′-carbonyldiimidazole (216 mg, 1.332 mmol Aldrich). After it was stirred at rt for 4 days under an argon atmosphere, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give [1-(imidazole-1-carbonyl)-piperidin-4-yl]acetic acid ethyl ester (293.3 mg, 1.10 mmol, 89.6%) which was used without further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)C=O.[CH3:11][O:12][N:13]=[C:14]([C:18]1[N:19]=[C:20]([NH:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:21][CH:22]=1)[C:15](O)=[O:16].[NH2:43][CH:44]1[C:69](=[O:70])[N:46]2[C:47]([C:53]([O:55][CH:56]([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[O:54])=[C:48]([CH2:51][Cl:52])[CH2:49][S:50][C@H:45]12>C(Cl)Cl.C(OCC)(=O)C>[Cl:52][CH2:51][C:48]1[CH2:49][S:50][C@@H:45]2[CH:44]([NH:43][C:15](=[O:16])[C:14](=[N:13][O:12][CH3:11])[C:18]3[N:19]=[C:20]([NH:23][C:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[S:21][CH:22]=3)[C:69](=[O:70])[N:46]2[C:47]=1[C:53]([O:55][CH:56]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:54]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
6.35 ml (68 mmol) of phosphorus oxychloride was added to 20 ml of dry ethyl acetate. 5.28 ml (68 mmol) of N,N-dimethylformamide was dropwise added thereto at 0° C., and the mixture was stirred at the same temperature for 15 minutes. To this solution, 180 ml of dry methylene chloride was added. 25.2 g (57 mmol) of 2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (syn-isomer) was added thereto at 0° C., and the mixture was stirred for 30 minutes. Then, to this solution, 23.6 g (57 mmol) of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate was added, and the mixture was stirred at 0° C. for 2 hours. The reaction solution was adjusted to pH 7.0, and insoluble substances were filtered off. The filtrate was washed sequentially with a 5% sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 44.5 g (yield: 99%) of benzhydryl 3-chloromethyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn-isomer).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=[C:7]([F:13])[C:5]=2[N:6]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15].Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[F:13][C:7]1[C:5]2[N:6]=[C:2]([NH:17][CH:14]([CH3:16])[CH3:15])[S:3][C:4]=2[CH:10]=[C:9]([CH:11]=[O:12])[CH:8]=1
Reactant: O=Cc1cc(F)c2nc(Br)sc2c1
Reactant: CC(C)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)Nc1nc2c(F)cc(C=O)cc2s1
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-4-fluorobenzo[d]thiazole-6-carbaldehyde (0.110 g, 0.423 mmol) and isopropylamine (0.15 ml, 1.76 mmol) in 1,4-dioxane (5 mL) was heated at reflux for 36 hr. The solution was allowed to cool to rt and 1N HCl (1 mL) was added. The mixture was heated at 60° C. for 1 hr. After it cooled to rt, the mixture was poured into saturated NaHCO3 solution (20 mL) and extracted with AcOEt (3×25 mL). The combined extract was dried over anhydrous MgSO4 and concentrated to dryness under vacuum to provide the title crude compound, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C@H:11]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH2:12]2)[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25].C[Si]([N:30]=[N+:31]=[N-:32])(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C@H:11]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]4[NH:32][N:31]=[N:30][N:21]=4)=[CH:22][CH:23]=3)[CH2:12]2)[CH3:9])=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1cc([C@@H](C)N[C@H]2CC[C@@H](c3ccc(C#N)cc3)C2)ccc1F
Solvent: Cc1ccccc1
Product: COc1cc([C@@H](C)N[C@H]2CC[C@@H](c3ccc(-c4nnn[nH]4)cc3)C2)ccc1F
Temperature: 118 °C
Reaction time: 8 h

Procedure:
4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]benzonitrile (5.1 g, 14.4 mmol) in toluene (160 ml) was treated with trimethylsilylazide (9.5 ml, 72 mmol, dropwise addition) followed by SnBu2O (717 mg, 2.88 mmol). The reaction mixture was stirred at 118° C. overnight. The precipitate was filtered off, and the filtrate was evaporated and purified by flash chromatography (gradient of 0-10%, MeOH in DCM containing 2% NEt3). The product thus obtained was precipitated from EtOH, redissolved in DCM and extracted with aqueous HCl (pH 1). The aqueous phase was neutralized to pH 5-6 with NaOH aq. (1M), and the resulting precipitate was filtered off and dried to afford the title compound. 1H NMR (300 MHz, DMSO) δ 7.89 (d, J=8.2 Hz, 2H), 7.39 (dd, J=8.3, 1.8 Hz, 1H), 7.33-7.23 (m, 3H), 7.14-7.03 (m, 1H), 4.38 (q, J=6.5 Hz, 1H), 3.86 (s, 3H), 3.45-3.32 (m, 1H), 3.09-2.95 (m, 1H), 2.38-2.25 (m, 1H), 2.10-1.64 (m, 5H), 1.56 (d, J=6.7 Hz, 3H).