Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)=[C:13]([O:27][CH3:28])[CH:12]=3)[C:7]([NH2:9])=[N:8][C:4]=2[CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][C:34](=[O:38])[CH2:33]1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[NH2:9][C:7]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[C:13]([O:27][CH3:28])[CH:12]=2)[C:5]2[CH:4]=[CH:3][C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][C:34]3=[O:38])=[CH:30][C:29]=2[N:8]=1
Reactant: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)ccc43)cc2OC)cn1
Reactant: CN1CCNC(=O)C1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(N5CCN(C)CC5=O)ccc43)cc2OC)cn1
Temperature: 145 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amine (0.25 g, 0.48 mmol) in 1,4-dioxane (8 mL) was added 4-methylpiperazin-2-one (0.11 g, 0.96 mmol), CuI (0.036 mg, 0.19 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.044 g, 0.38 mmol), and tribasic potassium phosphate (0.32 g, 1.52 mmol). The mixture was heated to 145° C. in a microwave reactor. After 3 h, the mixture was allowed to cool to room temperature and was filtrated through Celite. The filtrate was concentrated, and the residue was purified by silica gel chromatography (2-5% methanol/dichloromethane elute) followed by prep-HPLC to afford 0.030 g (12%) of the product as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.66 (dd, J=8.0, 2.0 Hz, 1H), 7.25 (s, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.76-6.74 (m, 2H), 6.64 (d, J=7.5 Hz, 1H), 4.99 (s, 2H), 4.89 (br s, 2H), 4.81 (s, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 3.72 (t, J=5.0 Hz, 2H), 3.30 (s, 2H), 2.82 (t, J=5.0 Hz, 2H), 2.44 (s, 3H) ppm; (M+1)=503.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(N(CC)CC)C.[C:15]([O-])(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].S([O-])([O-])(=O)=O.Cl.[OH-].[Na+:38]>O.C(OCC)(=O)C.CO>[Na+:38].[C:15]([NH:1][C@@H:2]([C:5]([O-:7])=[O:6])[CH2:3][OH:4])(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCC(=O)[O-]
Reactant: N[C@H](CO)C(=O)O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(=O)N[C@H](CO)C(=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
D-serine 2.0 g (0.02 mole) and triethylamine 2.8 ml (0.02 mol) were dissolved in 60 ml of water. Myristate of 4-hydroxyphenyldimethylsufomethyl sulfate (trade name: SANCELER My-DSP, manufactured by Sanshin Kagaku Kogyo Co. Ltd.) 9.52 g (0.02 mol) was added to the solution, and the mixture was stirred for 12 hours at room temperature. The solution reacted was adjusted to pH 2 or 3 with 1N-HCl and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and freed of solvent in vacuo. The residue obtained was dissolved in ethyl acetate - methanol (3:1), and the solution was adjusted to pH 11 with a 10% solution of sodium hydroxide. After observation of precipitates, the solution was concentrated under reduced pressure. The product crystallized was washed with ethyl acetate and then hexane to obtain 3.1 g of N-myristoyl-D-serine sodium salt.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16](/[CH:20]=[CH:21]/[C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([Cl:32])=[CH:27][CH:28]=5)[N:23]=4)[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C>[Cl:32][C:26]1[CH:25]=[C:24]2[C:29]([CH:30]=[CH:31][C:22](/[CH:21]=[CH:20]/[C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[O:13][CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[N:7]=[C:3]([C:1]5[NH:35][N:34]=[N:33][N:2]=5)[O:4][C:5]=4[CH:11]=3)=[N:23]2)=[CH:28][CH:27]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1nc2ccc(COc3cccc(/C=C/c4ccc5ccc(Cl)cc5n4)c3)cc2o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc2ccc(/C=C/c3cccc(OCc4ccc5nc(-c6nnn[nH]6)oc5c4)c3)nc2c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A solution-suspension of (E)-2-cyano-6-[3-(7-chloro-2-quinolinylethenyl)phenoxymethyl]benzoxazole (950 mg, 2.17 mmol), sodium azide (432.1 mg, 6.51 mmol) and ammonium chloride (348.1 mg, 6.51 mmol) in DMF (15 ml) is heated to 100° C. for 7 hours and stirred at room temperature for 12 hours. The mixture is poured over ice-water and the pH is adjusted to 10 with 1N NaOH. The aqueous mixture is washed with ether and the pH adjusted to 4 with 1N-HCl. The precipitated solid is filtered and washed successively with water, ethanol and methylene chloride. Recrystallization from DMF affords (E)-5-(6-[3-(7-chloro-2-quinolinyl-ethenyl)phenoxymethyl ]benzoxazol-2-yl)tetrazole. (M.P. 272° C. (dec.))
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH:3]=1.[C:15]([O:19][C:20]([NH:22][C:23]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=S)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:29]([O:28][C:26]([NH:25][C:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[N:11][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH:9]=1)=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ccnc(-c2cccc(N)c2)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2.5 h
Yield: 62.1 %

Procedure:
To a suspension of 3-(4-methylpyridin-2-yl)aniline (276 mg), N,N′-bis (tert-butoxycarbonyl )thiourea (539 mg) and diisopropylethyl-amine (0.601 ml) in dichloromethane (15 ml) was added 1-methyl-2-chloropyridinium iodide (498 mg), and the mixture was stirred for 2.5 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 45 g, n-hexane:ethyl acetate=9:1) to give N,N′-bis(tert-butoxycarbonyl) -N″-(3-(4-methylpyridin-2-yl)phenyl)guanidine (397 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH:16]2[CH:14]([C:15]2([C:19]2[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH3:18])[CH2:13]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:12]1[CH2:17][CH:16]2[CH:14]([C:15]2([C:19]2[CH:20]=[C:21]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:22]=[CH:23][CH:24]=2)[CH3:18])[CH2:13]1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)c3cc4ccccc4o3)CC21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(Cc3cc4ccccc4o3)CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a suspension of N-{3-[3-(1-benzofuran-2-ylcarbonyl)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenyl}methanesulfonamide (Preparation 127, 200 mg, 0.487 mmol) in anhydrous tetrahydrofuran (5 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.97 ml, 0.97 mmol) and the reaction mixture was stirred at room temperature overnight. The rapidly stirred reaction mixture was treated sequentially with water (1.0 ml), sodium hydrogen carbonate (1.0 g) and ethyl acetate (15 ml). After 5 min, the reaction mixture was filtered and concentrated in vacuo to afford 180 mg of a pale yellow oil. This was purified by chromatography using a Biotage Flash 12™ cartridge packed with silica gel (8 g) eluting with hexane:ethyl acetate (100:0 to 0:100 over 30 min) then ethyl acetate:methanol (100:0 to 0:100 over 15 min) to afford the title compound as a white foam (136 mg, 70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.C[Sn](C)(C)[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=1)[C:26]#[N:27]>[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=2)[C:26]#[N:27])[CH:7]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: C[Sn](C)(C)c1cncc(C#N)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nc(Cl)cc(-c2cncc(C#N)c2)n1)c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 17 h
Yield: 25.1 %

Procedure:
187 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 175 mg of 5-(trimethylstannyl)nicotinonitrile, 25 mg of copper iodide and 75 mg of tetrakis(triphenylphosphine)palladium were added in turn to 3 ml of degassed toluene, and the mixture was stirred at 110° C. for 17 hours under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 58 mg of (S)-5-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin 4-yl}nicotinonitrile as colorless oil.
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([CH:9]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][CH:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:1]1[N:11]2[C:12]3[C:8]([CH:9]4[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH2:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:23])[CH2:14][CH2:13][CH:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1
Reactant: c1cc2c3c(c1)C1CCNCCC1N3CCO2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(CCCN1CCC2c3cccc4c3N(CCO4)C2CC1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
1,2,7,8,9,10,11,11a-octahydro-6bH-azepino[4,5-b][1,4]oxazino[2,3,4-hi]indole (97.8 mg, 0.42 mmol), 4-chloro-1-(4-fluorophenyl)-1-butanone (172 mg, 0.86 mmol), KI (71.2 mg, 0.43 mmol), and DIEA (550 mg, 4.3 mmol) were suspended in dioxane (2 mL). The reaction mixture was refluxed for 18 hrs. After cooling to rt, the solution was concentrated. The residue was immediately purified by column chromatography to afford the title compound. MS-ESI: 395[MH]+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].I[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>CO.O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:12][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])[CH:4]=1
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: COC(=O)c1ccccc1I
Solvent: CO
Solvent: O
Product: COC(=O)c1ccccc1Nc1cc(C(F)(F)F)ccc1C(=O)O
Yield: 43 %

Procedure:
Reaction of 4-trifluoromethylanthranilic acid and methyl 2-iodobenzoate by the reported method [Rewcastle and Denny, Synth, Comm 1987, 17, 309 gave 4-trifluoromethyl-2-(2-methoxycarbonylphenyamino)benzoic acid (43%), mp (MeOH/H2O) 206-207° C. 1H NMR [(CD3)2SO] δ 3.87 (s, 3 H, CO2CH3), 7.12 (ddd, J=8.0, 6.1, 2.1 Hz, 1 H., H-5'), 7.23 (dd, J=8.3, 1.0 Hz, 1 H, ArH), 7.55-7.62 (m, 3 H, 3×ArH), 7.95 (dd, J=8.0, 1.3 Hz, 1 H, ArH), 8.12 (d, J=8.2 Hz, 1 H, ArH). Formation of the corresponding imidazolide and immediate reduction of this as above gave methyl-2-[N-(5'-trifluoromethyl-2'-hydroxymethyl)phenyl-amino]benzoate (86%), mp (hexane) 86-87° C. 1H NMR (CDCl3) δ 2.00 (t, J=5.6 Hz, 1 H, OH), 3.92 (s, 3 H, CO2CH3), 4.78(d, J=5.3 Hz, 2 H, CH2), 6.84 (td, J=7.6, 1.1 Hz, 1 H, ArH), 7.15 (dd, J=8.6, 0.8 Hz, 1 H, ArH), 7.31-7.39 (m, 2 H, 2×ArH), 7.52 (d, J=7.7 Hz, 1 H, ArH), 7.70 (s, 1 H, H-6'), 8.76 (dd, J=8.0, 1.6 Hz, 1 H, ArH), 9.72 (s, 1 H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35].CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[C:34]([O:38][C:39](=[O:42])[CH2:40][NH:41][C:14]([C:13]1[CH:17]=[CH:18][C:10]([CH2:9][S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:32])([F:31])[F:33])[CH:24]=2)(=[O:22])=[O:21])=[CH:11][CH:12]=1)=[O:16])([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C(O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)CN
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (98 mg, 0.18 mmol), glycine t-butyl ester (36 mg, 0.27 mmol), 4-methyl morpholine (60 μl, 0.55 mmol) and EDC (53 mg, 0.27 mmol) in DMF (3 ml) was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc (2×5 ml). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (30%-100% EtOAc in hexane) to afford the title compound (92 mg, 78%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](=[O:12])(OC)[O:8][CH3:9].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].O>O1CCCC1>[CH3:20][C:19]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH:13][C:7](=[O:12])[O:8][CH3:9]
Reactant: Cc1ccncc1N
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Nc1cnccc1C
Temperature: 17.5 °C
Yield: 88.2 %

Procedure:
Potassium tert-butoxide (10.3 g, 92.5 mmol) in tetrahydrofuran (25 mL) was stirred at 23 to 27° C. for 30 minutes, and dimethyl carbonate (4.67 mL, 55.5 mmol) was added while the temperature was kept at 35° C. or below. To the reaction mixture, 3-amino-4-methylpyridine (5.00 g, 46.2 mmol) in tetrahydrofuran (40 mL) stirred at 32 to 38° C. for 90 minutes was added dropwise at 20 to 35° C. over 2 hours with stirring. The resulting reaction mixture was cooled to 15 to 20° C., stirred with water (25 mL) at 25° C. or below for 1 hour and extracted with tetrahydrofuran. The organic layer was azeotropically distilled with toluene under reduced pressure to a volume of about 50 mL and stirred at 23 to 27° C. for one day. The precipitated solid was collected by filtration, washed with toluene and dried under reduced pressure to give the title compound as a brown solid (6.77 g, yield 88%).
Reaction SMILES: C(O)=O.FC(F)(F)C(O)=O.Cl.[NH2:12][C:13]1[S:17][N:16]=[C:15]([C:18](=[N:49][O:50][CH2:51][C:52]([OH:54])=[O:53])[C:19]([NH:21][C@@H:22]2[C:47](=[O:48])[N:24]3[C:25]([C:44]([O-:46])=[O:45])=[C:26]([CH2:29][N+:30]4([CH3:43])[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[CH2:27][S:28][C@H:23]23)=[O:20])[N:14]=1>C(OCC)(=O)C>[NH2:12][C:13]1[S:17][N:16]=[C:15]([C:18](=[N:49][O:50][CH2:51][C:52]([OH:54])=[O:53])[C:19]([NH:21][C@@H:22]2[C:47](=[O:48])[N:24]3[C:25]([C:44]([O-:46])=[O:45])=[C:26]([CH2:29][N+:30]4([CH3:43])[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[CH2:27][S:28][C@H:23]23)=[O:20])[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[N+](C)(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O=CO
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CCNCC1
Reaction time: 1.5 h
Yield: 33 %

Procedure:
To a mixture of formic acid (10 ml) and trifluoroacetic acid (5 ml) was added 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-4-tert-butoxycarbonyl-1-piperazinio)methyl-3-cephem-4-carboxylate hydrochloride (syn isomer) (5.7 g) at 20° C. under stirring. The stirring was continued for 1.5 hours at the same temperature. The reaction mixture was poured into ethyl acetate (200 ml). The resulting precipietes were collected by filtration, added to water. The mixture was adjusted to pH 2.0 with a saturated aqueous solution of sodium bicarbonate and filtered. The filtrate was subjected to column chromatography on Diaion HP-20 using 10% aqueous isopropanol as an eluent. The eluate was evaporated in vacuo to remove isopropanol and then lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (1.50 g).
Reaction SMILES: [C:1]1([C:7]([OH:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][CH2:12][C:13](Cl)=[O:14]>>[Br:11][CH2:12][C:13]([O:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8])=[O:14]
Reactant: CC(C)(O)c1ccccc1
Reactant: O=C(Cl)CBr
Product: CC(C)(OC(=O)CBr)c1ccccc1

Procedure:
The sub-title compound was prepared analogously to the procedure described in Example 30(i) from 2-phenyl-2-propanol (3 g; 22 mmol) and bromacetylchloride (4.16 g, 26 mmol). Yield 1.2 g (44%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH2:10][CH2:11][OH:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>O1CCCC1>[CH2:17]([O:16][C:14]([N:7]1[CH2:8][CH2:9][C:4]([CH2:3][CH2:2][OH:1])([CH2:10][CH2:11][OH:12])[CH2:5][CH2:6]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCC1(CCO)CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(CCO)(CCO)CC1

Procedure:
1-benzyloxycarbonyl-4,4-bis-(2-hydroxyethyl)piperidine is prepared by reaction of 4,4-bis-(2-hydroxyethyl)piperidine with benzyl chloroformate in tetrahydrofuran in the presence of triethylamine.
Reaction SMILES: [N:1]1([CH:6]([CH3:19])[CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27].N>CCO.CO.C(Cl)Cl>[N:1]1([CH:6]([CH3:19])[CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:26]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)=[NH:27])=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CN1CCCc2cc(N)ccc21)N1CCCC1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: N
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CC(CN1CCCc2cc(NC(=N)c3cccs3)ccc21)N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 1-(2-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (130 mg, 0.50 mmol) in 10 mL EtOH was treated with methyl thiophene-2-carbimidothioate hydroiodide (285 mg, 1.00 mmol) and stirred at room temperature for 3 days. Argon was bubbled through the solution for 20 minutes. The solution was partitioned between CH2Cl2 (100 mL) and saturated sodium carbonate (15 mL). The organic layer was separated and the aqueous layer was extracted with an additional 50 mL CH2Cl2. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a yellow residue which was subjected to flash chromatography on silica gel using 2.5% MeOH/CH2Cl2 then 5-10% 2M NH3 in MeOH/CH2Cl2. A light orange solid was obtained (100 mg, 54.3%). 1H-NMR (DMSO-d6) δ: 7.67 (d, J=3.6 Hz, 1H), 7.55 (d, J=4.2 Hz, 1H), 7.08-7.05 (m, 1H), 6.56-6.48 (m, 3H), 6.25 (br s, 2H), 3.44 (dd, J=4.5, 14.4 Hz, 1H), 3.33-3.25 (m, 2H), 2.95 (dd, J=8.7, 13.8 Hz, 1H), 2.72-2.58 (m, 7H), 1.86-1.82 (m, 2H), 1.67 (br, 4H), 1.03 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[CH:15]OC)[CH:11]([CH3:18])[CH2:10]2)=[CH:4][CH:3]=1.Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29]N)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[OH-].[NH4+]>C(Cl)(Cl)Cl.ClCCl>[Cl:22][C:23]1[CH:24]=[C:25]2[C:12]3([CH2:13][CH2:14][N:9]([CH2:8]/[CH:7]=[CH:6]/[C:5]4[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:10][CH:11]3[CH3:18])[CH2:15][NH:29][C:26]2=[CH:27][CH:28]=1
Reactant: COC=C1CCN(CC=Cc2ccc(Cl)cc2)CC1C
Reactant: NNc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C/C=C/c2ccc(Cl)cc2)CCC12CNc1ccc(Cl)cc12
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A mixture of 1-(4-chlorocinnamyl)-4-[1-methoxy-methylidene]-3-methyl-piperidine (1.25 g) and 4-chlorophenylhydrazine hydrochloride (0.85 g) in chloroform (43 ml) was treated with trifluoroacetic acid (4.3 ml) and heated at reflux under argon for 12 hours. The reaction mixture was cooled to room temperature, triethylsilane (3.1 ml) was added and the solution refluxed for 2 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane, neutralised with aqueous ammonium hydroxide, washed with brine, dried (sodium sulphate) and concentrated. The dark residue was purified by silica gel chromatography (cyclohexane:ethyl acetate 1:1+0.5% triethylamine) to afford 5-chloro-1′-[trans-3-(4-chlorophenyl)allyl]-3′-methyl-spiro[indoline-3,4′-piperidine] (1.63 g). 1H NMR (600 MHz, CDCl3) 0.69 (d, J=9 Hz, 3H), 1.89 (m, 2H), 2.0 (m, 3H), 2.86 (dd, 1H), 2.95 (m, 1H), 3.17 (d, J=7.2 Hz, 2H), 3.31 (d, J=12 Hz, 1H), 3.58 (d, J=12 Hz, 1H), 3.65 (m, 1H), 6.30 (dt, J=7.2, 18.0 Hz, 1H), 6.49 (d, J=8.0 Hz, 1H), 6.50 (d, J=7.0 Hz, 1H), 2H), 6.94 (d, J=0.9 Hz, 1H), 6.97 (dd, J=7.0, 0.9 Hz, 1H), 7.25-7.33 (m, 4H); MS (ES+) 387/389 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13][N:30]3[CH:25]4[CH2:26][CH2:27][CH:28]3[CH2:29][CH:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24]4)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2cc(F)ccc21
Yield: 30 %

Procedure:
The compound (S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20) (0.208 g, 0.59 mmol) and 3-Pentyl-8-azabicyclo[3.2.1]octane (0.106 g, 0.58 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF30) (0.070 g, 29%). 1H NMR (CDCl3) δ 7.23-7.19 (m, 1H), 6.66-6.60 (m, 2H), 4.60-4.46 (m, 2H), 4.05-3.99 (m, 1H), 3.95-3.90 (m, 1H), 3.06-3.03 (m, 1H), 2.99-2.96 (m, 1H), 2.24-2.19 (m, 1H), 2.07-1.94 (m, 3H), 1.90-1.73 (m, 3H), 1.60-1.45 (m, 3H), 1.33-1.25 (m, 2H), 1.24-1.12 (m, 8H), 0.83-0.78 (m, 6H); 13C NMR (CDCl3) δ 164.1, 158.8 (d, J=243.3 Hz), 146.4 (d, J=11.5 Hz), 125.1 (d, J=3.1 Hz), 116.6 (d, J=9.3 Hz), 108.9 (d, J=22.8 Hz, 105.0 (d, J=25.7 Hz), 67.7, 60.9, 58.8, 58.1, 45.4, 38.3, 36.8, 36.6, 32.1, 31.6, 28.5, 28.4, 28.1, 27.0, 22.8, 17.0, 14.2.