Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:14].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl.C1(NC2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[CH:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][C:4]([Br:14])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1
Reactant: [Br-]
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Brc1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a 1000-mL Erlenmeyer flask were placed 20 g (118.1 mmol) of diphenylamine, 500 mL of chloroform, and an ellipsoidal stirring chip. In a 500-mL beaker was placed 113.8 g (236.2 mmol) of tetrabutylammoniumtribromide (TBABr3), which was dissolved in 200 mL of chloroform added later. The resulting solution was added dropwise to the chloroform-diphenylamine solution, and the mixture was stirred for 20 hours at room temperature in the air. Then, the chloroform-diphenylamine solution was transferred to a 1000-mL separatory funnel and washed seven times with 100 mL of saturated aqueous solution of sodium thiosulfate. The organic layer was transferred to a 1000-mL Erlenmeyer flask and then dehydrated with 100 g of anhydrous magnesium sulfate. With the anhydrous magnesium sulfate removed by filtration, the chloroform solution was transferred to a 1000-mL eggplant-shaped flask and freed of chloroform by means of an evaporator. The resulting crude product was purified by means of a silica gel column (hexane:chloroform=1:1) (Yields: 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][CH2:8]1)=[O:6].[BrH:21]>O>[BrH:21].[CH3:1][C:2]1[CH:3]=[C:4]([C:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[O:6])[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)N1CCC(C(=O)c2cccc(C)c2)CC1
Agent: Br
Solvent: O
Product: Cc1cccc(C(=O)C2CCNCC2)c1

Procedure:
A mixture of 12 parts of ethyl 4-(3-methylbenzoyl)-1-piperidinecarboxylate and 225 parts of a hydrobromic acid solution 48% in water is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is crystallized from 2-propanol, yielding 7.5 parts of (3-methylphenyl) (4-piperidinyl)methanone hydrobromide.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3([OH:17])[CH2:16][CH2:15][CH2:14][O:13][CH2:12]3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[N:18]1([C:2]2[C:3]3[C:10]([C:11]4([OH:17])[CH2:16][CH2:15][CH2:14][O:13][CH2:12]4)=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: OC1(c2c[nH]c3ncnc(Cl)c23)CCCOC1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OC1(c2c[nH]c3ncnc(N4CCOCC4)c23)CCCOC1
Temperature: 70 °C

Procedure:
To a solution of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol (C32) (200 mg, 0.79 mmol) and morpholine (134 mg, 1.54 mol) in n-butanol (10 mL) was added N,N-diisopropylethylamine (305 mg, 2.36 mol), and the reaction mixture was heated at 70° C. for 2 hours. After concentration in vacuo, preparative reversed phase high-performance liquid chromatography (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: aqueous ammonia, pH 10; Mobile phase B: acetonitrile; Gradient: 9% to 29% B) provided the product as a white solid. Yield: 180 mg, 0.59 mmol, 75%. LCMS m/z 305.1 [M+H+]. 1H NMR (400 MHz, CDCl3+D2O) δ 8.73 (s, 1H), 7.52 (s, 1H), 3.92-4.03 (m, 4H), 3.74-3.88 (m, 4H), 3.32-3.40 (m, 2H), 3.15-3.24 (m, 2H), 2.07-2.16 (m, 1H), 1.88-2.06 (m, 2H), 1.57-1.68 (m, 1H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:33]=[CH:32][C:12]([O:13][CH2:14][C:15]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:16]=3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=2)O1.Br[C:36]1[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1>>[C:20]([O:19][C:17]([C:16]1[CH:24]=[C:25]([C:28]([F:31])([F:29])[F:30])[CH:26]=[CH:27][C:15]=1[CH2:14][O:13][C:12]1[CH:32]=[CH:33][C:9]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:37]=2)=[CH:10][CH:11]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CC(C)(C)OC(=O)c1cc(C(F)(F)F)ccc1COc1ccc(-c2cccc(CC(=O)O)c2)cc1

Procedure:
According to a method similar to Example (8-1), from tert-butyl 2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-5-(trifluoromethyl)benzoate (88 mg, 0.18 mmol) obtained in Example (2-4) and 3-bromophenylacetic acid (50 mg, 0.23 mmol), the title compound was obtained as a yellow powder (4.5 mg, yield: 29%).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.[NH2:34]CC(N)=O.CN1CCOCC1>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][C:16]([NH2:34])=[O:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NCC(N)=O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Yield: 52 %

Procedure:
The title compound was prepared by a procedure similar to the one described for (±)3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide using glycine amide HCl (1.2 g, 10.95 mmol) as the amine and with an addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (1.79 g, 52%) as white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.97 (dd, 1H, J=1.6 Hz), 7.73 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.53 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 4.01 (d, 2H, J=1.6 Hz), 2.18 (s, 3H), 2.13 (s, 3H); ES-HRMS m/z 477.1128 (M+H C22H20ClF2N4O4 requires 477.1136).
Reaction SMILES: C(=O)([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH:20]=2)[CH:9]=1)OC(C)(C)C.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[C:25]1([C:21]2[CH:20]=[C:19]([C:10]3[CH:9]=[C:8]([OH:7])[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[N:11]=3)[CH:24]=[CH:23][CH:22]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3cccc4ccccc34)c2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2cccc(-c3cccc4ccccc34)c2)nn1-c1ccccn1
Yield: 97 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 41 of Example C-15 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][CH2:41][OH:42]>>[OH:42][CH2:41][CH2:40][NH:39][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([S:27]([CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:28])=[O:29])=[CH:38][CH:37]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Product: O=C(NCCO)c1ccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 47.1 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 2-aminoethanol (31 mg, 0.50 mmol, 1.0M in DMF) were combined to give 27 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 574 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[N:6][CH:7]=1.C([Mg]Cl)(C)C.CN([CH:26]=[O:27])C>C1COCC1>[F:10][C:9]([F:12])([F:11])[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH:3]=1)[CH:26]=[O:27])([OH:17])[C:13]([F:16])([F:15])[F:14]
Reactant: OC(c1cncc(Br)c1)(C(F)(F)F)C(F)(F)F
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=Cc1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 258 (0.347 g, 1.07 mmol) in dry THF, cooled to 0° C., was added isopropyl magnesium chloride (1.2 mL, 2.4 mmol) drop wise and stirred for 10 min followed by the addition of DMF (0.015 ml, 1.94 mmol) to the reaction and stirred for additional 2 h. After completion of the reaction, it was quenched with saturated ammonium chloride solution. The organic layer was separated and aqueous phase was extracted again with diethyl ether, the combined organic layer was dried over sodium sulphate and concentrated to get the crude compound 5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)nicotinaldehyde 259 used directly to proceed for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:41][OH:42].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([C:38](=[N:41][OH:42])[NH2:39])[CH:35]=[CH:36][CH:37]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
To a suspension of N-{(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}-4-[6-(3-cyano-phenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-amine (0.050 g, 0.086 mmol) in 80% ethanol-water (2.5 mL) was added an aqueous solution (0.50 mL) containing 6.65 mg of hydroxylamine hydrochloride (1.1 equivalents) and 4.61 mg of sodium carbonate (0.5 equivalents). The resulting solution was heated at 80° C. for 20 hours. Solid was collected by filtration and treated with hot (80° C.) 80% ethanol-water (2 mL×5). Solid was collected and dried under vacuum at 45° C. overnight to afford 25 mg (48%) of the title compound as a yellow solid. M.p.=272-273° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 9.52 (s, 1H), 8.70 (bs, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.77-7.73 (m, 3H), 7.67-7.66 (m, 2H), 7.59 (d, J=6.8 Hz, 1H), 7.47-7.40 (m, 2H), 7.11 (d, J=7.6 Hz, 1H), 6.38 (d, J=4.4 Hz, 1H), 5.68 (s, 2H), 3.94 (br. s, 1H), 3.73 (d, J=8.4 Hz, 1H), 3.48 (d, J=10.8 Hz, 1H), 2.49-2.48 (m, 1H), 2.35 (t, J=8.8 Hz, 1H), 1.95-1.84 (m, 2H), 1.60-1.5 (m, 1H), 1.46-1.30 (m, 1H). LCMS: 610 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].O.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15](S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(=O)CCCC1.C(O)(=O)C>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:15]3([CH2:16][CH2:17][CH2:12][CH2:22]3)[NH:1][C:2]=2[CH:6]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: O=C1CCCC1
Product: O=C1NC2(CCCC2)Nc2cc(Br)sc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 918 %

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxamide (0.072 g, 0.33 mmol) and p-toluenesulfonic acid monohydrate (0.013 g, 0.066 mmol) in cyclopentanone (2 mL) and acetic acid (1 mL) was stirred at 70° C. for 2 h. Then, the reaction mixture was cooled, carefully poured into sat. NaHCO3 (50 mL), and extracted with 2:1 ethyl acetate/tetrahydrofuran (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to give crude 6′-bromo-1′H-spiro[cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one as a brown gum (0.174 g), which was used without further purification. A mixture of the crude 6′-bromo-1′H-spiro[cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (0.172 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.349 g, 1.80 mmol), 2 M sodium carbonate (1.2 mL, 2.4 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.073 g, 0.090 mmol) in 1,4-dioxane (3 mL) was microwave-irradiated at 140° C. for 1 h. Then, the reaction mixture was cooled, and concentrated with silica gel, and the residue was purified by flash chromatography (Combiflash, silica gel, ethyl acetate to 90:10 ethyl acetate/methanol), and purified again by flash chromatography (Combiflash, silica gel, dichloromethane to 90:10 dichloromethane/methanol) to give the title compound (0.045 g, 2 step yield 50%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].[N:13]([O-])=O.[Na+]>C(O)(=O)C>[N+:10]([C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[C:5]2[C:4]=1[CH:9]=[N:13][NH:6]2)([O-:12])=[O:11]
Reactant: Cc1c(N)ccc(Cl)c1[N+](=O)[O-]
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(Cl)ccc2[nH]ncc12
Temperature: 25 °C

Procedure:
To 4-chloro-2-methyl-3-nitroaniline (1.63 g, 8.8 mmol) dissolved in acetic acid (75 mL) at room temperature was added a 2M aqueous solution of sodium nitrite (4.4 mL). The suspension was then diluted with acetic acid (100 mL) and then heated at reflux for 4 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was then partitioned between ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL). The separated organic layer was then washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography of the reside (hexane/ethyl acetate (2:1) afforded the desired product. 1H NMR (500 MHz) (DMSO-d6) δ 8.32 (s, 1H); 7.95 (d, J=8.7 Hz, 1H); 7.68 (d, J=8.7 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11].[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>>[CH2:12]([NH:14][C:15]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[S:16])[CH3:13]
Reactant: Cc1ncoc1CSCCN
Reactant: CCN=C=S
Product: CCNC(=S)NCCSCc1ocnc1C

Procedure:
Also, reacting 5-[(2-aminoethyl)thiomethyl]-4-methyloxazole with ethyl isothiocyanate by the procedure of Example 1 gives N-ethyl-N'-[2-((4-methyl-5-oxazolyl)methylthio)ethyl]thiourea.
Reaction SMILES: [NH2:1][CH:2]1[C:29](=[O:30])[N:4]2[C:5]([C:13]([O:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[C:6]([CH:9]=[CH:10][CH2:11][Cl:12])[CH2:7][S:8][C@H:3]12.[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH:31](=[N:1][CH:2]1[C:29](=[O:30])[N:4]2[C:5]([C:13]([O:15][CH:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])=[C:6]([CH:9]=[CH:10][CH2:11][Cl:12])[CH2:7][S:8][C@H:3]12)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCCl)CS[C@H]12
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C=CCCl)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Temperature: 0 °C
Yield: 111 %

Procedure:
To an ice-cooled mixture of the crystalline 7-aminocephem intermediate XVIII (Z isomer) (13.4 g, 28 mmole) and benzaldehye (3.3 g, 31 mmole) in ethyl acetate (150 ml) was added dropwise 0.5N sodium hydroxide (56 ml, 28 mmole) over a period of 20 minutes, to maintain the temperature of the reaction mixture below 10° C. The mixture was stirred with cooling for another 15 minutes, and the organic layer was separated, washed with saturated aqueous sodium bicarbonate (100 ml×2) and dried over magnesium sulfate. To the dried solution was added a small amount of charcoal and the mixture was filtered. The filtrate was concentrated to dryness. The residual oil was dissolved in carbon tetrachloride (50 ml), and concentrated again. This procedure was repeated 3 times, and the mixture was monitored by reverse phase tlc to confirm that all of the starting 7-aminocephalosporin was converted to the Schiff's base. Removing the solvent in vacuo gave 16.45 g of the title compound XVII (Z isomer) as a pale yellow powder (estimated purity 85%; M.p. 74° C. (dec.), which was used for the next step without purification.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.O[CH2:14][C:15]1[CH2:20][N:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17][CH:16]=1.C([O-])(O)=O.[Na+].[N-:34]=[N+:35]=[N-:36].[Na+]>C(Cl)Cl>[N:34]([CH2:14][C:15]1[CH2:20][N:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17][CH:16]=1)=[N+:35]=[N-:36]
Reactant: CC(C)(C)OC(=O)NN1CCC=C(CO)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN1CCC=C(CN=[N+]=[N-])C1
Temperature: 80 °C

Procedure:
At 0° C., triethylamine (3.7 ml, 26.2 mmol) and, dropwise, methanesulphonyl chloride (1.2 ml, 15.44 mmol) were added to a solution of tert-butyl 5-hydroxymethyl-3,6-dihydro-2H-pyridine-1-carbamate (Tetrahedron 1998, 54, 7045–7056, 2.8 g, 13.1 mmol) in DCM (50 ml). The reaction mixture was stirred at 0° C. for 20 minutes before a saturated solution of NaHCO3 (40 ml) was added, and the two phases were separated. The aqueous phase was extracted with dichloromethane (40 ml). The combined organic phases were washed with saturated sodium chloride solution and dried over MgSO4 and concentrated. The crude product was dissolved in DMF (50 ml), and sodium azide (1.7 g, 26.1 mmol) was added. The mixture was heated to 80° C. Reaction monitored by LCMS. Once the reaction was complete, the mixture was cooled and concentrated. The residue was taken up in EtOAc and water and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic phases were washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel (EtOAc/hex 1/6).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][SH:9].[Cl:10][C:11]([Cl:38])([Cl:37])[CH2:12][O:13][C:14]([C:16]1[N:21]2[C:22](=[O:34])[C@@H:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:20]2[S:19][CH2:18][C:17]=1[CH2:35]Br)=[O:15].C(O)C>CN(C)C=O>[CH3:8][S:9][CH2:35][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22](=[O:34])[N:21]2[C:16]=1[C:14]([O:13][CH2:12][C:11]([Cl:38])([Cl:37])[Cl:10])=[O:15]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CBr)CS[C@H]12
Reactant: CS
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCO
Product: CSCC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
Triethylamine (0.70 ml, 5 mmole) and a solution of methanethiol (2.8 ml, ca. 10 equiv.) in dimethylformamide (10 ml,), previously cooled to -30°, were added to a solution of 2,2,2-trichloroethyl-3-bromomethyl-7β-phenylacetamidoceph-3-em-4-carboxylate, 1β-oxide (2.79 g, 5 mmole) in dimethylformamide (40 ml) cooled to -30°. The reaction solution was allowed to warm to 20° and then stirred at this temperature for 30 minutes then dilution of an aliquot with ethanol gave a solution with λmax. 274 nm. Nitrogen was passed through the dimethylformamide solution for 45 minutes to remove the excess of thiol and potassium iodide (5 g.) and acetyl chloride (5 ml.) were added. After 4 hours at 20°, t.l.c. (acetone-methylene chloride, 1:15) showed that reduction was complete. The solution was cooled in an ice-bath, and 0.1 N-sodium thiosulphate solution was added until the solution became pale-yellow. Methylene chloride and water (80 ml of each) were added and the aqueous layer was separated and reextracted with methylene chloride (100 ml.). The combined methylene chloride layers were washed with water (3 × 100 ml.), dried and evaporated to give the title ester as a solvated yellow gelatinous solid (2.76 g), λmax. 268 nm (E1cm1% 133).
Reaction SMILES: N1(S(N[C:9](=O)[C:10]2[CH:15]=C(Cl)C(OCC3(C(F)(F)F)CCCC3)=CC=2F)(=O)=O)CCC1.[N:30]1([S:34]([NH:37][C:38](=[O:58])[C:39]2[CH:44]=[C:43](Cl)[C:42]([O:46][CH2:47][CH:48]3[CH2:56][CH2:55][C:51]4([CH2:54][CH2:53][CH2:52]4)[CH2:50][CH2:49]3)=[CH:41][C:40]=2[F:57])(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31]1>>[N:30]1([S:34]([NH:37][C:38](=[O:58])[C:39]2[CH:44]=[C:43]([CH:15]3[CH2:10][CH2:9]3)[C:42]([O:46][CH2:47][CH:48]3[CH2:56][CH2:55][C:51]4([CH2:54][CH2:53][CH2:52]4)[CH2:50][CH2:49]3)=[CH:41][C:40]=2[F:57])(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CCC3(CCC3)CC2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CCC3(CCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 165 and making variations as required to replace N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamide with N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[3.5]nonan-7-ylmethoxy)benzamide, the title compound was obtained (0.06 g 19%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.66 (d, J=16.2 Hz, 1H), 7.59 (d, J=9.1 Hz, 1H), 6.56 (d, J=14.5 Hz, 1H), 4.24 (t, J=7.7 Hz, 4H), 3.81 (d, J=6.1 Hz, 2H), 2.26 (q, J=7.7 Hz, 2H), 2.09-2.00 (m, 1H), 1.90-1.63 (m, 10H), 1.36-1.10 (m, 5H), 0.96-0.89 (m, 2H), 0.69-0.63 (m, 2H); MS (ES−) m/z 449.3 (M−1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([O:7][CH3:8])=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([N:1]1[CH2:4][CH:3]([C:5]([O:7][CH3:8])=[O:6])[CH2:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C1CNC1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a solution of methyl azetidine-3-carboxylate (5.0 g, 33.1 mmol) and DIEA (10.7 g, 82.8 mmol) in DMF (50 mL) was added dropwise bromomethyl benzene (5.7 g, 33.1 mmol) at 0° C. over 10 min. After stirring for 2 hr at rt, the mixture was poured to water (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated and purified by chromatography column on silica (EA/PE=1/4) to give the product (3.5 g, 51.6%) as a light yellow oil. 1H NMR (DMSO-d6) δ 7.34-7.20 (m, 5H), 3.62 (s, 3H), 3.53 (s, 2H), 3.41-3.35 (m, 1H), 3.29-3.31 (m, 2H), 3.19-3.22 (m, 2H). MS (ESI, m/e) [M+1]+ 206.0.